Hair and Scalp Diseases

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Dermatology Hair and Scalp Diseases:

about the book… Hair and Scalp Diseases: Medical, Surgical, and Cosmetic Treatments is a succinct and comprehensive guide examining the treatment of scalp and hair disorders, with a special concentration on ethnicity, hair type, and morphology of hair. Treatments that go beyond accepted US and international guidelines are incorporated, Hair and Scalp as the authors examine the use of off-label medications in case-sensitive scenarios. Packed with photographs of the scalp and hair that document the pathology, clinical cases, and treatment solutions, Hair and Scalp Diseases: Medical, Surgical, and Cosmetic Treatments • examines effective treatments that may differ from package inserts, allowing treatments for a wide range Diseases of patients with differing hair types • integrates ethnic-related variables into discussions of diagnosis, treatment, and management across all chapters Medical, Surgical, and • discusses approaches for patients with irritant and allergic contact dermatitis reactions of the scalp • lists ingredients and results of data from treatments, including: – mechanism of action Cosmetic Treatments

– absorption characteristics Medical, Surgical, and Cosmetic – general pharmacology in cosmetic, non-prescription, and prescription agents • provides a full chapter devoted to photographic analysis of hair for clinical use, including: – camera type – varying angles – speciﬁc steps for an effective photo

about the editors... AMY J. MCMICHAEL is Associate Professor and Dermatology Residency Program Director, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Dr. McMichael received her M.D. from the University of Pennsylvania, School of Medicine, Philadelphia, and her post-doctoral training consisted of an Internship in Internal Medicine, Thomas Jefferson University Hospital, Philadelphia Pennsylvania, Dermatology Residency, University of Michigan, Ann Arbor, and advanced training in Epidemiology, Wake Forest University School of Medicine. Her research focuses on hair and scalp disorders and skin disease of deeply pigmented skin. She is on the Editorial Board of Cosmetic Dermatology, is the CME editor of Skin & Aging, and has served as a consultant to the pharmaceutical industry. Dr. McMichael also sits on the board of directors for the Women’s Dermatology Society and is a Fellow of the American Academy Edited by Amy J. McMichael and Maria K. Hordinsky of Dermatology. Treatments MARIA K. HORDINSKY is Professor and Chair of the Department of Dermatology at the University of Minnesota, Minneapolis. She received her B.A. from Fordham University, New York, and her M.D. from the University of North Dakota, Grand Forks. She completed her ﬁrst post-graduate year at Henry Ford Hospital, Detroit Michigan, and her dermatology residency at the University of Minnesota. Additional training in dermatology and clinical research was subsequently supported with a fellowship from the Dermatology Foundation and a National Research Service Award from the National Institutes of Health. Dr. Hordinsky is recognized for her expertise and research in hair diseases and the peripheral nervous system as it relates to hair follicle biology. McMichael Dr. Hordinsky is a recipient of the Leonard Tow Humanism in Medicine Award, sits on the board of directors Hordinsky of the American Dermatologic Association and is a Fellow of the American Academy of Dermatology. ■ Printed in the United States of America $+

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BASIC AND CLINICAL DERMATOLOGY

Series Editors ALAN R. SHALITA, M.D. Distinguished Teaching Professor and Chairman Department of Dermatology SUNY Downstate Medical Center Brooklyn, New York

DAVID A. NORRIS, M.D. Director of Research Professor of Dermatology The University of Colorado Health Sciences Center Denver, Colorado

1. Cutaneous Investigation in Health and Disease: Noninvasive Methods and Instrumentation, edited by Jean-Luc Lévêque 2. Irritant Contact Dermatitis, edited by Edward M. Jackson and Ronald Goldner 3. Fundamentals of Dermatology: A Study Guide, Franklin S. Glickman and Alan R. Shalita 4. Aging Skin: Properties and Functional Changes, edited by Jean-Luc Lévêque and Pierre G. Agache 5. Retinoids: Progress in Research and Clinical Applications, edited by Maria A. Livrea and Lester Packer 6. Clinical Photomedicine, edited by Henry W. Lim and Nicholas A. Soter 7. Cutaneous Antifungal Agents: Selected Compounds in Clinical Practice and Development, edited by John W. Rippon and Robert A. Fromtling 8. Oxidative Stress in Dermatology, edited by Jürgen Fuchs and Lester Packer 9. Connective Tissue Diseases of the Skin, edited by Charles M. Laﬁ ére and Thomas Krieg 10. Epidermal Growth Factors and Cytokines, edited by Thomas A. Luger and Thomas Schwarz 11. Skin Changes and Diseases in Pregnancy, edited by Marwali Harahap and Robert C. Wallach 12. Fungal Disease: Biology, Immunology, and Diagnosis, edited by Paul H. Jacobs and Lexie Nall 13. Immunomodulatory and Cytotoxic Agents in Dermatology, edited by Charles J. McDonald 14. Cutaneous Infection and Therapy, edited by Raza Aly, Karl R. Beutner, and Howard I. Maibach 15. Tissue Augmentation in Clinical Practice: Procedures and Techniques, edited by Arnold William Klein 16. Psoriasis: Third Edition, Revised and Expanded, edited by Henry H. Roenigk, Jr., and Howard I. Maibach 17. Surgical Techniques for Cutaneous Scar Revision, edited by Marwali Harahap 18. Drug Therapy in Dermatology, edited by Larry E. Millikan 19. Scarless Wound Healing, edited by Hari G. Garg and Michael T. Longaker 20. Cosmetic Surgery: An Interdisciplinary Approach, edited by Rhoda S. Narins 21. Topical Absorption of Dermatological Products, edited by Robert L. Bronaugh and Howard I. Maibach 22. Glycolic Acid Peels, edited by Ronald Moy, Debra Luftman, and Lenore S. Kakita 23. Innovative Techniques in Skin Surgery, edited by Marwali Harahap 24. Safe Liposuction and Fat Transfer, edited by Rhoda S. Narins McMichael PTR 01/23/08 SeriesPage

25. Pyschocutaneous Medicine, edited by John Y. M. Koo and Chai Sue Lee 26. Skin, Hair, and Nails: Structure and Function, edited by Bo Forslind and Magnus Lindberg 27. Itch: Basic Mechanisms and Therapy, edited by Gil Yosipovitch, Malcolm W. Greaves, Alan B. Fleischer, and Francis McGlone 28. Photoaging, edited by Darrell S. Rigel, Robert A. Weiss, Henry W. Lim, and Jeffrey S. Dover 29. Vitiligo: Problems and Solutions, edited by Torello Lotti and Jana Hercogova 30. Photodamaged Skin, edited by David J. Goldberg 31. Ambulatory Phlebectomy, Second Edition, edited by Mitchel P. Goldman, Mihael Georgiev, and Stefano Ricci 32. Cutaneous Lymphomas, edited by Gunter Burg and Werner Kempf 33. Wound Healing, edited by Anna Falabella and Robert Kirsner 34. Phototherapy and Photochemotherapy for Skin Disease, Third Edition, Warwick L. Morison 35. Advanced Techniques in Dermatologic Surgery, edited by Mitchel P. Goldman and Robert A. Weiss 36. Tissue Augmentation in Clinical Practice, Second Edition, edited by Arnold W. Klein 37. Cellulite: Pathophysiology and Treatment, edited by Mitchel P. Goldman, Pier Antonio Bacci, Gustavo Leibaschoff, Doris Hexsel, and Fabrizio Angelini 38. Photodermatology, edited by Henry W. Lim, Herbert Hönigsmann, and John L. M. Hawk 39. Retinoids and Carotenoids in Dermatology, edited by Anders Vahlquist and Madeleine Duvic 40. Acne and Its Therapy, edited by Guy F. Webster and Anthony V. Rawlings 41. Hair and Scalp Diseases: Medical, Surgical, and Cosmetic Treatments, edited by Amy J. McMichael and Maria K. Hordinsky 42. Anesthesia and Analgesia in Dermatologic Surgery, edited by Marwali Harahap and Adel R. Abadir McMichael_978-1574448221_TP.indd1 1 1/25/08 11:01:25 AM Hair and Scalp Diseases Medical, Surgical, and Cosmetic Treatments

Edited by Amy J. McMichael Wake Forest University School of Medicine Winston-Salem, North Carolina, USA Maria K. Hordinsky University of Minnesota Minneapolis, Minnesota, USA

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Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017

No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1

International Standard Book Number-10: 1-57444-822-6 (Hardcover) International Standard Book Number-13: 978-1-57444-822-1 (Hardcover)

This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use.

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Library of Congress Cataloging-in-Publication Data

Hair and scalp diseases : medical, surgical, and cosmetic treatments / edited by Amy J. McMichael, Maria K. Hordinsky. p. ; cm. -- (Basic and clinical dermatology ; 41) Includes bibliographical references and index. ISBN-13: 978-1-57444-822-1 (hb : alk. paper) ISBN-10: 1-57444-822-6 (hb : alk. paper) 1. Hair--Diseases--Treatment. 2. Scalp--Diseases-- Treatment. I. McMichael, Amy J. II. Hordinsky, Maria K. III. Series. [DNLM: 1. Hair Diseases--therapy. 2. Hair Diseases--ethnology. 3. Scalp Dermatoses--ethnology. 4. Scalp Dermatoses--therapy. W1 CL69L v.41 2008 / WR 450 H15245 2008]

RL151.H25 2008 616.5’46--dc22 2007042262

Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com McMichael PTR 01/23/08 FM

Our thanks to Ralph, Jessica, and Jacob Thomas and Bob, Irene, Catherine, Alexander, and Kristina Kramarczuk for their help and support. Their understanding about the late nights at the computer, the many conference calls, and the missed family time was the key that allowed us to ﬁ nish this endeavor. We could not have done it without you! —Amy J. McMichael Maria K. Hordinsky McMichael PTR 01/23/08 FM McMichael PTR 01/23/08 FM

Series Introduction

During the past 30 years, there has been a vast explosion in new information relating to the art and science of dermatology as well as fundamental cutaneous biology. Furthermore, this information is no longer of interest only to the small but growing specialty of dermatology. Clinicians and scientists from a wide variety of disciplines have come to recognize both the importance of skin in fundamental bio logical processes and the broad implications of understanding the pathogenesis of skin disease. As a result, there is now a multidisciplinary and worldwide interest in the progress of dermatology. With these factors in mind, we have undertaken this series of books specifi cally oriented to dermatology. The scope of the series is purposely broad, with books ranging from pure basic science to practical, applied clinical dermatology. Thus, while there is something for everyone, all volumes in the series will ultimately prove to be valuable additions to the dermatologist’s library. The current volume represents what I believe to be the defi nitive work on the management of hair and scalp disorders by recognized authorities in the fi eld. It should prove to be a valuable resource for clinicians, students, and educators in dermatology.

Alan R. Shalita, M.D. Distinguished Teaching Professor and Chairman Department of Dermatology SUNY Downstate Medical Center Brooklyn, New York, U.S.A. McMichael PTR 01/23/08 FM McMichael PTR 01/23/08 FM

Preface

Our goals were several in developing and editing Hair and Scalp Diseases: Medical, Surgical, and Cosmetic Treatments. First, we wanted to give the readers of our text a comprehensive view of treatment for each scalp and hair disorder. Rather than follow previous models, we strove to create the quintessential text on treatment of these disorders with a special concentration on ethnicity, hair type, and cultural haircare practices for each entity in a composite fashion. We wanted to impart widely the information that has been accumulated by specialists in the fi eld of hair and scalp disorders and to do so in a way that was easy to follow, practical, and complete. Finally, we strove to enumerate treatments that may go beyond accepted U.S. and international guidelines and incorporate off-label use of medications when data indicates this may be necessary. We charged our contributors with the challenge of approaching each hair disorder with a therapeutic ladder. The treatment of each disorder begins in the simplest form and becomes more complex, dependent upon patient response, cultural practices, and concomitant disease. We asked each author to create treatment plans that look beyond the best-described treatments to those that incorporate creative, thoughtful approaches to the management of the multitude of hair and scalp disorders that challenge dermatologists. While physicians must be savvy about product inserts for recommended dosage schedules, we asked our contributors to consider how practical and effective treatment may differ from package inserts or must be altered to allow for treatment of a wide range of patients with different hair types. We asked authors to report how the treatments that they chose worked, including mechanism of action, absorption characteristics, and general pharmacology of the agent or agents. We felt this was imperative for both cosmetic, nonprescription, and prescription agents. To make this text current, we asked authors to include data on the effi cacy or benefi ts of many of the latest product additives. We felt that the phenomenon of allergic responses of scalp skin and the appropriate agents to use in the face of suspected or known sensitivities is important, but often overlooked. This book serves as a primer for those seeking an approach to the patient with irritant and allergic contact dermatitis reactions of the scalp. With all this in mind, our authors were asked to include all ethnicities and hair types when discussing choice of treatment and product effi cacy. We specifi cally hoped to avoid creating a separate ethnic haircare chapter by requesting that each contributor integrate this information into each of their chapters, where diversity in approach can be appreciated and put into perspective. The audience for this work is wide. Practicing dermatologists and dermatologists in training will fi nd the therapeutic regimens presented here to be practical and helpful. Staff in pharmaceutical and cosmetic companies can benefi t from understanding the dermatologist’s approach to the diagnosis and management of hair and scalp disorders. We fi rmly believe that anyone interested in hair and scalp diseases will benefi t from using this book as a resource.

Amy J. McMichael Maria K. Hordinsky McMichael PTR 01/23/08 FM McMichael PTR 01/23/08 FM

Contents

Series Introduction Alan R. Shalita . . v Preface ...... vii Contributors ...... xi 1. Human Hair 1 John Gray 2. Evaluation Techniques 19 Christopher L. Gummer 3. Photographic Imaging in Hair Loss 35 Douglas Canﬁ eld 4. Hair Follicle Anatomy in Human Scalp Biopsies 41 David A. Whiting and Lady C. Dy 5. Nonmedicated Grooming Products and Beauty Treatments 59 Zoe Diana Draelos 6. Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 73 Janet G. Hickman 7. Alopecia Areata 91 Maria K. Hordinsky and Ana Paula Avancini Caramori 8. Androgenetic Alopecia 107 Andrew G. Messenger 9. Telogen Efﬂ uvium 119 Wilma F. Bergfeld 10. Cicatricial Alopecia 137 Paradi Mirmirani 11. Structural Hair Abnormalities 149 Hope V. Dinh, Rodney D. Sinclair, and Jack Green 12. Scalp Prostheses: Wigs, Hairpieces, Extensions, and Scalp-Covering Cosmetics 163 Ingrid E. Roseborough 13. Hair Transplantation 175 Ron Shapiro and Valerie D. Callender 14. Alternative Treatments for Hair Loss 197 Christine Jaworsky 15. Hirsutism and Hypertrichosis 211 Katherine R. Kerchner and Amy J. McMichael 16. Light-Assisted Hair Removal 225 Brian Zelickson and Lydia Sahara McMichael PTR 01/23/08 FM

x Contents

17. Allergic Contact Dermatitis 237 Sharone K. Askari and Erin M. Warshaw 18. The Biopsychosocial Aspects of Hair Disease 267 Lucinda S. Buescher and David Resch 19. Scalp Infections and Infestations 277 Bryan K. Chen and Sheila Fallon Friedlander 20. Sources of Alopecia Information for Physicians and Patients 297 Jennifer Conde and Amy J. McMichael 21. Approach to the Patient with Alopecia 301 Lynne J. Goldberg

Index 309 McMichael PTR 01/23/08 FM

Contributors

Sharone K. Askari Department of Dermatology, St. Louis University Hospital, St. Louis, Missouri, U.S.A.

Wilma F. Bergfeld Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland, Ohio, U.S.A.

Lucinda S. Buescher Department of Dermatology, Southern Illinois University School of Medicine, Springﬁ eld, Illinois, U.S.A.

Valerie D. Callender Department of Dermatology, Howard University College of Medicine, Washington, D.C. and Callender Skin and Laser Center, Mitchellville, Maryland, U.S.A.

Douglas Canfi eld Canfi eld Imaging Systems, Fairfi eld, New Jersey, U.S.A.

Ana Paula Avancini Caramori Department of Dermatology, Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, Brazil

Bryan K. Chen Rady Children’s Hospital and Health Center, UC San Diego School of Medicine, San Diego, California, U.S.A.

Jennifer Conde Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Hope V. Dinh Department of Dermatology, St. Vincent’s Hospital, Melbourne, Victoria, Australia

Zoe Diana Draelos Dermatology Consulting Services, High Point, North Carolina, U.S.A.

Lady C. Dy Department of Dermatology, Rush University Medical Center, Chicago, Illinois, U.S.A.

Sheila Fallon Friedlander Rady Children’s Hospital and Health Center, UC San Diego School of Medicine, San Diego, California, U.S.A.

Lynne J. Goldberg Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, U.S.A.

John Gray Gray’s Medical Practice, Gosbury Hill Health Center, Chessington and Proctor and Gamble Beauty, Surrey, U.K.

Jack Green Department of Dermatology, St. Vincent’s Hospital, Melbourne, Victoria, Australia

Christopher L. Gummer Cider Solutions Ltd., Chilworth, Surrey, U.K. McMichael PTR 01/23/08 FM

xii Contributors

Janet G. Hickman Dermatology Consultants, Inc. and The Education and Research Foundation, Inc., Lynchburg, Virginia, U.S.A.

Maria K. Hordinsky Department of Dermatology, University of Minnesota, Minneapolis, Minnesota, U.S.A.

Christine Jaworsky Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, U.S.A.

Katherine R. Kerchner Department of Dermatology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, U.S.A.

Amy J. McMichael Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Andrew G. Messenger Department of Dermatology, Royal Hallamshire Hospital, Shefﬁ eld, U.K.

Paradi Mirmirani Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, and University of California, San Francisco, California, U.S.A.

David Resch Division of Medicine/Psychiatry, Southern Illinois University School of Medicine, Springﬁ eld, Illinois, U.S.A.

Ingrid E. Roseborough Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

Lydia Sahara Department of Dermatology, University of Minnesota, Minneapolis, Minnesota, U.S.A.

Ron Shapiro Shapiro Medical Group, Bloomington, Minnesota, U.S.A.

Rodney D. Sinclair Department of Dermatology, St. Vincent’s Hospital and Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia

Erin M. Warshaw Department of Dermatology, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, Minnesota, U.S.A.

David A. Whiting Department of Dermatology and Pediatrics, University of Texas Southwestern Medical Center, Baylor Hair Research and Treatment Center, Dallas, Texas, U.S.A.

Brian Zelickson Department of Dermatology, University of Minnesota, Minneapolis, Minnesota, U.S.A. McMichael PTR 01/21/08 Chapter 01

1 Human Hair

John Gray Gray’s Medical Practice, Gosbury Hill Health Center, Chessington, and Proctor and Gamble Beauty, Surrey, U.K.

INTRODUCTION As the ﬁ fth and naked ape, modern humans do not possess an all-encompassing, thick and pigmented pelage once the intrauterine lanugo hairs are shed. Selection for shorter and ﬁ ner body hair has resulted in only head hair remaining in any quantity. This however is capable of growing to greater lengths than that of any other mammal (Fig. 1). Since the human head bears some 100,000–150,000 hair follicles, an individual adult with 30 months continuous, unstyled growth, will carry some 30 kilometers of hair. This in itself has consequences for grooming and overall appearance.

STRUCTURE OF HAIR Many other publications describe in detail the human hair follicle (1). It is worth mentioning some of the salient features that relate to the human hair shaft. The cross section of the hair shaft has three major components: the cuticle, the cortex, and the medulla (Fig. 2). The main constituents of hair are sulphur-rich protein, lipids, water, melanin, and trace elements (2). The cortex, the main bulk of a fully keratinized hair shaft, contributes almost all the mechanical properties of the hair, including strength and elasticity (2). The cuticle consists of six to eight layers of fl attened overlapping cells with their free edges directed upward to the tip of the hair shaft (2). Innermost is the endocuticle, derived from the developing cell cytoplasm contents. The exocu- ticle lies closer to the external surface and comprises three parts: the b-layer, the a-layer, and the epicuticle. The b-layer and the a-layer are largely proteinaceus. The epicuticle is a hydrophobic lipid layer of 18-methyleicosanoic acid on the surface of the fi ber, or the f-layer. The epicuticle is not visible on routine microscopy. The normal cuticle has a smooth appearance, allowing light refl ection and limiting friction between the hair shafts. It is responsible for the luster and texture of the hair (3). The cuticle may be damaged by frictional forces (brushing, combing or blow-drying) as chemical removal of the f-layer, particularly by oxidation, eliminates the fi rst hydrophobic defense and leaves the hair more porous and vulnerable. Cuticle disruption with alkaline chemicals is the fi rst step in permanent hair styling (3). If the cuticle is damaged there is little change in the tensile properties of hair. The cortex consists of closely packed spindle-shaped cortical cells rich in keratin fi laments that are oriented parallel to the longitudinal axis of the hair shaft (2), and an amorphous matrix of high sulphur proteins. The intermediate fi lament hair keratins (40–60 kDa), comprising 400 to 500 amino acid residues in heptad sequence repeats, form hard keratin polypeptide chains that pair together to form protofi laments, which make up a keratin chain. The keratin chains have a large number of sulphur-containing cysteine residues. Cysteine residues in adjacent keratin fi laments form covalent disulphide bonds, which create a strong crosslink between adjacent keratin chains (6). The disulphide bonds confer shape, stability, and resilience to the hair shaft. Other weaker bonds link the keratin polypeptide chains together, such as Van der Waal interactions, hydrogen bonds, and coulombic interactions known as salt links (6). These weaker bonds can be overcome with water (6). The medulla consists of a cortex like framework of spongy keratin supporting thin shells of amorphous material bonding air spaces of variable size. It is absent in most human terminal hair, other than gray hairs. 2 Gray

FIGURE 1 Human hair grows longer than that of any other mammal.

Hair Color Hair color is determined by the melanocytes found only in the matrix area of the follicle at the base of the cortex directly above the follicular papilla. Melanocytes transfer packages of melanin (melanosomes) to the cortical cells during anagen. Eumelanin is the dominant global pigment and confers black/brown hair. Pheomelanin, a mutation of eumelanis, is the predominant pigment found in blonde or red hair (4). Graying of hair is a normal manifestation of aging and illustrates progressive reduction in melanocyte function. The proportions of eumelanin and pheomelanin and the total amount of melanin determine the ﬁ nal natural color of the hair (5).

FIGURE 2 Multiple hair shafts. One hair displays a medulla. McMichael PTR 01/21/08 Chapter 01

Human Hair 3

Black and dark brown hair are the prevalent natural hair colors of peoples of all regions, accounting for more than 90% of all human hair. Dark hair is characterized by very high levels of the dark pigment eumelanin. Blonde hair frequency is reported as 1.8% worldwide. Blonde hair is characterized by low levels of the dark pigment eumelanin and higher levels of the pale pigment pheomelanin. Shades range from light brown to pale blonde. In certain European populations, the occurrence of blonde hair is more frequent, and often remains throughout adulthood, leading to misinterpretation that blondeness is a uniquely European trait. Based on recent genetic information, it is probable that humans with blonde hair became more numerous in Europe about 10,000 to 11,000 years ago during the last ice age, as a result of Fisherian runaway mechanisms. Prior to this, early Europeans had dark brown hair and dark eyes, as is predominant in the rest of the world. In humans of many ethnicities, lighter hair colors occur naturally as rare mutations, but at such low rates that it is hardly noticeable in most adult populations. Light hair color is commonly seen in children, and is curiously common in children of the Australian Aboriginal population. Lithuania has the highest percentage of people with blonde hair. Bleaching of hair is common, especially among women. Bleached blonde hair can be distinguished from natural blonde hair by exposing it to ultraviolet light, as heavily bleached hair will glow, while natural blonde hair will not. There are no comparable data for red hair, but in the areas of obvious frequency (the fringes of Western and Eastern Europe) it is at a maximum of 10%. In Scotland, 35% of the population carries the recessive gene for red hair. Eighty percent of redheads have the melanocortin-1 receptor gene anomaly. Controversial estimations of the original occurrence of the red-haired gene at 40,000 years ago are probable. Red hair is associated with the melanocortin-1 receptor, which is found on chromosome 16. Red hair may be an example of incomplete dominance. When only one copy of the red-hair allele is present, red hair may blend with the other hair color, resulting in different types of red hair including strawberry blonde (red-blonde) and auburn (red-brown).

The Record of the Hair The hair shaft records repeated cosmetic practices—the so-called record of the hair (7). Hair grows at ≈ 0.4 mm per day for between two and seven years, sometimes up to 10 years (7). Newly emerging hair has properties that are different from those of the hair tips. The more distal part of the hair shaft, particularly the tip, has typically undergone several hundred washes, the application of hot styling implements, and other cosmetic procedures such as bleaching, permanent coloring, and perming in addition to normal exposure to the environment. It may show the effects of weathering. The root may be less porous and have different chemical properties (7).

MORPHOLOGY OF HUMAN HAIR The varied morphology of humans and their hair may be explained by both genetics and the adaptive consequences that occurred after the ﬁ rst diaspora of Homo sapiens. Genetic evidence suggests that Homo sapiens originated only 200,000–250,000 years ago somewhere in the East African savannah. Despite their apparent phenotypic variation, today’s world population is potentially derived from as few as 1,000 to 10,000 individuals. Using average rates of genetic mutation, this population lived at a time that coincided with the massive Toba volcanic disas- ter, which affected global climate, effectively wiped out all other hominids, and devastated Homo sapiens. Descendants of these “modern” humans migrated out of Africa when the climate improved and populated the earth. The human genome is minute compared to that of other species. This is due in the most part to the gross reduction in breeding pairs in the late Pleistocene era. This core of humanity, survived near-extinction and went on to populate the entire world in less than 5000 generations. In less than 100 generations and 2000 years, world population has risen from 3 million to 6 billion. The majority (61%) live in Asia. Of the remainder, 14% live in the Americas, 13% in Africa, and 12% in Europe with only 0.5% in Oceania. Hair form arose from these clans and, as much as skin color, denotes local origins. 4 Gray

“Race” and Hair Form After the fi rst migration out of Africa the human genotype spread, localized, and adapted, to create the basic stock phenotypes still seen today (8). Despite serial migrations, the original groups have been preserved largely on a regional basis. Bands, which are the simplest form of human society, and still exist (Inuit, indigenous Australians) expanded into clans and subsequently tribes. Until the advent of global agriculture some 7,000 ago, genetic lineages were probably tightly maintained. Thereafter, gene sharing occurred on a steadily widening basis. Where and when the emergence of the archetypal hair forms that are described in the literature occurred is not known. Similarly, knowledge of the hair phenotype of early humans and whether the tightly curled hair of today’s equatorial Africa or a more wavy appearance predominated is speculative (Figs. 3 and 4). Any given physical characteristic is generally found in multiple groups (9). Demonstrat- ing that environmental selective pressures shaped specifi c physical features is diffi cult, since such features may have resulted from sexual selection for individuals.

Causcasoid, Negroid, and Mongoloid The literature perpetuates the taxonomy of hair as caucasoid, negroid, and mongoloid. These terms not only have a pejorative ring but from a practical standpoint are scientiﬁ cally inac- curate and no longer employed by publishers. Further, they are geopolitically incorrect. Other alternatives, such as Equatorial-African, Indo-European (IE), and Asian, might better allocate the dominant phenotypes while recognizing the impact of past passive and forced migrations, and the increasing homogenicity of the scalp hair of Homo sapiens through gene sharing.

Hair Morphology Studies Human hair morphology varies from the ﬂ at to the round (Fig. 5). Typically these have been allocated to perceived “racial” groups (Fig. 6). However, certain human scalps often bear a multiplicity of hair phenotypes.

FIGURE 3 This woman’s clan is from Eastern Africa (modern Ethiopia). Her hair displays varied phenotypic adaptability—straight hair when pregnant and tightly coiled in the nonpregnant state. Curiously she is a doppleganger for the proposed African Eve published in Newsweek (see Fig. 4). McMichael PTR 01/21/08 Chapter 01

Human Hair 5

FIGURE 4 African Eve as represented in Newsweek magazine.

In many parts of the world, groups have mixed in such a way that many individuals have relatively recent ancestors from widely separated regions. Although genetic analyses of large numbers of loci can produce estimates of the percentage of a person’s ancestors coming from various continental populations (10,11), these estimates may assume a false distinctiveness of the parental populations since human groups have exchanged mates from local to continental scales throughout history (12). Even with large numbers of markers, information for estimat- ing admixture proportions of individuals or groups is limited and estimates typically will have wide conﬁ dence intervals (13). The alleged relationship between the cross-sectional shape of the hair shaft and the form of the hair, e.g., curly or straight hair, is less than dogmatic. Three-dimensional computer-aided reconstructions have documented that the follicle form determines the appearance of the hair, e.g., the “African” follicle has a helical form, whereas that of the Asian follicle is completely straight. The IE follicle represents variations between these extremes. However, even a straight IE follicle may produce a hair shaft that has an oval cross (14). Few biological data on curly hair follicles have been reported in the literature. However, follicles dissected from scalp skin samples from African, Guyanese, and Caucasian volunteers

FIGURE 5 Cross section of (left to right) Asian, Indo-European, and African hair. 6 Gray

FIGURE 6 EMG of (left to right) Asian, Indo-European, and African hair. Note the propensity of African hair to fold (curl). were observed macroscopically in culture in Williams’ E medium, and by immunohistochemistry. Macroscopic study of scalp biopsies obtained from African volunteers showed that the dermal implantation of follicles was curved with a retro-curvature at the level of the bulb, as opposed to a straight shape in Caucasian (IE) follicles. The bulb itself was bent, in the shape of a golf club, while both the outer root sheath (ORS) and the connective tissue sheath were asymmetrical along the follicle (15). In vitro growth of curly hair follicles was slightly slower than that of Caucasian follicles but, more importantly, the curvature was maintained in the hair shaft produced in vitro. Immu- nohistochemistry revealed that the proliferative matrix compartment of curly hair follicles was asymmetrical, with Ki-67-labeled cells more numerous on the convex side and extending above the Auber line. On the convex part of the follicle, the ORS was thinner and the differentiation programs of the inner root sheath and hair shaft were delayed. Some ORS cells expressed alpha-smooth muscle actin protein on the concave side of the curvature, refl ecting a mechanical stress. The authors concluded that hair curliness is programmed from the bulb and is linked to asymmetry in differentiation programs. Alternatively, the origin of the curliness of human hair has been reported from studies employing scanning microbeam small angle X-ray scattering (SAXS), based on the nanostructure of keratin fi ber arrangement. Scanning microbeam SAXS patterns of single hair fi bers have been measured across the fi bers. The differences in the patterns between the inner and the outer sides of the curvature were successfully detected (16). The analysis of the equatorial and azi- muthal scattering intensity profi les showed that the arrangement of the intermediate fi laments was different between the inner and the outer sides of the curvature. From the analogy with Merino and Romny wool, it is suggested that different types of cortices exist in human hair. It is concluded that, regardless of the ethnic origins, the macroscopic curl shape of the hair fi ber originates from the nonhomogeneity of the internal nanostructure, arising from unhomoge- neous distribution of two types of cortices.

Adaptive Changes in Hair Morphology Since Africa is the home of humankind, it is appropriate to commence here with a discussion of hair morphology. “African” phenotypes show as much diversity as do their genotypes. The classical hair of equatorial Africa is also seen in equatorial regions of Indonesia and Australia. This type of hair is tightly coiled, with a thick appearance and feel. Curiously, some Indo-Euro- peans also express this phenotype (Fig. 7). Many of the populations of northeastern Africa have looser, less tightly coiled hair than most other Africans. Andamanese peoples, the Negrito, are phenotypically African but are in fact a recent Asian branch. Their small stature, heavily pigmented skin, and tightly coiled hair represent a recent adaptation to equatorial existence. Melanesian peoples express the same traits. Late African phenotypes are thinly spread throughout the world. Indigenous Australian peoples exhibit the same phenotype and some Aboriginal infants are born with blonde hair. Wooly hair syndrome is a condition affecting a small percentage of persons of IE and Asian heritage. It is characterized by extremely frizzy and wiry hair that looks almost wooly in appearance. Wooly hair is a rare defect in the structure of scalp hair. This hair is either present at birth or appears during the ﬁ rst months of life. The curls, with an average diameter of 0.5 centimeter, lie closely together and usually make the hair difﬁ cult to comb. In addition, the hair may be more fragile than usual. The syndrome usually lessens in adulthood, when wavy hair often takes the place of wooly hair. McMichael PTR 01/21/08 Chapter 01

Human Hair 7

FIGURE 7 A northwestern European child with tightly curled hair.

The difference between wooly hair in Africans and the hair found in non-Africans with the syndrome is that African hair lies typically separate and is tightly coiled or spiraled, while the curls of the latter tend to merge. This type of hair often only covers portions of the scalp.

Weathering Weathering is the progressive degeneration from the root to the tip of the hair of the cuticle and then later the cortex due to routine everyday wear and tear. Although all hair exhibits some degree of weathering, longer hair, subjected to repeated insults, inevitably shows more severe changes of weathering (Fig. 8). Features of weathering include damaged cuticles, longitudinal ﬁ ssures known as split ends, and transverse ﬁ ssures resembling the nodes seen in trichorrhexis nodosa (1).

Function of Human Hair The function of human hair is, curiously, unresolved. Hypotheses vary: Is it a relic of the hypo- thetical aquatic phase of human development where a pelage would be an impairment? Is hair an integral adaptation for thermoregulation and ultraviolet protection, a mere adornment, or the result of Fisherian runaway sexual selection? All these theories can be disproved not least by the tendency for humans of both sexes to bald. Hair may and often is interpreted as a marker of age, healthy nutrition, and fecundity. In its styled form it is employed in all societies to express social status or cultural afﬁ liation. Hair in most cultures is at its zenith on the wedding day as a mark of health, wealth, and sexual attraction. By contrast, sociological studies have revealed the full impact of so-called bad hair days, where subjective and objective negative assessment of hair may reduce self-esteem.

FIGURE 8 Severe weathering. 8 Gray

HUMAN HAIR AND ATTRACTIVENESS Although hair is cited as a factor contributing to human attractiveness, it is seldom described in terms more explicit than “healthy.” From an attractiveness standpoint, a person’s face would not have been easily visible across the open grassland, plain, or tundra for early humans or, in subsequent generations, across a darkened dance fl oor. The appearance of scalp hair, in conjunction with body form, is the key and immediate component of attraction. Physical attractiveness can have very real effects. A survey of 11,000 people conducted by London Guildhall University revealed that people who were described as physically attractive earned on average 13% more than those who were deemed less attractive (17). This fi nding, however, might be construed to be the result of the increased self-confi dence of people who perceive themselves as more physically attractive. Certain advantages do accrue to such persons: the ability to obtain better jobs, pay, and promotions; more choices in partners and, consequently, more power in relationships; and the opportunity to marry into families with more resources (money) (Fig. 9). At a distance, or from behind, the quality of a person’s hair may imply an age (youth, health, and fecundity) not realized by facial markers (Fig. 10). Conversely, facial beauty may be marred or distracted from by unkempt or unhealthy hair. Of all the parameters by which hair is assessed, shine may be construed as is the most representative of healthy hair and, perhaps by implication, a healthy body (Fig. 11).

Hair, Shine, and Attraction The face, at close quarters, is the apparent focus of an observer’s attention. A considerable body of literature defi nes and discusses the assessment of facial attractiveness. However, many authors, including Matt Ridley in his acclaimed work The Red Queen: Sex and the Evolution of Human Nature (18), discuss the role of hair in attracting a mate. Hair shine is an optical phenomenon that depends on the parallelism of the incident light, the (micro)roughness of the surface of the body this light strikes, and the translucence of this object. In the case of hair fi bers, their morphology, particularly their ellipticity, is of relevance and the interpretation of the photoelectric impulses received by the brain via the eyes is critical. Each hair bears layers of external cells forming the cuticle. Each acts as a mirror that refl ects a certain ratio of the incident light, and the higher the number of layers, the higher the ratio of the refl ected light and, consequently, the more intense the luster (Fig. 12). Contrast luster is the contrast of the refl ected light viewed against an angular dependency. Put in simpler terms, if the source of light, or the observer, moves, the luster changes. Contrast luster may be affected by hair surface damage, hair color, and hair morphology (whether the hair is curly or straight). Other factors that infl uence contrast luster include the interaction of light with the sawtooth- shaped fi ne structure of the hair cuticle, or the presence of sebum, which eliminates this fi ne structure and renders the hair dull and unattractive by an interference mechanism (Fig. 13). All of these physical factors may subconsciously infl uence the perception of attractiveness in the eye of the beholder.

Hair Forms, Styles, and Fashions Until the advent of readily available and reliable cosmetic products, the hairstyle of early Homo sapiens must have been somewhat of a gamble. Naturally short hair is an advantage in hot and humid climates and long hair is perhaps more benefi cial in cold regions. However, what is ultimately achievable is determined by the phenotype and length of anagen of each hair (Fig. 14). TABLE 1 Cosmetic Treatments and the Resulting Alteration of Contrast Luster Effect of product Factor that infl uences Dying Bleach contrast luster Styling products (deeper color) (lighter color) Conditioners Perms Refl ection properties Increased Increased Decreased Various Unchanged Hair set (straight, curled) Unchanged Unchanged Unchanged Increased Decreased Hair damage Unchanged Unchanged Decreased Unchanged Decreased Overall effect Increased Increased Decreased Various Decreased McMichael PTR 01/21/08 Chapter 01

Human Hair 9

FIGURE 9 Healthy hair framing symmetrical features.

For most of the world’s current population, straight, darkly pigmented hair is the norm (Fig. 15). This phenotype demonstrates a largely circular shaft with a diameter varying between 50 and 120 microns. Curly hair is the classical phenotype of subequatorial African peoples. The hair shaft tends to be ﬂ atter and is intrinsically more vulnerable to weathering. Curly hair is more common in Europe and North Africa. It has the advantage of conferring natural volume but presents challenges in grooming (Figs. 16–18). Straight hair is the arch-phenotype of Asians and Native Americans. The Americas were populated by migrants from the former across the Bering Strait some 12,000 years ago. While some IE hair is straight, particularly in the Indian subcontinent, in regions closer to Europe there is a mixture of straight, wavy, and curly hair. Various aspects of Asian and IE hair have been investigated and compared. The number of cuticle layers, width of the cuticle cells, degree of their inclination, and the interval between surface cuticle edges, have been recorded in a study of two hundred subjects for each of these two ethnic groups. It has been reported that there are statistically meaningful differences between all these attributes for the two hair

FIGURE 10 This lady with extraordinarily long hair might be perceived to be a teenager. She is, however, in her ﬁ fth decade. Women with long hair may be perceived as “more attractive,” as the ability to grow long, healthy- looking hair (and nails) is deemed a reﬂ ection of the youth and health of the individual. 10 Gray

FIGURE 11 The shine band of hair attracts the eye and is the most important parameter for implied “health.” types. Asian hair has more cuticle layers and wider cuticle cells than IE hair, and the cuticular inclination of Asian hair is steeper and its cuticular interval is narrower than that of IE hair. In addition, it was found that there are differences in how cuticle cells weathered. Under extension stress, Asian hair cuticles fail as large pieces while keeping their original shape. On the other hand, IE hair cuticles tend to collapse, forming small fragments. Measurements revealed that IE cuticles are more fragile than Asian cuticles. These results were interpreted to show a difference in the strength of cuticular subcomponents. However, the contention that this is the

FIGURE 12 Contrast luster is dependent on optical phenomena that differ for the 2% of people with blonde hair compared with the 98% of people with hair of other colors. McMichael PTR 01/21/08 Chapter 01

Human Hair 11

FIGURE 13 Two hairs with radically different cuticular profi les. Each layer acts as a mirror. The less-damaged hair (top) has a higher ratio of refl ected light and more intense luster and shine. single weak point of IE hair must be treated with caution, as wig makers routinely remove the cuticular layer from human hair with no demonstrable reduction in stress resistance (19). In a study to collect qualitative and quantitative data about the morphology, structure, geometry, water-swelling, and mechanical properties of hair fi bers, samples were obtained from subjects of different ethnic origins. X-ray analyses, cross-sectional measurements, tensile testing, and water swelling were performed on samples of hair collected from European, Asian, and African subjects. No differences in the intimate structures of fi bers were observed among these three types of hair, whereas geometry, mechanical properties, and water swelling dif- fered according to clan origin. In addition, the behavior of hair fi ber under mechanical stress was visualized with environmental scanning electron microscopy.

Hair and Cultural Attitudes Hair, as the one readily adaptable natural human asset, can be arranged, or styled, in a multitude of ways. It has an unsurpassed ability to convey social status and cultural afﬁ liation (Fig. 19). However, almost all societies have found it necessary to cut or conﬁ ne the hair for the simple expedience of utility in daily life. Three trends dominate historical record.

Shaved Hair In pharaonic Egypt, hair was often shaved, especially among children, where long hairstyles would prove uncomfortable or parasites, such as head lice, were a problem. Wigs were the privilege of the ruling classes, a trend that recurred for the next 5000 years as evinced by the fashionable courts of Europe and the British judiciary.

FIGURE 14 Classical hairstyles from around the world. 12 Gray

FIGURE 15 Classical Oriental straight hair moderated with modern cosmetic products.

Shaved heads may also indicate a religious sect or aspiration. Buddhist monks shave their heads as a renunciation of the world, and Muslim men may wear a single long lock of hair on their otherwise shaved heads to evince hair’s religious signiﬁ cance. As a rite of passage, Hindu males shave their heads when they reach adolescence. The Manchu of China left only a braided queue residue as a mark of submission, which became a mark of dignity and manhood. As a tribal signal, pre-Columbian Native Americans in eastern North America were sometimes entirely shaven, save for a ridge, or comb, of hair along the crown. Plains Indians wore two long plaits. The habit of shaving has persisted into the twenty-ﬁ rst century. Shaving hair has similarly been imposed on residents of military and penal institutions and World War II female collaborators. This act implies diminution of status (the Samson effect).

Short Hair Short hair has obvious beneﬁ ts. In Classical Greece and Rome, where hairdressing matured into a public service, hair was worn short and was a clear sign of civilization in comparison

FIGURE 16 Curly hair confers volume but is more difﬁ cult to groom. McMichael PTR 01/21/08 Chapter 01

Human Hair 13

FIGURE 17 Hair classical of indigenous Australian peoples.

to the barbarian neighbors. This trend persisted in Europe until the thirteenth and fourteenth centuries when pageboy styles emerged as part of an aristocratic fashion. The clerical pudding- basin, ear-revealing style of the early ﬁ fteenth century was superseded by a longer pageboy style—rough in the north and coiffured in Italy. By contrast, in Mesoamerica Inca chiefs wore relatively short hair, and commoners wore progressively longer hair. The French Revolution and the accompanying militarism induced short styles for both men and women. Women classically adopted short curls that framed the face or smooth plaits around the head. They also wore colored wigs. In the industrial nineteenth century, among the emerging middle class, men wore short curled and dressed hair with a moustache, sideburns, or beard. The exigencies of the World Wars, particularly World War I, prompted a return to short hair and loss of facial adornment, which apart from the counterculture of the 1960s established a norm that has persisted into the twenty-ﬁ rst century. In the West, women cut or “bobbed” their hair as a symbol of their political and social emancipation after World War I. This trend was followed by a succession of celebrity-inspired short, head-clinging hairstyles. The permanent wave, invented by the German Charles Nessler around 1905, offered styling to the masses. In the same vein, the invention of rollers for waving made possible the very short, layered Italian look. In the 1960s the availability of natural-looking hair pieces in the form of full wigs, half wigs, or long falls, at all prices, enabled almost every woman to own one or more to suit her taste and mood.

FIGURE 18 Atypical curly hair in Thailand. 14 Gray

FIGURE 19 Hair as a mark of clan style.

Long Hair In the ancient world, long hair and long-haired wigs were the province of aristocracy. Sumeri- ans and Persians powdered, curled, crimped and dyed their hair, and the horse-borne barbar- ians who overran Europe in the Middle Ages wore long fl owing locks and beards. In Africa, where hair frequently denoted sex and status, the Massai males wore their hair waist-length, whereas, women and noncombatants shaved their heads. Chinese and Japanese women traditionally wore long hair, possibly under a bandeau or worn as a knot, which might be decorated. Unmarried girls signifi ed their status with long plaits. In Japan, the introduction of pomade in the seventeenth century led to the familiar sweep, arranged with combs, bars, ribbons, and ornamental hairpins, which revealed the nape of the neck. In Muslim cultures, the hair was and still is frequently concealed in public. In many parts of the world a henna rinse is common. In the fi fteenth century, fashionable ladies of northern Europe plucked their hairline to make their foreheads seem higher and scraped their hair back under an elaborate pointed or wired headdress. In the twenty-fi rst century, when hair fashions are so driven by celebrity, long hair in the West is associated with young females and males of an artistic bent. Unlike the rebellious 1960s and 1970s, long hair is now uncommon as a male phenomenon.

Celebrity Hair Hairstyles in the West have been greatly infl uenced by changing fashions for generations. For the moneyed classes, wigs were worn until the advent of World War I. Elizabeth I transformed Europe for redheads, who had hitherto been reviled. Many stained-glass representations of Judas depict him with red hair. Balding royalty, most notably Louis XIV, drove a wig culture for a time. Civil wars and religion have infl uenced fashions with the long curling locks of the royalist Anglican Cavaliers and the cropped hair of the parliamentarian Puritan Roundheads. The portraits of Flemish artist Sir Anthony Van Dykes infl uenced facial hairstyles in the late seventeenth century. In the 1890s the Gibson Girl’s pompadour was combed over a pad, making a high wide frame for the face, and swept up behind. Heated irons, such as the waving iron invented by the French hairdresser Marcel Grateau in the 1870s, allowed women to achieve curls, crimping, and the natural-looking Marcel wave. In the twentieth century the broad reach of print and electronic media increasingly infl uenced the world of fashion, including hairstyles. In Asia, permanent hair dyeing is epidemic—not always to best effect (Fig. 20). McMichael PTR 01/21/08 Chapter 01

Human Hair 15

FIGURE 20 Permanent hair dyeing is common among Asians.

Hair and Ethnic Allegiance The wearing of dreadlocks is very closely associated with ethnic allegiance, has biblical associations (Leviticus 21:5), and is in deliberate opposition to the straighter hair of Caucasian persons. Interestingly, dreadlocks are no longer exclusive to people of direct African descent. Indeed there are ascetic groups within nearly every major religion that have at times worn their hair in this fashion. The way to form natural dreadlocks is to allow hair to grow in its natural pattern, without cutting, combing, or brushing, and washing it with pure water. During the 1960s and 1970s, Black Power and other black pride movements in the United States brought about the emergence of the Afro hairstyle. Men and women grew their hair out to signiﬁ cant diameters away from their head as a rejection of Eurocentric standards of beauty, an embracing of African heritage and roots, and a conﬁ rmation of the idea that “Black Is Beautiful.” The Afro is sometimes texturized so that it is not in its true African state, but slightly relaxed with a frizzier and more wiry appearance that springs out. Eventually, this hairstyle grew away from its political and cultural connotation and was embraced by the mainstream. Afros became popular even among those with loosely curled hair. Other hairstyles often worn by people of African descent are cornrows and braids, two styles that survived in the African diaspora. While recent years have brought about a movement among women of African descent to wear their hair naturally, most in the Western world have their hair relaxed or straightened (Fig. 21).

Haircare The “care” of hair is of greater social importance than perhaps is immediately apparent. It is a key component of the so-called “physical attractiveness phenomenon” and is the last aspect of our appearance we attend to in the mirror as we leave for work or play. Advice on haircare is an increasingly frequent part of the dermatologist/trichologist’s role. Patients with diffuse hair loss, the recovering alopecia areata, and post-chemotherapy patients all rightly expect cosmetic advice as part of holistic management.

FIGURE 21 Relaxed and re-curled hair in New York. 16 Gray

In recent decades, haircare products have been transformed from the functional but often unpleasant, to versatile and creative and quality-of-life enhancing. A haircare regimen includes a basic cleansing and conditioning product often with a number of variants to meet consumer needs. These products are generally used separately, and conditioning usage is much less than shampoo. Combination, or 2-in-1, products developed by Procter and Gamble in the late 1980s delivered for the fi rst time cleansing and conditioning benefi ts from a single bottle. Regimen ranges were classically designed for three hair types: normal, dry, or damaged hair. Subsequent generations of products were created to deliver a desired end-benefi t, such as “smooth and sleek,” “perfect curls,” and “color radiant.” A range of styling products to create long-lasting styles has also emerged to complement the cleansing and conditioning products. These can enhance or alter most common aesthetic styling problems. Foremost among these is the control of “volume,” either too little or too much. Managing frizzy hair is important and products for so-called “ethnic” hair are emerging.

Haircare Regimens A hair-care regimen can vary from zero to six products a day. While previous generations may have had nothing and relied solely on grooming, in an increasingly competitive society, the prolonged wearing of unwashed, matted, and neglected hair is considered unusual at the very least. In some developed societies, bar soaps for washing the scalp, particularly among men, are still common. These harsh anionic surfactant systems are not just poor cleansers, but also lead to extensive calcium salt buildup in the hair and reduced grooming capability. Daily shampooing alone can be harmless to the hair shaft, and in itself can improve the ability to groom and style. Haircare products, in comparison to skin care are inexpensive and ubiquitous.

Shampoos Modern high-quality shampoos have evolved from agents that once merely and harshly removed grease (sebum), perspiration, environmental dirt, and dead corneocytess. In the twenty-ﬁ rst century they contain agents that enhance the natural beauty of hair and mitigate the damage inﬂ icted by the owners. Shampoos consist of three major components: primary surfactants for detergency and foaming power, secondary surfactants to improve and condition the hair, and additives that complete the formulation and add special aesthetic effects. The surfactants or detergents act by removing the dirt from the hair with a lipophilic component and transferring it to the rinse water with hydrophilic component.

Moisturizing Shampoos The latest generation of shampoos, designed for dry hair, can include essential oils such as petrolatum as well as the surfactant systems described above. They are orientated toward those with hair of African origin or hair that is excessively dry. They leave the hair feeling moistur- ized and easy to comb. These products are also designed to help weathered and colored hair. Originally there were no shampoos specifi cally designed for African hair. The prevailing belief was that a shampoo was a shampoo, and that anything available in the general market could be used for all hair types. However, African hair benefi ts from shampoos that contain mild cleansing agents (detergents) that help detangle the hair and are pH balanced in the range of 4.5–5.5. Shampoos formulated for other hair types may not help to detangle hair suffi ciently, contributing to combing damage. Variants for African hair can be purchased in North America and Southern Africa.

Conditioning Agents Conditioning hair is critical to its sustained integrity as it inevitably weathers over time. Chemi- cal and physical processing remove the outer lipid coating (the f-layer) and result in amino acid degradation in the cortex of up to 50%. Conditioners are substances that increase the manageability, shine, and moisture content of each hair shaft. Modern products are designed to provide one or more of the following func- McMichael PTR 01/21/08 Chapter 01

Human Hair 17 tions: increase the ease of wet and dry combing; smooth, seal and realign damaged areas of the hair shaft; minimize porosity; impart sheen and a silken feel to hair; provide some protection against thermal and mechanical damage; moisturize; add volume and body; and eliminate static electricity. Dry, woolly hair generally requires heavier deposits of conditioners than other hair types. The use of leave-in or “intensive” conditioners is growing. The use of moisture-retaining ingredients (humectants) such as panthenol, can be augmented by cationic ingredients (e.g., polyquarternium derivatives), which leave hair manageable. Treatment with polymeric conditioning agents that bond to the hair at points of damage also aid in improving resistance to breakage. Regular conditioning contributes signiﬁ cantly to the preservation of the external architecture and internal chemistry of each hair shaft. Frequent chemical processing makes conditioning even more important.

CONCLUSION Hair is indeed humankind’s crowning glory. It is not to be neglected as an evolutionary relic, but a clever tool of Mother Nature in the game of survival and mating success. Care of hair allows individuals to fully express their well-being. Modern high-quality cosmetic products allow the realization of that potential in a manner never before possible.

REFERENCES 1. Dawber RPR, Diseases of the Hair and Scalp. Malden, MA: Blackwell Science, 1997. 2. Dawber RPR, Messenger AG. Hair follicle structure, keratinisation and physical properties of hair. In: Dawber R, ed. Diseases of the Human Hair and Scalp. Oxford, Blackwell Science, 1997:23–50. 3. Drealos Z. Hair cosmetics. Dermatol Clin 1991; 9(1):19–27. 4. Ha T, Rees JL. Red hair--a desirable mutation? J Cosmet Dermatol 2002; 1(2):62–65. 5. Dawber RPR, Gummer CL. The color of hair. In: Dawber R, ed. Diseases of the Human Hair and Scalp. Oxford: Blackwell Science, 1997:408. 6. Feughelman M, Lyman DJ, Willis BK. The parallel helices of the intermediate fi laments of alpha- keratin. Int J Biol Macromol 2002; 30(2):95–96. 7. Gummer CL. Cosmetics and hair loss. Clin Exp Dermatol 2002; 27(5):418–421. 8. Harding RM, Fullerton SM, Griffi ths RC, et al. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am J Hum Genet 1997; 60(4):772–789. 9. Lahr MM, Foley RA. Towards a theory of modern human origins: geography, demography, and diversity in recent human evolution. Am J Phys Anthropol 1998; (Suppl 27):137–176. 10. Mao X, Bigham AW, Mei R, et al. Measuring European population stratifi cation with microarray genotype data. Am J Hum Genet 2007; 80(5):948–956. 11. Bamshad M, Wooding S, Salisbury BA, Stephens JC. Deconstructing the relationship between genetics and race. Nat Rev Genet 2004; 5(8):598–609. 12. Mountain JL, Cavalli-Sforza LL. Inference of human evolution through cladistic analysis of nuclear DNA restriction polymorphisms. Proc Natl Acad Sci USA 1994; 91(14):6515–6519. 13. Pfaff CL, Barnholtz-Sloan J, Wagner JK, Long JC. Information on ancestry from genetic markers. enet Epidemiol 2004; 26(4):305–315. 14. Lindelof B, Forslind B, Hedblad MA, Kaveus U. Human hair form. Morphology revealed by light and scanning electron microscopy and computer aided three-dimensional reconstruction. Arch Dermatol 1988; 124(9):1359–1363. 15. Bernard BA. The biology of hair follicle. J Soc Biol 2005; 199(4):343–348. 16. Kajiura Y, Watanabe S, Itou T, et al. Structural analysis of human hair single fi bers by scanning microbeam SAXS. J Struct Biol 2006; 155(3):438–444. 17. Gray J. Reduction of skin hyperpigmentation-cosmetic considerations. RSM Press, 2007, ISBN 1 - 85315-7007-7. 18. Ridley M. The red queen:sex and the evolution of human nature. Original Publication by Penguin Books, Great Britain, 1993. Reprinted by HarperCollins Publishers, Inc, NY, NY 2003:277–306. 19. Franbourg A, Hallegot P, Baltenneck F, Toutain C, Leroy F. L’oreal Recherche, Clichy, France. Current research on ethnic hair. J Am Acad Dermatol 2003; 48(6 Suppl):S115–S119. McMichael PTR 01/21/08 Chapter 01 McMichael PTR 01/21/08 Chapter 02

2 Evaluation Techniques

Christopher L. Gummer Cider Solutions Ltd., Chilworth, Surrey, U.K.

INTRODUCTION Hair lends itself well to a variety of evaluation techniques. However, data are regularly misinterpreted due mainly to a lack of understanding of the hair’s environment. Hair is easily sampled, already fi xed, and is best studied with relatively simple tools available to every dermatologist. Prior to evaluation, the researcher must understand the relationship of the hair to its owner, the progression of changes that can occur on a normal head of hair, and the interplay of simple follicle biology. When a hair patient presents for the fi rst time the approach of the cosmetic scientist is often very different from that of the dermatologist. Where the dermatologist may look for the progression of symptoms to understand the disease process, the cosmetic scientist looks more to those habits and practices that may have contributed to the appearance of the hair. The dermatologist may look for the development of a disease leading to the current symptoms. In contrast, the cosmetic scientist will look to the hair shaft as a record of the previous treatments used by the patient. When combined, these two points of view can provide a powerful tool for the diagnosis of the many challenging symptoms presented by hair patients. It is often said that perception is reality. This is quite true for the hair patient. Their hair is constantly on display and is often perceived as a marker of either one’s health or attention to personal detail. It should be no surprise to the clinician that the patient may have a very different perception of their hair problem than the clinician does. The hair follicle is considered to be a highly proliferative unit, which produces scalp hair at approximately 0.3 mm per day. However, from the patient’s point of view hair grows slowly and seems to take forever to grow to a cosmetically acceptable standard. At 1 cm per month, it may take a year for a woman to grow even a short, acceptable style. This growth rate assumes that the shaft is always in perfect condition and that the hair is of normal density and diameter Hair is on one’s head for a very long time! While this is an obvious statement, this fact is largely overlooked by hair patients. A vast diversity of hair fi bers, growth stages, cosmetic practices, and so on are present on any head on any given day. A hair shaft of shoulder-length will have been on the head for nearly 2 years, and each fi ber will have experienced a vast range of habits and practices, care, and trauma. All of these considerations will affect the overall appearance, condition, and style of the hair, as well as how the patient feels about their hair. Therefore, a broad understanding of haircare practices is essential to form a correct diagnosis and to manage patient expectations. When investigating the fi ne details of a patient’s hair from the root in the follicle through to the tip it is important to have a broad understanding of the large variety of observations that can be made on cosmetically normal hair. Hair shafts can be on the head for a considerable time and even perfectly normal, unadulterated hair will show a remarkable degree of variability. Once changed by various chemical and physical practices, new observations will become the expected norm for that hair type and should not be mistaken as markers of pathology. It is also important to be familiar with the appropriate investigative techniques and their value in adding to a diagnosis. Simple techniques often provide the most information.

HAIR IN TIME AND SPACE The generally accepted ﬁ gures for a normal head of hair are a growth rate of 1cm per month, 10% of hairs in telogen and 100–150,000 hairs per head. While these numbers are open to debate, they serve to provide a good conceptual position for understanding a head of hair. It is McMichael PTR 01/21/08 Chapter 02

20 Gummer important to view the hair as a complex array of fi bers with different properties and behavior at different places in the array. If we were to shave a normal head and then measure the properties of the array in time and space as the hair grew back, a number of differences soon become obvious. As hair emerges from the scalp the fi bers are held apart by the spatial arrangement of the follicles in the scalp. While the fi bers are short they cannot interact with each other. The short new hairs are stiff to the touch, rather like beard stubble. Once the fi bers attain a length of 1–2 cm they begin to interact. The tips of the fi bers now have a degree of freedom to move in three dimensions. As the hair grows progressively longer, the fi ber tips gain increasing freedom and can interact with more and more fi bers. Eventually, the hair will become long enough, e.g., 20 cm, so that with styling every fi ber has the potential to interact with every other fi ber on the head (Fig. 1). Interestingly, the hair now feels soft to the touch, even though the fundamental bending and frictional properties of the fi bers have not changed. Therefore, as the hair grows longer it forms an increasingly complex array. Even the terminology for this same set of fi bers changes depending on length, from prickly or stiff to soft and tangled. Tangles cannot occur in short hair. The complexity of the array is further compounded by the forth dimension of time. As each hair grows it will be subject to the traumas of everyday life, e.g., brushing, combing, washing, etc. Consequently, the basic properties are progressively, albeit subtly, changing. Most changes are so small that it would be diffi cult to measure differences over 1 or 2 cm. However, over 10 cm, equivalent to 10 months of wear and tear, the differences in both

FIGURE 1 As hair grows longer the array becomes increasingly complex. Each hair now has the potential to interact with every other hair. McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 21 external and internal properties are quite obvious. Increased friction, changes in cutical scale structure, and reduced tensile and torsional strength are all evident. When more drastic changes are made within this period, such as perms, coloring, or relaxing, then measurable changes to the fi bers can be quite remarkable. Consequently, the overall affect on the array is much more noticeable. Understanding the hair array would be relatively simple if any change to a fi ber represented a single event of no further consequence. However, remembering that hair will stay on the head for some time, an intervention such as a perm or color will change the physico-chemical properties of that fi ber until either the fi ber is lost or the changes have grown beyond the length of the style and the hair is cut. Chemical changes, in particular, and aggressive physical changes, will change the rate at which the fi ber weathers. In turn this increases friction and, as a result, the degree of interaction between adjacent fi bers. There is, fortunately, a distinct advantage to the hair remaining on the head for so long. It offers an additional historical means of interrogating the patient’s history, either real or perceived. For example “all my hair fell out and it has taken 3 months to grow back” would be in confl ict with the presence of mid- to shoulder-length hair. While statements of “all my hair . . .” are typically an exaggeration, one would still expect to observe signifi cant numbers of hairs, complete with anagen tips, at 5 cm or less. Similarly, the hair shaft provides a unique record of cosmetic treatments. “I haven’t permed or colored my hair for over 3 months” is relatively easy to check. Most people are aware of the unsightly root growth experienced by regular hair coloring (Fig. 2). Rather than being a problem, this growth line provides a unique piece of diagnostic evidence for the last coloring event. Consideration should be given to the patient’s age as habits and practices will vary (Table 1). Permanent hair coloring under the age of 16 is unusual, whereas it dominates in the over-40 female population. Hair bleaching is common between the ages of 18 and 30, with more natural colors used as age increases. Temporary hair straightening for teenagers and women in their twenties has become a fashion essential. In ethnic circles voluminous Afro styles have given way to elegant, chemically straightened hair. And in all groups, style length progressively decreases with age. Fashion and social acceptance are powerful dicta- tors of hairstyles.

FIGURE 2 The typical “growth” line of a regular user of hair colors demonstrates both when the hair was last colored and the natural hair color. McMichael PTR 01/21/08 Chapter 02

22 Gummer

TABLE 1 Changes in Habits and Practices Reﬂ ect Age, Fashion, and Social Acceptance Age (yrs) 0–12 12–16 16–35 35–60 60+ General All haircare Hairstyles High body and Concern over Acceptable all- trends practices and change in length. image awareness; gray hair over gray styles dictated Haircare and fashion-conscious. dominates Short styles by parents or temporary Experimental Haircare regimen schools alterations under period begins designed to teenager’s Haircare regimen reﬂ ect lifestyle control ranges from ideal and hair type to poor Shorter styles with increasing age Hair color Natural color Temporary colors Fashion colors “Natural” shade Some natural, (semi / demi including permanent permanent permanents) high-lift blondes colors to shades Color chemistry = cover gray permanent, demi’s and semi’s Hairstyle Temporary Temporary Temporary and Permanent styles Permanent styles, bands, styles with high permanent styles (perms/ styles (perms/ braids, corn incidence of (perms/relaxers) relaxers) on relaxers) rows, styling heated on hair of all progressively products straighteners lengths shorter hair

COSMETIC PRACTICES AFFECTING FIBER STRUCTURE, FUNCTION, AND APPEARANCE All cosmetic practices affect the fi ber structure and function of hair and whereas all are done to benefi t the appearance of the owner, none truly benefi t the hair fi ber (1–3). In a very visual world where individuals are judged on personal appearance, it is essential for hair to look its very best. To achieve fashion and social acceptance, extreme modifi cation of the hair shaft is often required. Even typical day-to-day cosmetic regimens have a subtle, yet accepted, negative effect on hair. There is little doubt that hair that is clean, conditioned, and manageable refl ects positively on the owner. To achieve healthy-looking hair requires the use of surfactants that, over time, elute lipids and proteins from the hair. It has long been recognized that regular washing steadily elutes proteinaceous material from the endocuticle, which results in an increase in the number of holes under each cuticle cell toward the tip of the fi ber (Fig. 3). Regular grooming causes physical damage to the cuticle and hyper-extension of the cortex. However, routine shampooing and combing form an acceptable balance between small negative changes to the fi ber and large visual benefi ts to both the hairstyle and the owner. Indeed, it is only with the advent of modern shampoo and conditioner formulations that the individual can achieve the desired hair appearance for the days or years that a fi ber remains on the head. It is only when the more aggressive physical and chemical processes are conducted on the hair that the rate of damage exceeds both the durability of hair and the replacement of fi bers. Some women may even believe that they cannot grow long hair. In truth they can, by matching the cosmetic damage to the rate of growth and not exceeding the parameters. If care is not taken, the end effects are rapid hair breakage, loss of shine, tangling, and occasionally, temporary loss of hair density and length. On very rare occasions permanent scarring and hair loss can occur (Table 2).

Permanent Hair Coloring The aim of this section is to look at the changes induced in the hair ﬁ ber by coloring processes and not the detailed chemistry of hair coloring. However, a brief overview gives a greater understanding of how and why the fundamental structure of the ﬁ ber is affected. Permanent hair colors result in a change to the natural color of hair that, although subject to fading, will only be completely lost when the hair is cut or re-colored. This class of products also includes products designed to lighten, or bleach, the natural color of hair. Permanent colorants typically McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 23

FIGURE 3 Elution of the endocuticle by routine washing steadily increases toward the tip of the hair fi ber. contain three components: two for coloring and one for conditioning. To change the natural color of hair the following steps must occur: (i) remove or lighten the natural hair color, i.e., with bleach melanin, and (ii) form new colors (dye couples) within the hair cortex. To achieve the color, low pH hydrogen peroxide (developer) is mixed with high pH dyes (tint). The activated or alkaline hydrogen peroxide both bleaches melanin in the cortex and develops the new colors from the tint. In particular, blonde shades are not simply achieved by bleaching melanin and they require the formation of new dye colors to offset red and brass tones left by the incomplete degradation of melanin. As alkaline hydrogen peroxide diffuses through the fi ber it encounters transition metal ions that occur naturally in hair, as well as those acquired from the environment, e.g., copper absorbed from tap water. Rapid degradation of peroxide forms the highly damaging and nonspecifi c hydroxyl radical. A fundamental challenge to the colorant formulator is accessing and decolorizing melanin that occurs only in the cortex while minimizing damage to the rest of the fi ber. This presents two problems. First, alkaline peroxide must travel through the cuticle and will cause damage en route. Second, the path of the peroxide is not specifi c to melanin. Due to the relatively low concentration of melanin in Caucasian hair there is a greater chance that the peroxide will interact with the hair structure and damage the proteins in the cortex than that it will interact with melanin. As a result, permanent hair colors cause measurable damage to the tensile and torsional properties of the hair fi ber. Of greater importance is the effect on the hair surface. All unmodifi ed cuticle cells are covered in a covalently bound fatty acid on the outer aspect of the cell. The fatty acid 18-methyl eicosanoic acid, termed the f-layer (4), is readily cleaved by perhydrolysis, which changes the surface of the cell from hydrophobic to hydrophilic. The consequence of this change is two-fold. First, when the hair is wet the hair fi bers are held tightly together by fi lms of water. This makes the hair diffi cult to detangle. Second, many conventional silicone-based conditioners, which are typically hydrophobic in nature, fail to deposit on the hair and as a result provide little or no protection. Fortunately, the level of damage is relatively low and can be managed as is evidenced by the numerous examples of individuals with long hair who have used colorants multiple times. But it is essential for patients to understand that the hair is changed by the coloring process McMichael PTR 01/21/08 Chapter 02

24 Gummer and, while its appearance is enhanced its properties are altered. Failure of patients to increase conditioning, which will counteract these changes, will lead to rapid weathering and breakage and is often typiﬁ ed by trichorrhexis nodosa. The patient must be encouraged to reduce the frequency of coloring and the amount of styling, while greatly increasing the amount of conditioning.

High-Lift Bleaches The peroxide blonde hair color worn by Marilyn Monroe cannot be achieved with hydrogen peroxide alone. The addition of ammonium persulphate, which is usually supplied as a powder, is required to completely decolorize melanin and achieve the platinum blonde effect. This process causes damage of a much higher magnitude than conventional permanent colors and hence the degree of haircare must be suitably increased. Permanent colors and high-lift bleaches are biologically aggressive treatments that are well-tolerated by the hair when utilized properly. Problems such as hair breakage and straw- like appearance can result from a lack of understanding of how the hair is changed by these processes. A patient with shoulder-length hair will require treatments once every six to eight weeks. As a result, the ends of the ﬁ bers will have experienced signiﬁ cantly more chemical and physical insult compared to the roots.

Permanent Changes in Hair Shape Two main practices are involved in permanently changing the shape of individual fi bers, i.e., permanent waves and relaxers. While different chemistry is used by these two processes, both have a similar clinical impact on the fi ber. Permanent waves, generally used to increase curls, are based on alkaline ammonium thyo- glycollate. This reduces disulphide bonds in the cuticle and cortex and allows hydrogen peroxide to reform bonds in their new position. As covalent bonds adopt new positions, the extensive network of salt bridges and hydrogen bonds do so as well. Although the process and formulations are quite different, it should be remembered that thyoglycollates are also the bases for effective depilatories. When used for hair removal the reductive step is left to progress further and is not neutralized by hydrogen peroxide. There are a number of recorded cases of severe hair breakage following permanent waves, no doubt caused by poor control of the reductive step. Straightening or relaxing techniques are designed to remove curls. These processes use high-pH sodium or guanidine hydroxide. Those that use the latter are termed no-lye relaxers. Most relaxers are used to straighten curly hair, in which case the term relaxer is something of a misnomer. It suggests the hair is in perhaps a “less stressed” state than before! In order to straighten the hair it must also be pulled straight to form its new shape, so straight hair is not a relaxed state of a curl. Relaxers or straighteners require additional tension to pull the fi ber straight on already weak hair, and may also involve the use of hot irons resulting in hair that is particularly weak but far from relaxed. One should remember that high concentrations of sodium hydroxide are a useful tool for dissolving hair for analytical tests. Relaxers left on for too long can certainly cause widespread hair breakage close to the scalp as well as extensive scalp irritation. Both permanent waves and relaxers remove the f-layer from the fi ber and damage intercellular cements. In addition, changes in the extractable proteins and amino acid profi les are always evident. These combined effects result in fi bers that are hydrophilic, of reduced tensile and torsional strength, are prone to tangling, and show an increased rate of weathering (Table 2).

IDENTIFYING COSMETIC DAMAGE TO THE HAIR SHAFT Due to the wide variety of treatments and the fact that a cosmetic regimen takes place virtually every day, it is often difﬁ cult to ascribe changes to one particular treatment unless the event is catastrophic. Many clinicians are aware of personal injury litigation in which obvious hair changes have taken place following a major hair event such as a perm or bleach. In contrast, McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 25

TABLE 2 Changes in Hair Properties Caused by a Range of Normal Cosmetic Treatments Weathering vs. Treatment Visible hair surface Internal changes Tensile strength shampooed hair Shampoo Intact f-layer Surfactant deposition Very slight decrease No increase in Small increase in with increasing cysteic acid metal content, esp. length calcium Some protein loss Permanent F-layer removed Increased cysteic acid Reduced Cuticle weathers colors Increased cysteic Increased metal (Ca, faster but is (includes acid = more Cu) content dependent on the demi- negative charge Increased protein loss haircare regimen permanents) Increased metal Reduced cystine (Ca, Cu) content Melanin partially removed “High-lift” F-layer removed Much increased Signifi cantly Cuticle weathers bleaches Increased cysteic cysteic acid reduced much faster and usually acid = more Increased metal (Ca, lifts; dependent on persulphate- negative charge Cu) content care regimen based Increased metal Increased protein loss Straw-like appearance (Ca, Cu) content Reduced cystine Brittle ends, split Melanin removed ends, tangling Permanent F-layer removed Increased mixed Signifi cantly Cuticle weathers wave Slight increase in disulphides reduced faster and lifts but cysteic acid Increased lanthionine is dependent on Increased protein loss care regimen Reduced cystine Prone to tangles Relaxers F-layer removed Increased mixed Signifi cantly Rapid weathering (lye and Cell membranes disulphides reduced dependent on care no-lye) damaged/ Increased lanthionine regimen removed Increased protein loss Requires extreme Reduced cystine care Possible breaks mid-shaft Longitudinal splits (African hair type)

matted hair, an equally catastrophic event, may be the result of treatments conducted more than 6 months prior to the event and can result from a failure to adopt an appropriate cosmetic regimen. Unraveling a patient’s cosmetic story can be difﬁ cult. There are, however, a number of clinical markers that will point the clinician to poor cosmetic practices.

Trichorrexhis Nodosa Investigation: When numerous fi bers are affected, small white spots are easily seen on the hair with the naked eye and can be confi rmed with a hand lens. Transmitted or plane polarized light microscopy shows characteristic focal burst along the fi ber or brush breaks where the node has parted. Additional observations should be made of the apparently normal parts of the fi ber to rule out any predisposing conditions, such as pili annulati or pili torti, that may previously have gone unnoticed. While it is important to exclude any underlying pathology or metabolic changes, it is unlikely that a patient who previously had normal hair will have developed signifi cantly weaker hair. It must be remembered that where trichorrhexis nodes appear toward the tips on longer fi bers, that part of the hair was actually formed many months before the patient presented with trichorrexhis nodosa. It is, therefore, unlikely that a fundamental fi ber weakness has “grown in.” It is most probable that the trichorrehexis nodes are a result of cosmetic practices. These practices may create only minimal damage to the fi ber. However, the combination of insults and insuffi cient care may result in catastrophic fi ber damage. In order to understand McMichael PTR 01/21/08 Chapter 02

26 Gummer the severity of a patient’s cosmetic regimen it may be useful to measure the distance from the scalp to the ﬁ rst onset of trichorrhexis nodosa as an indication of how long the best part of the ﬁ ber can withstand the current level of trauma. It is probable that a chemical (permanent wave) or thermal (tongs) insult is indicated in the process. The current fashion trend for perfectly straight hair has spawned a number of treatments and straightening irons that claim to be good for the hair. The author has observed an increase in trichorrhexis nodosa among young females who are seemingly “wedded” to their straightening irons.

Bubble Hair Investigation: Routine light microscopy, or a hand lens, reveals swelling and honeycomb-like structures at the broken, distal end of the ﬁ ber (5). They are more easily observed when the hair has been immersed. Very small (~5 micron) dome-like protrusions on cuticle scales are common on normal hair, though difﬁ cult to see by light microscopy, and should not be confused with bubble hair.

“Sudden Onset” Hair Loss This is characterized by a perception of hair loss that actually results from increased hair breakage often very close to the scalp (6). The patient presents with a single episode of claimed hair loss that may affect either the whole of the scalp or one of more poorly defi ned areas. When associated with a specifi c chemical treatment, hair breakage often begins several days after the causative procedure. Traction alopecia or other hair pulling dystrophies should also be excluded. Investigation: True hair loss from the follicle rarely, if ever, occurs due to cosmetic practices. If present, then associated skin infl ammation or scarring would be expected. Close inspection of the scalp may reveal short, broken fi bers. Routine light microscopy of the shed fi bers normally shows a fracture or trichorrhexis nodosa brush break at the proximal end. The distal end can present either as damaged, or often as a clean scissor cut, particularly when a haircut has preceded a chemical treatment.

Matting or Tangling Even hair in perfect condition is prone to tangling, especially when wet. Obviously, short hair is not affected. Severe tangling or matting, which may be impossible to unravel, can occur in hair approaching shoulder length or longer and is an indication of both poor hair condition and poor handling of the hair. As seen with all chemical treatments the hair becomes more hydrophilic. Wet keratin is higher in friction. Progressive damage, subsequent to chemical treatments, makes fi bers higher in friction and rougher to the touch. Consequently the hair is more likely to tangle or mat. In extreme cases it is termed “bird’s-nest hair.” Unfortunately, there is little point in attempting to unravel the tangles as it will take an inordinate amount of time and the condition of the hair means it will be prone to further matting. The best approach is to advise on a high quality cut and counsel on the time it will take to regrow the hair. Matting that requires a patient to present to a clinician is a single catastrophic event. It will suddenly occur and may, or may not, coincide with a change in cosmetic products. Low- conditioning shampoos, while not a cause, can exacerbate the situation. However, the patient may have had some degree of pre-warning with small tangles or knots appearing at the ends of their hair during routine shampooing and grooming. These are typical in chemically damaged hair and appear to be “understood” by most consumers. Matting typically affects a single location but involves many, many adjacent fi bers and hence may have extensive involvement on the head. The site of matting is invariably at the back of the head and typically occurs during the washing or conditioning step and only when the hair is wet. The location is due primarily to the diffi culty in reaching and handling the hair when shampooing, such that the hair is piled up leading to massive fi ber-to-fi ber interactions. Investigation: Matting is always obvious to the naked eye and requires no further investigative techniques. The initial predisposing factor, e.g., chemical or thermal treatment leading to hair damage, may have occurred many months before. In and of itself it is unlikely to cause the hair to mat. However, it is possible that there is no history of such treatments as even poorly McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 27 handled normal hair will mat. The actual matting event is unlikely to be related to any particular product use.

INVESTIGATIVE TECHNIQUES FOR THE CLINICIAN There is a wide range of investigative techniques readily available to the clinician, but they should be assessed as to when and where they should be used. The principal question to ask is, “What additional value does the investigation bring to the diagnosis and treatment of the patient?” followed by, “What are the typical characteristics of this patient’s hair type?” For example, cross-sectional shape, degree of curl, color, and texture vary according to racial origin. Each patient represents a consumer group adopting typical habits and practices, all of which may be considered “normal” for that individual but will have a deﬁ nite and visible impact on the hair. An appreciation of the patient as a consumer is essential before further analysis is undertaken. This section is designed to explore the available techniques in order of “usefulness” to the clinician. An important point to remember is that nature has produced in hair a highly cross-linked protein sample that is easy to harvest in quantity. It does not require additional ﬁ xation and is easily stored and transported in plain envelopes. Although hair samples will degrade slowly in both visible and UV light, the rate of change is remarkably slow and unlikely to present a problem. When sampled, it is best kept in order with all the roots at the same end. During sampling it is easy to damage the hair as follows:

1. Crimping the fi ber (7). The use of forceps to pluck the hair can easily squash the fi ber leading to apparent fl at sides or indentations on the fi ber. Longitudinal ridges or “fl utes” are often found on normal hair, but one should always be concerned about focal indentations. 2. Stretching the fi ber when extracting the hair root. Pulling hair fi bers will cause the cuticle to “stand up” giving the impression of higher levels of damage when viewed by techniques such as scanning electron microscopy. Although this may be unavoidable, parallel, cut samples can be used to provide a truer picture of the hair surface (Fig. 4). 3. Root damage on extraction. During sampling, both the hair bulb and the proximal end of the shaft may be damaged. The bulb is often distorted and sometimes termed dystrophic. One should only consider the bulb to be dystrophic if the hair attached to the bulb is malformed. A normal hair shaft will derive from a normal bulb and should indicate that a bulb abnormality was induced during sampling. 4. Damage to the proximal shaft, still within the follicle, appears as rolled-back cuticle scales caused as the hair cuticle is pulled against the opposing inner root sheath cuticle. The speed of the pluck and the number of fi bers with attached outer root sheaths will affect the number of fi bers showing this damage. The resulting image should not be confused with loose- anagen syndrome (Fig. 5).

FIGURE 4 SEM picture of raised hair cuticle caused by over-stretching the ﬁ ber. McMichael PTR 01/21/08 Chapter 02

28 Gummer

FIGURE 5 SEM of the hair cuticle within the follicle. The soft scales are pulled past the opposing inner root sheath cuticle causing them to roll backwards. This is a common feature when the hair is plucked without the root sheaths.

Light Microscopy A number of techniques are included within the category of light microscopy.

Transmitted Light Microscopy A conventional compound microscope is suffi cient for the majority of hair work. Most observations are conducted below x40 objective magnifi cation. In order to minimize the number of samples to prepare, hair is fi rst mounted dry under large cover slips. Tape can be used to secure the cover slip at either end. Due to the thickness of the hair shaft and optical interference from the hair surface it may be diffi cult to resolve very sharp images. However, damaged fi ber ends, brush breaks, tichorrhexis nodosa, bubble hair, and changes in fi ber shape such as pili torti are all easily observed. Transmitted light microscopy in liquids is shown in Figures 6 and 7. Due to the difference in refractive index between dry hair, air, and glass, combined with the thickness of the sample it is diffi cult to see beyond the hair surface. The addition of either distilled water or immersion oil between the cover slip and slide removes most of the refractive index differences. Water is the liquid of choice, as this can be easily instilled by capillary action along the edge of a dry mount slide. Water also has little effect on the fi ber should it be required for storage or further investigation. Using a liquid provides more detail of the cortex in conditions such as bubble hair or pili annulati.

Polarized Light Microscopy This is an important tool, although it is rarely diagnostic in hair conditions. Perhaps the one exception is in the identiﬁ cation of “tiger tail” hair for conditions such as trichothiodystrophy

FIGURE 6 (See color insert.) Typical light microscope picture of the hair surface. Although the cuticle is visible, little information is gained from the inside of the ﬁ ber. McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 29

FIGURE 7 Light microscope picture of the hair immersed in water. The medulla is clearly visible. Differences in the appearance of the medulla are due to the interaction of light with spaces of different sizes. The appearance may change with the inclusion of water.

(Fig. 8). However, polarized light has one distinct use—it often shows abnormalities in different colors making them more obvious to the observer (Fig. 9). The hair fi ber cortex is naturally bi-refringent due to the longitudinal organization of the cortex. Occasionally this is obscured by multiple dichroic colors appearing on the hair surface due to surface damage. When this occurs on many fi bers one should suspect some additional cosmetic procedure, although it is not uncommon to see on the occasional fi ber in a sample.

Fluorescent Light Transmitted Microscopy This has relatively little use except for fungal infections of the hair shaft. The technique is further complicated by bleaches or colors that both change and add to the natural ﬂ uorescence of hair. Note that hair dyes are selectively ﬂ uorescent.

Refl ected Light Microscopy This can be used to confi rm conditions such as pili annulati but has limited use at higher magnifi cations. The best use of refl ected light is with the naked eye or a hand lens (loop). Overall, low-power refl ected light and routine transmitted light microscopy are the most powerful and easy-to-use investigative tools available to the clinician, although they do take time and some small skill to master.

Other Investigative Techniques The following techniques can be used and may be of particular value to forensic or investigative scientists:

FIGURE 8 (See color insert.) Polarized light micrograph of trichothiodystrophy showing a typical “tiger tail” appearance. McMichael PTR 01/21/08 Chapter 02

30 Gummer

FIGURE 9 (See color insert.) Unpolarized and polarized images of a telogen root. The polarized image reveals more information of the keratinization pattern within the telogen club root.

Tensile Strength The cosmetic industry places a great deal of emphasis hair strength, yet the goal of fi nding an ingredient that strengthens hair in a consumer-noticeable way is as yet unachieved. However, for the clinician tensile strength is of little value except to prove the obvious, i.e., that damaged hair is weaker, or to disprove a claimed patient history. It is well known that chemical treatments weaken the hair fi ber. In experienced hands the shape of the tensile stress–strain curve can give insight into how the fi ber has been treated. But for the clinician who has been told that the hair has been permed or straightened it is no surprise to fi nd a reduced tensile strength. Tensile strength measurements also require large sample numbers (~100 fi bers), diameter measurements for each fi ber, and a high degree of expertise. Hence, they are of little added value to clinicians.

Amino Acid Analysis Hair is composed of 20 to 21 amino acids. Analysis of hair requires expertise, as amino acid values may be changed by the preparation technique. The amino acid analysis method is only available at specialized institutes and universities. Although of little value as a diagnostic tool, it can be useful in litigation cases for corroborating patient histories, i.e., to prove whether excessive treatment has occurred or treatment was denied. For example, hair straightened using chemical relaxers typically shows an increase in lanthionine, an amino acid typically absent in normal hair. Similarly, cysteic acid, normally present at approx.< 0.5 mol % is increased in colored or oxidatively bleached hair. In rare cases of excessive bleaching very high levels of cysteic acid will result (Table 3). The technique has important research value to understand chemical mechanisms or hair alteration.

Scanning Electron Microscopy (SEM) This technique provides excellent pictures for publications and talks, but its use in daily practice is questionable. Virtually all clinical hair conditions can be identifi ed using light microscopy combined with an understanding of where, and how long, the hair sample has been on the head. SEM simply provides better pictures! If SEM is used for investigation it is essential to have a detailed knowledge of “normal hair,” which contains many surface irregularities that are often dependent on the racial origin of the hair, the hair length, or treatments that have been used. SEM does, however, provide insight into exactly what is happening to the surface topography of hair as it becomes damaged by different treatments or by routine weathering. For example, the progression of damage at the cuticle edge, progressing from tiny chips to larger areas of scale loss, is easily observed. Longitudinal cracking, typical in the curly hair of African descent, can be observed long before the hair breaks. And with skill, even the type of instrument used to cut the hair can be identifi ed, within reason. SEM can deliver convincing pictures that are far easier to comprehend than transmitted light micrographs. The increased depth of fi eld obtainable with the SEM makes interpretation of images far easier than with light micrographs. However, this has to be balanced against the McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 31

TABLE 3 Amino Acid Values of Normal Hair Compared with Over-Highlighted Hair Showing an Atypical Increase in Cysteic Acid and Large Decrease in Cysteine. Most Other Amino Acids Remain Unchanged Amino acid analysis (mol/100 mol) Normal hair Treated hair Cysteic acid 0.42 12.94 Aspartic acid 5.88 5.91 Threonine 7.81 7.77 Serine 11.40 10.97 Glutamic acid 13.19 13.07 Proline 7.99 7.38 Glycine 6.22 5.96 Alanine 4.95 4.89 Valine 6.10 5.73 Cysteine 10.49 2.31 Methionine 0.50 0.14 Isoleucine 3.02 2.87 Leucine 6.84 6.66 Tyrosine 2.44 1.86 Phenylalanine 1.80 1.78 Ornithine 0.03 0.03 Lysine 2.82 2.57 Histidine 0.91 0.60 Arginine 7.01 6.46 Lanthionine 0.10 time, effort, and expertise required for SEM investigations. With a detailed knowledge of hair cosmetics and the materials designed to deposit on hair, SEM can show product distribution, fi ber-to-fi ber interactions, and over-deposition and product interactions. Where patients complain of “over-deposition” or “build-up” the results can usually be found on the hair as coatings that obscure the cuticle pattern. However, by the very nature of many cosmetic products, these coatings are intentional. There are also a number of surface deposits that are not easily visible with conventional SEM techniques. For example, the very fi ne deposition of silicones from 2-in-1 shampoos or conventional conditioners is not visible. Due to the variety of cosmetic and treatment products and their means of application, the results are easily and regularly misinterpreted (Figs. 10 and 11).

Transmission Electron Microscopy (TEM) This technique is really of value only for research purposes (8,9). Hair is a difﬁ cult material to prepare for high quality TEM studies, requiring skill and technical expertise particularly in the

FIGURE 10 SEM of trichorrexhis nodosa. This striking picture provides little additional information for diagnosis compared to a general light micrograph. McMichael PTR 01/21/08 Chapter 02

32 Gummer

FIGURE 11 SEM can provide additional information on surface deposits, in this case hair sprays, but requires careful interpretation. cutting stages. Hair does not require fi xing prior to viewing by TEM except for detailed studies of cell membrane lipids with stains such as ruthenium tetroxide. All other stain methods do not require pre-fi xing; indeed, fi xation can often induce additional artifacts. TEM studies have proven to be of value in understanding the fi ne structure and organization of the hair. Similarly, they have shown the exact changes in the fi ber resulting from genetic diseases. How- ever, as with all investigations, detailed knowledge of normal hair is a prerequisite to avoiding misinterpretation.

Atomic Force Microscopy (AFM) This excellent research tool for studying surface structures is of little value to the clinician. The very high-quality images require skilled operators and interpretation. The large sample variation observed when using SEM is further ampliﬁ ed by the very small areas available to AFM (Fig. 12).

Analytical Chemistry The use of wet analytical chemistry to analyze hair has increased in recent years, especially as a tool for identifying drug abuse (10), poisoning (including date rape drugs) (11), and analysis for exposure to toxic material (12). As hair is constantly exposed to the environment, it is important that analysis is conducted by experts in the ﬁ eld as it is too easy to draw erroneous conclusions.

Surface Analysis A number of methods, including X-ray (13), TOF-SIMS (14), proton probe, and so on have been used to study hair surface chemistry with particular regard to the deposition mechanisms of various compounds. It is unlikely that these will be of value to the clinician except in speciﬁ c

FIGURE 12 Atomic force image of new hair cuticle showing distinctive ridges of unknown origin or function. McMichael PTR 01/21/08 Chapter 02

Evaluation Techniques 33 areas of research or in areas of litigation. Again, these methods require a high degree of expertise in both sample handling and interpretation. One also has to keep in mind that the sample size is typically very small and may not be indicative of the whole head.

SUMMARY Detailed knowledge of the wide variety of investigative techniques is not a prerequisite for the practicing dermatologist. However, a strong knowledge of hair biology, consumer habits, and practices combined with a simple compound microscope is essential. For any other disease process a clinician would expect quite remarkable changes over periods of 1–2 years. Yet the hair, which in some cases is on the head for an even longer period is looked at as a whole and with little regard for the myriad changes that might have occurred over that time. Care should be taken to make sure the patient’s description of the problem actually ﬁ ts with the biology and the haircare treatments. Overall, the hair presents a unique clinical record that is easily sampled, stored, and explored. With some expertise and a logical, sequential approach, it is easily read and interpreted.

REFERENCES 1. Robbins CR. Chemical and Physical Behavior of Human Hair. 4th ed. New York: Springer-Verlag, 2002. 2. Zviak C. The Science of Hair Care. NY:Informa, 1986. 3. Olsen EA. Disorders of Hair Growth, Diagnosis and Treatment. NY: McGraw-Hill Inc., 1994. 4. Breakspear S, Smith JR, Luengo G. Effect of the covalently linked fatty acid 18-MEA on the nanotribology of hair’s outermost surface. J Struct Biol 2005; 149(3):235–242. 5. Gummer CL. Bubble hair: a cosmetic abnormality caused by brief, focal heating of damp hair fi bers. BJD 1994; 131:901–903. 6. Gummer CL. Cosmetics and hair loss. Clin Exp Dermatol 2002; special issue. 7. Bentley-Philips B, Bayles MAH. A previously undescribed hereditary hair anomaly (pseudomonilethrix). Brit J Dermatol 89:159. 8. Gummer CL, Price VH, Dawber RPR. Trichothiodystrophy: an ultrastructural and electron histochemical study of the hair shaft. BJD 1984; 439–449. 9. Gummer CL, Dawber RPR. Monilethrix: an electron microscopic and electron histochemical study. BJD 1981; 105:529–541. 10. Stout PR, Ropero-Miller JD, Baylor MR, Mitchell JM. External contamination of hair with cocaine: evaluation of external cocaine contamination and development of performance-testing materials. J Anal Toxicol 2006; 30(8):490–500. 11. Negrusz A, et al. Deposition of 7-aminofl unitrazepam and fl unitrazepam in hair after a single dose of Rohypnol. J Forensic Sci 2001; 46(5):1143–1151. 12. Adams JB, Holloway CE, George F, Quig D. Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res 2006; 110(3):193–209. 13. Kempson IM, Skinner WM, Kirkbride KP. Advanced analysis of metal distributions in human hair. Environ Sci Technol 2006; 40(10): 3423–28. 14. Ruetsch SB, Kamath YK. Penetration of cationic conditioning compounds into hair fi bers: a TOF-SIMS approach. J Cosmet Sci. 2005; 56(5):323–330. McMichael PTR 01/21/08 Chapter 02 McMichael PTR 01/21/08 Chapter 03

3 Photographic Imaging in Hair Loss

Douglas Canfi eld Canfi eld Imaging Systems, Fairfi eld, New Jersey, U.S.A.

INTRODUCTION Photography has become an important tool in managing patients with hair loss (1). The ability to photographically document a patient’s condition and monitor change is especially useful in recording the subtle changes often associated with hair loss. Hair loss experts rely on various photographic methods to manage their patients, and both minoxidil and ﬁ nasteride have relied on hair imaging to support both their primary and secondary efﬁ cacy endpoints for FDA approval (2,3). Photographic methods for documenting hair loss usually include descriptors, such as non-invasive, global, semi-invasive, macro, epiluminenscence microscopy and phototrichogram.

GLOBAL PHOTOGRAPHY Global photographs of the scalp are clinically relevant because they represent an accurate record of the cosmetic state of the patient (4). Global photographic methods range from a snapshot with a point-and-shoot camera to highly standardized serial photographs taken with registration equipment. Any method requires great care to ensure that the only difference between photographic time points is the change (or lack of) in scalp coverage. Global photography requires a patient with clean, dry hair and a detail-oriented tech- nician able to take the time to comb and prepare the hair precisely the same way at each offi ce visit. If possible, the patient should be advised to maintain the same hairstyle and hair color to further control confusing variables. This is especially important in patients with curly hair, since small changes in hair length may have a dramatic effect on the perception of scalp coverage. The challenges associated with patient preparation are numerous. Oily and/or wet hair increase refl ection and also cause the hair to clump, revealing more scalp and portraying the patient as having less hair. If the hair is not recorded precisely the same way at follow-up visits, photographs will record exposure of different areas of the scalp making assessment diffi cult or even impossible. Extraneous information, such as shirt collars and distracting backgrounds, should be eliminated or masked. Backgrounds should be medium color density with blue being the most popular owing to its pleasing contrast to skin tones. Background paper is readily available and can be hung on an open wall in the exam room (behind the door is often a convenient area). Felt is also a good option since it does not crease or wrinkle as easily as paper. A drape cloth is recommended to mask shirt collars. For male pattern hair loss, four global views are usually recommended and are demonstrated in Figure 1: the vertex, top scalp, frontal, and temporal views. For the vertex view, the hair should be combed out like the spokes of a wheel; for the top scalp view, the hair should be center parted; in the frontal and temporal views, the hair should be pulled back to expose the hairline. The most valuable views for assessing male pattern hair loss are the vertex and top scalp view, and for female pattern hair loss, the top scalp view (5). Additional side and back views may be useful when assessing other hair loss conditions. Depending on the coarseness, length, and style of the hair, combing can be quite a challenge, and the time required to comb the hair, especially the center part for the top scalp view, can be extensive. When photographing patients with alopecia areata, the use of hair clips can help expose the areas of scalp involvement. McMichael PTR 01/21/08 Chapter 03

36 Canﬁ eld

FIGURE 1 (Left to right) Vertex view, hair combed away like the spokes of a wheel. Top scalp view, hair carefully center parted. Frontal view, hair combed back to reveal hairline. Temporal view, hair combed away to expose hair line.

CAMERA AND LIGHTING CONTROL Variability in lighting is one of the most criticized aspects when comparing before-and-after photos. Angle and distance of the light source to the patient must be optimized and fi xed. The most popular cameras in clinical practice are point-and-shoot cameras, which typically have an integrated fl ash and zoom lens. While this is not an ideal scenario there are several variables that can become fi xed for your hair photos:

Note the location of the point fl ash on your camera and choose whether to hold the camera vertically or horizontally based on the direction you want the fl ash to rake over the scalp. Choose a zoom setting in advance and match the fi eld size between visits. This will help to keep the fl ash at the same distance from the subject. Or connect the camera to a computer and use software to control all of the camera settings while capturing images directly into a patient’s chart. An advantage of using some of the more advanced software is that, at follow-up visits, you can retrieve the patient’s baseline image and ghost it over a live preview ensuring that the patient is oriented in the exact same position.

To improve the quality of your global photographs consider using a professional lighting system. Using more than one fl ash and diffusing the light will allow for better visualization of the hair and a more cosmetically appealing image. Exposure control is critical when taking dermatologic photographs. Even slightly overexposed photos will capture less detail, and fi ner hairs will not be recorded. Slightly underexposed photos can create the perception of less scalp, and thus more hair. For those interested in having more control and superior quality images, an SLR body and lens is still required. While most of the better point-and-shoot cameras have the same resolution as the sensors in a professional SLR camera, the overall size of the SLR sensor is larger allowing for larger pixels and a better quality image. The key advantage of the SLR is the ability to mount a high quality lens. Today there are two main manufacturers of lens, Nikon and Canon. Reproduction ratios can be adjusted from 1:1 to infi nity simply by rotating the focusing ring on the lens. Good serial photography requires standardization of magnifi cation, which can be accomplished by selecting the reproduction ratio and/or distance setting shown on the macro lens. Medical photographer Bill Slue has written about the “three views method,” an approach in which the photographer selects from three standardized magnifi cations to photo document any dermatologic case (often using a combination of a close-up and overview photo). Once a suitable reproduction ratio is selected, focusing is accomplished not by the traditional method of rotating the focus ring (or auto focusing), but rather by adjusting the distance between the subject and the camera. This method of focusing by distance is referred to as body focusing (6). The key advantage of body focusing over autofocus is that McMichael PTR 01/21/08 Chapter 03

Photographic Imaging of Hair Loss 37 the magniﬁ cation will be consistent in before-and-after photos. On today’s cameras the f-stop of the lens is indicated and controlled from the camera. Using either manual or aperture priority and actually setting the f-stop will allow the maximum depth of ﬁ eld to be achieved. The actual f-stop will depend on the lighting, actual distance, and the relative sensitivity (ISO) but will typically be between f11 and f16. The capability of controlling an SLR camera from a computer alleviates potential errors and, with image management software, reduces the amount of time handling the images.

CAMERA-TO-PATIENT REGISTRATION The medical photographer should always maximize the amount of clinical information recorded on the image. The global photographs shown were taken by framing the head vertically and using the highest magnifi cation possible while still obtaining a global view. When framing the head for serial photography you need to develop a consistent method for patient positioning. One aid is a stereotactic head device which precisely positions the patient in a head support while the camera is mounted on a rotating arm that can move around the patient’s head. Figure 2 illustrates the camera in a mid position to capture the top scalp. Note that stereotactic equipment was developed for the exacting needs of clinical trials and may not be practical for most clinical practices. Using a tripod or IntelliStudio™ as shown in Figure 3 (Canfi eld Imaging Systems, Fairfi eld, NJ) may be more practical because of the added versatility. Having the patient seated on an adjustable stool on casters will help in aligning the patient. The vertex photo can be taken by having the patient’s back to the camera and instructing the patient to look at the ceiling. By adjusting where the patient is looking, you can adjust the angle to maximize the vertex scalp to the camera. While keeping the lens parallel to the fl oor, one moves toward or away from the patient until focus is achieved and then the picture is taken. The patient is then asked to look at the photographer and, after center parting the hair, asked to tip the head down to look at the fl oor. An alignment is again obtained and the focusing steps are repeated before the photo is taken.

FIGURE 2 Stereotactic head device precisely positions the patient in a head support while the camera is mounted to a rotating arm. The chin support rotates into a 45-degree position for the temporal hairline view. McMichael PTR 01/21/08 Chapter 03

38 Canﬁ eld

FIGURE 3 A portable photographic studio with three calibrated and color balanced ﬂ ash units that move vertically with the camera mount to ensure studio-quality lighting.

At follow-up it is very important to have the baseline images viewable either as reference prints or on screen so exact angles can be matched.

COMPUTER-ASSISTED HAIR MEASUREMENTS While there have been reports of analyzing the area of the hair part width or vertex pattern from global photographs, most computer-assisted hair measurements are made from highly magnifi ed images of the scalp. Macrophotography coupled with computer analysis offers a quantitative method for understanding the dynamics of hair (7–10). There are several considerations when preparing the target site for photography. The fi rst decision should be around which metrics you are interested in capturing. Hair count, width, and color can be made with a single visit using a single image. Anagen/telogen ratios (referred to as a phototrichogram) and growth rate can be calculated by having the patient return 1–3 days after the fi rst photo and measuring the anagen hairs (hairs which have grown). In Cauca- sian patients with light color hair, the application of hair dye on the target site will aid visualization (lash and eyebrow dye is preferred). Use of hair dye in patients with darker skin types is of no benefi t. Selecting an appropriate target site is critical when trying to understand the current physiological state of the hair loss condition. Most clinical trials have relied on the selection of a representative target site in a transitional area with active thinning. If you are planning on following the patient over time, placing a permanent dot tattoo to identify the exact same area at follow-up may be necessary. Recording measurements from the nose and ears may be useful in fi nding the dot tattoo at follow-up but are not adequate on their own to accurately identify the same area. While clipping of the target area to ~1 mm in length is not necessarily required, it is currently the most common method (clipping to ¼ mm may be required if you are capturing anagen/telogen ratios or growth rate 1–3 days later). The size of the target area is another consideration. The bigger the better from a statistical perspective, but your patient might not agree. Currently, most clinical studies have used a 1 cm2 circular area with a dot tattoo placed in the center to allow for relocation of the same target site at follow-up visits. McMichael PTR 01/21/08 Chapter 03

Photographic Imaging of Hair Loss 39

FIGURE 4 Epiluminescence microscopy image being captured using a Nikon D80 and Canﬁ eld EpiFlash. The camera is tethered to the computer, allowing for complete camera control, analysis, and image management.

Epiluminescence microscopy (ELM) is the current choice for capturing macro photographs for analysis. The combination of a coupling fl uid (clear hair gel works well) and the fact that the hairs in the target site are forced fl at against the scalp by the contact plate allow for more accurate width and length measurements. Several systems are available including lower resolution video based systems, point-and-shoot cameras and SLRs. If a point-and-shoot camera with an ELM attachment is used, a consistent zoom setting needs to be maintained. The advantages of the SLR for macrophotography are the same as for global photography discussed above. Figure 4 demonstrates a Nikon D80, 60mm micro-Nikkor lens extended to 1:1 with a Canfi eld EpiFlash . There are several software systems available for detecting and analyzing scalp hair (11– 13). Considerations include reliability of measurement, types of measurement, ease of use, and ultimately cost. For clinical studies, the system used must also be validated and conform to the requirements of regulatory authorities. Current measurements include hair count and width from a single visit, and anagen/telogen ratios and growth rate if the patient returns two days later. In addition, width measurements allow for categorization of hairs as vellus/ vellus-like, small, medium, and large terminal hair (14). By capturing and storing individual hair length and width measurements, any threshold can be selected and reported.

SUMMARY Photography is an important tool in the management of patients with hair loss. By having and following a basic photographic protocol, reproducible high quality images can be obtained that can be used for both qualitative and quantitative analysis.

REFERENCES 1. Canﬁ eld D. Photographic documentation of hair growth in androgenetic alopecia. Dermatol Clin 1996; 14:2713–2721. 2. Kaufman KD, Olsen EA, Whiting D, et al. Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol 1998; 39:578–588. McMichael PTR 01/21/08 Chapter 03

40 Canﬁ eld

3. Kaufman K, Binkowitz B, Savin R, Canfi eld D. Reproducibility of global photographic assessments of patients with male pattern baldness in a clinical trial with fi nasteride[poster]. 56th Annual Meeting of of the Society for Investigative Dermatology. J Invest Dermatol 1995; 104:659. 4. Chamberlain AJ, Dawber PR. Methods of evaluating hair growth. Australasian Journal of Dermatology, 2003; 44:10–18. 5. Olsen EA. The Midline Part: An important physical clue to the clinical diagnosis of androgenetic alopecia in women. J Am Acad Dermatol 1999; 40:106–109. 6. Slue WE, Paglialunga A, Neville J, et al. Better dermatologic photography: getting started. Cutis, 1994; 54:177–178 7. Courtois M, Loussouarn G, Hourseau C, Grollier JF. Ageing and hair cycles. British Journal of Dermatology 1995; 132:86–93. 8. Van Neste D. Assessment of hair loss: clinical relevance of hair growth evaluation methods. Clinical and Experimental Dermatology, 2002; 27:358–365. 9. Van Neste D, V Fuh, P.Sanchez-Pedreno, E.Lopez-Bran, et al. Finasteride increases anagen hair in men with androgenetic alopecia. British Journal of Dermatology, 2000; 143:804–810. 10. Van Neste D. Contrast enhanced phototrichogram (CE-PTG): an improved non-invasive technique for measurement of scalp hair dynamics in androgentic alopecia- validation study with histology after transverse sectioning of scalp biopsies. European Journal of Dermatology 2001; 11:326–331. 11. Hoffman R. Trichoscan: A novel tool for the analysis of hair growth in vivo. Journal of Investigative Dermatology Symposium Proceedings 2003; 8:109–115. 12. Kohut B, Wanser R, Reardon R, Canfi eld W, Canfi eld D. A Methodology Study Comparing Traditional 35mm Hair Counts to Automated Image Analysis Measurements, and Assessing Visualization Sensitivity of Hair Dyeing when Quantifying Hair Loss in Men and Women with Androgenetic Alopecia [poster]. European Hair Research Society, 2005; July 7–9. 13. Harness JA, Kohut B, Garner J, Canfi eld W, Canfi eld D, Bertolino A. Evaluation of Hair Count and Thickness Measurements in Male and Female Pattern Hair Loss Using a Computer-Assisted Technique [poster]. European Hair Research Society, 2005; July 7–9. 14. Whiting DA, Canfi eld D, Canfi eld W, Jingirian A. Quantifying Progression or Reversal of Follicular Miniaturization in Androgentic Alopecia by Image Analysis in Drug Studies [poster].Tri-continental Meeting of Hair Research Societies, 2001; June. McMichael PTR 01/21/08 Chapter 04

4 Hair Follicle Anatomy in Human Scalp Biopsies

David A. Whiting Department of Dermatology and Pediatrics, University of Texas Southwestern Medical Center, Baylor Hair Research and Treatment Center, Dallas, Texas, U.S.A. Lady C. Dy Department of Dermatology, Rush University Medical Center, Chicago, Illinois, U.S.A.

INTRODUCTION Knowledge of hair follicle anatomy was amassed by European histologists in the nineteenth and early twentieth centuries. Initial studies were limited to gross and light microscopic examination of the hair follicle. Further progress was made later in the twentieth century through sci- entiﬁ c research involving molecular biology. This led to profound new insight into mechanisms of hair growth. Gross and microscopic hair follicular analyses were primarily performed on white populations. Later, studies of the hair structure of people of different ethnic backgrounds such as Asians, blacks, and Hispanics ensued (1,2). A basic understanding of the differences in the physical, morphologic and histologic hair properties of the different ethnic groups is important in the assessment, diagnosis, and management of patients with hair loss. In addition, a working knowledge of the microscopic anatomy of the normal hair follicle in both vertical and horizontal sections is vital in the understanding of hair follicle disease, leading to accurate interpretation of scalp hair biopsies.

HAIR GROSS STRUCTURE To date, there are no biochemical differences seen in the hair of various ethnic groups but some structural differences are noted (3). Microscopic cross-sectional views of an Asian hair shaft reveal a round or oval shape, dark pigmentation, and a wide diameter. Black hair is elliptical, almost ﬂ at, tape-like in shape, and pigmented, and demonstrates a curved hair follicular bulb when viewed in a vertical section. The curvature of the black hair shaft is programmed from the follicular bulb (Fig. 1) (4). White hair is structurally between that of Asian and black hair. It is less elliptical and smaller in diameter than black hair (Fig. 2) (5). Hispanic hair has a structure comparable with white hair, in the authors’ experience. There are approximately 5 million hair follicles on the body and around 100,000 to 150,000 scalp hairs present on a normal scalp. The scalp possesses the greatest density of follicles ranging from 118–350 hair follicles/cm2 (6). Caucasians possess the highest density followed by blacks; Asians have the lowest density (7). There are two types of hair present on the scalp after lanugo hairs are shed. Terminal hairs are large with a diameter exceeding 0.03 mm and 1 cm in length, are often pigmented and medullated. Terminal hairs can be graded by hair shaft diameter as small (0.031–0.06 mm), medium (0.061–0.09 mm), or large (greater than 0.091 mm). Terminal hairs miniaturized to vellus hair proportions are described as vellus-like hairs such as seen in alopecia areata or androgenetic alopecia. Terminal hairs are rooted in subcutaneous tissue or the deep dermis, while vellus hairs are rooted in the upper dermis. A normal scalp averages seven terminal hairs per vellus hair. Vellus hairs are small with a diameter less than 0.03 mm, are often less than 1 cm in length, and lack melanin and medulla (8). True vellus hairs have thin, external root sheaths and short stelae in the upper dermis. Vellus-like miniaturized hairs have thicker external root sheaths and long stelae extending into lower dermis or subcutaneous fat (6). Follicular stelae, in the upper dermis only, indicate vellus hairs. Follicular stelae in the lower dermis indicate terminal, catagen, or telogen hairs or miniaturized vellus-like hairs (Figs. 3 and 4). McMichael PTR 01/21/08 Chapter 04

42 Whiting and Dy

FIGURE 1 Vertical section of scalp biopsy demonstrating curved hair follicle from an African-American female. FOLLICULAR MORPHOGENESIS Hair structure development starts after 8 weeks of fetal life. It begins with the appearance of placodes in the epidermal basal layer. Specialized mesenchymal cells organize in a small condensate directly beneath the basement membrane, stimulating the overlying epithelial stem cells to invaginate and penetrate into the dermis forming an epidermal peg (9,10). The epidermal peg continues to grow downward enclosing the dermal condensate forming the dermal papilla. The tip of the epidermal peg becomes the matrix portion of the hair bulb. Cells of the follicular matrix terminally differentiate into inner root sheath and the hair shaft that exits from the surface of the skin. Initial hair population is complete by 22 weeks. Fine lanugo hair develops in an advancing wave from the frontal to occipital scalp and it is shed by 36 weeks. A second coat of lanugo hair appears and it is shed in a synchronized wave pattern at 3 to 4 months of life. The bare occipital patch often seen in infants is usually physi-

FIGURE 2 (See color insert.) Horizontal scalp biopsy, upper sections. (Left) Asian hair with round to oval terminal hair shaft with heavy melanin pigmentation. (Center) Black hair with ﬂ attened terminal hair shaft with heavy melanin pigmentation. (Right) White hair with oval to round terminal hair shafts with mild melanin pigmentation. McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 43

FIGURE 3 (Left) Vellus hair, vertical section, upper and mid dermis. One vellus hair follicle is rooted in papillary dermis below a dilated infundibulum. One vellus-like hair follicle is rooted in upper dermis, but is attached to an underlying streamer (stela) extending down to reticular dermis, implying miniaturization of a terminal hair follicle. The third follicle shows a terminal hair in telogen at the level of insertion of the arrector pili muscle, the so-called “bulge” area where stem cells are found (elastin stain, 100x). (Right) Vellus hair, vertical section: Three vellus hairs are projecting into one follicular infundibulum (hematoxylin and eosin stain, 200x). ological, resulting from synchronized shedding of the ﬁ nal wave of lanugo telogen hairs prior to their replacement by normal scalp hairs (1). The maximum number of scalp hair follicles during the human life span is present at birth. Thus hair follicle density is greatest in neonates and lessens progressively during childhood and adolescence, due to expansion of cranium and scalp.

NORMAL HAIR GROWTH CYCLE During the prenatal period, hair follicular cycling is synchronized but postnatally is replaced by a mosaic pattern of asynchronous cycling where each hair follicle grows independently of one another. There are approximately 100,000 to 150,000 scalp hairs present on a normal scalp.

FIGURE 4 (Left) Vellus hair, horizontal section. The central vellus hair shaft has a diameter equal to the thickness of its investing inner root sheath. Its outer root sheath is fairly thin at two to three cell layers. It represents a true vellus hair (hematoxylin and eosin stain, 400x). (Right) Vellus hair, horizontal section. The diameter of the central hair shaft is slightly larger that the thickness of its inner root sheath. The outer root sheath is fairly thick at three to ﬁ ve cell layers. This suggests that it is a vellus-like hair, presumably a miniaturized terminal hair (hematoxylin and eosin stain, 400x). McMichael PTR 01/21/08 Chapter 04

44 Whiting and Dy

To produce new hairs, existing hair follicles undergo periods of growth (anagen), regression (catagen), and rest (telogen) (11–13). Between 90% and 95% of scalp hairs are in the growing phase. The variation in hair length is proportional to duration of the anagen depending on the body site. The anagen growth phase of scalp hair lasts one to seven years. Scalp hair grows an average of 1 cm per month. Therefore, scalp hairs can grow 12 to 84 cm in length. In contrast, eyebrow hairs remain in anagen for 8–12 weeks, leg hairs for 19–26 weeks, arm hairs for 6–12 weeks, and upper lip hairs for 4–14 weeks and produce short hairs (11). Studies on hair growth parameters indicated that scalp hair on blacks grows slower than on whites and Asians (14). However, the rate of hair growth is variable in ethnic groups as hair growth is not only dependent on genetic inﬂ uences but also on body site, climate, age, and nutritional, hormonal, and other factors. At the end of anagen, the follicle enters the intermediate or catagen phase, which is marked by programmed cell death or apoptosis and lasts approximately 2 weeks. In catagen, the hair shaft and inner root sheath retreat upward while the outer root sheath undergoes cell death, and the hyaline membrane thickens and folds as it compacts upward. The lower follicle disappears leaving an angioﬁ brotic strand or streamer (stela) indicating the former position of the anagen root. The ensuing telogen phase lasts an average of three months before a new anagen hair develops. In telogen, the resting club root is situated at the “bulge” level, where the arrector pili muscle inserts into the hair follicle (15). The telogen bulb lacks pigment and inner root sheath. The telogen hair is shed during washing and grooming referred to as “exogen phase.” This occurs in either late telogen or early anagen. It is unclear whether this event requires molecular signaling or mechanical stimulus to dislodge the telogen club hair (16). Since there are approximately 5% to 10% of scalp hairs in the resting phase, as many as 100 hairs per day may be lost. Eventually the next anagen cycle begins and the cycle is repeated.

BIOPSY OF HUMAN SCALP Scalp biopsy is a useful tool in the evaluation of hair disorders. It provides an objective way of assessing hair follicles. The biopsy should be taken from an area of active alopecia. Local anesthesia with lidocaine and epinephrine is suggested subject to patient hypersensitivity. A dis- posable 4 mm biopsy punch is used. The biopsy is angled in the direction of emerging hair follicles and should extend deep into subcutaneous tissue. Two biopsies are needed for adequate vertical and horizontal sectioning (6). One biopsy is bisected vertically parallel to the direction of the hair. Both halves are mounted in the block with cut surface downward, or one half is kept for additional studies such as immunoﬂ uoresence techniques (Fig. 5). Three successive sections should be taken initially, more if needed (6). The other 4-mm punch biopsy is bisected horizontally exactly parallel to the epidermis, 0.5 to 1 mm below the dermoepidermal junction. Both portions are mounted together in the block with cut surfaces downward. Sectioning progresses down toward the subcutaneous tissue in one half and up toward the epidermis in the other. Horizontal sections of scalp biopsies provide an accurate method for counting, typing, and sizing hair follicles (17).

Horizontal versus Vertical Sections In the past, vertical sections of scalp biopsies have provided the traditional view of hair follicles. Most anatomical and histopathological features of hair follicles have been described using the vertical histologic sectioning technique. The concept of horizontal sectioning was introduced by Headington in 1984 and an increasing number of dermatopathologists are now interpreting horizontal sections (8). Horizontal sections generally demonstrate 20 to 30 follicles compared to the traditional four to six hair follicles seen in vertical sections (Figs. 6 and 7). The horizontal sectioning technique readily allows quantiﬁ cation and assessment of the follicle density, follicle diameter, and the proportion of follicles in various stages of the hair cycle, i.e., anagen-telogen percentages. This technique also demonstrates normal ethnic variation in follicle size and density (7). Although some argue that horizontal sections are unnecessary in the interpretation of scalp McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 45

(A)

(B)

FIGURE 5 Diagram and method used for cutting and embedding scalp biopsies. (A) Vertical sectioning technique: Specimen is bisected in the direction of hairs pointing upward. Both halves of the specimens are mounted on a block with cut surfaces facing downward. (B) Horizontal sectioning technique: Specimen is bisected horizontally parallel to epidermis, 0.5–1 mm below the dermoepidermal junction and mounted together on a block, cut surfaces downward.

FIGURE 6 (Left) Vertical section. Upper and mid-dermis with ﬁ ve terminal hairs and two vellus hairs (hematoxylin and eosin stain, 40x). (Right) Horizontal section. Upper dermis at the sebaceous gland level. Thirty-seven hair follicles are seen (hematoxylin and eosin stain, 40x). McMichael PTR 01/21/08 Chapter 04

46 Whiting and Dy

FIGURE 7 (Left) Vertical section. Lower and mid dermis––terminal follicles and bulbs (hematoxylin and eosin stain, 40x). (Right) Horizontal section. Lower dermis and subcutaneous fat––terminal follicles and bulbs (hematoxylin and eosin stain, 40x). biopsies, in recent times horizontal sections have shown advantages over vertical sections in the diagnosis of speciﬁ c hair disorders (18). However, a combination of both vertical and horizontal sections is recommended to maximize diagnostic yield (19). A thorough knowledge of the follicular anatomy in both planes is essential to obtain maximum information from scalp biopsies.

Hair Count in Scalp Biopsy There were numerous studies describing the physical differences in various ethnic hair groups, but comparison of histologic parameters among ethnic groups has only been elicited in the last decade (17,20–22). The data on the normal control histologic parameters were gathered primarily from the white male population (3,20,22). Subsequently the data for normal controls of scalp biopsy specimens were reported on male blacks and Asians (Koreans) (7,21). The average total hair count (vellus and terminal hairs) taken from a 4-mm punch biopsy specimen that is horizontally sectioned is somewhat different among the three ethnic groups (Table 1). Asians have the lowest hair density followed by blacks then Caucasians, who have the highest hair density, as shown by studies from Sperling and Whiting (7,20,22). Slightly higher hair follicular counts were observed in females of all ethnic groups (Fig. 8) (7,20). Familiarity with the differences in qualitative and quantitative information provided by the plane of the scalp biopsy specimen is important in the successful interpretation of horizontal sections.

HAIR FOLLICLE MICROSCOPIC ANATOMY Microscopically, the terminal hair follicles can be viewed from vertical and horizontal planes of sections. The terminal hair follicle penetrates deep into the dermis extending into the subcutaneous tissue. In the vertical plane of section the terminal hair follicle consists of a permanent upper segment of follicular infundibulum and isthmus, and an impermanent lower segment of the hair follicle consisting of the lower follicle and root (bulb) (Fig. 9). The horizontal cross- sectional view of the hair follicle starting from the outermost to the innermost compartment

TABLE 1 Comparison of Average Hair Counts in Asians, Blacks, and Whites Average total hair Average total Average total Ethnicity count terminal hairs vellus hairs Asian 16.1 +/− 3.6 14.9 +/− 3.2 1.1 +/− 1.3 Black 21.5 +/− 5.0 18.4 +/− 5.0 3.0 +/− 2.1 White Studies performed by Whiting (20, 22) 40 +/− 2.2 35 +/− 2.1 5.0 +/− 0.6 Studies performed by Sperling (7) 35.5 +/− 5.5 30.4 +/− 6.4 5.1 +/− 3.1 McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 47

FIGURE 8 Horizontal section demonstrating hair counts from three ethnic groups. (Left) Asian hair: 28 terminal hairs and 5 vellus hairs. (Center) Black hair: 30 terminal hairs and 3 vellus hairs. (Right) White hair: 37 terminal hairs and 3 vellus hairs. includes the dermal sheath hyaline membrane, outer root sheath, inner root sheath, cuticle, hair shaft cortex, and hair shaft medulla (Figs. 9 and 13).

Infundibulum The infundibulum opens from the epidermal surface and ends at the entry of the sebaceous duct into the hair follicle. The infundibulum is lined with a keratinized skin surface epithelium that contains a granular layer and basket weave keratin (Fig. 10). Hence proliferation of the infundibulum gives rise to the epidermoid inclusion cyst (folliculo-infundibular cyst). The hair shaft is contained within the infundibulum and has no attachment to the isthmus or the infundibulum, allowing freedom of movement.

Isthmus The isthmus extends down from the opening of the sebaceous duct and ends at the “bulge” where the arrector pili muscle inserts into the follicle. It is lined by the trichilemmal keratin that is characterized by an eosinophilic compact keratin material, devoid of a granular layer. The inner root sheath crumbles and disappears in the mid-isthmus of the upper follicle (Fig. 11). There it is replaced by trichilemmal keratin formed by the outer root sheath or trichilemma. Proliferation of

FIGURE 9 Terminal anagen hair. The hair follicle consists of infundibulum that ends at the sebaceous duct, an isthmus ending at the insertion of the arrector pili muscle, and lower follicle and hair root (bulb). Source: From Ref. 6. McMichael PTR 01/21/08 Chapter 04

48 Whiting and Dy

FIGURE 10 (Left) Infundibulum, vertical section. The dilating follicular opening is surrounded by external root sheath lined by skin surface epidermis with granular layer and basket weave keratin (hematoxylin and eosin stain, 200x). (Right) Infundibulum, horizontal section. External root sheath is lined with skin surface epidermis with a granular layer (hematoxylin and eosin stain, 400x). the trichilemmal keratin leads to formation of a pilar cyst (folliculo-isthmic cyst). Trichilemmal keratin lines the upper isthmus extending to the level of entry of the sebaceous duct at the base of the infundibulum (Fig. 12) (6). The bulge area is located in the inferior portion of the isthmus near the insertion of the arrector pili muscle. The bulge contains stem cells that are slow cycling and when activated gives rise to transit amplifying cells that can differentiate into hair follicle (15). The bulge structure is difﬁ cult to identify in the adult human follicle.

Hair Bulb The follicular root consists of the hair bulb, which is found in the deepest portion of the hair follicle and surrounds the dermal papilla (Figs. 13 and 14). The bulb contains undifferentiated, actively dividing hair matrix cells that extend to the widest diameter of the hair bulb known as the critical line of Auber. Melanocytes are usually present at the apex of the dermal papilla. Hair matrix cells in this vicinity give rise to hair medullary cells. Hair matrix cells around this central area produce elongated cortical cells, which stream upward to form the developing hair shaft. Higher up in the keratogenous zone, these cells become compacted into hard keratin. The outer fringe of matrix cells forms the hair cuticle and the surrounding inner root sheath. The hair cuticle invests the hair ﬁ ber with six to ten overlapping layers of cuticle cells. Cuticle cells

FIGURE 11 (Left) Midisthmus, vertical section: Grayish inner root sheath is crumbling and disappearing (hematoxylin and eosin stain, original magniﬁ cation 200x). (Center) Midisthmus, horizontal section: Gray staining inner root sheath is crumbling and being replaced by red staining trichilemmal keratin from outer root sheath (trichilemma) (hematoxylin and eosin stain, original magniﬁ cation 400x). (Right) Midisthmus, horizontal section: Vanishing inner root sheath. McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 49

FIGURE 12 (Left) Upper isthmus, vertical section: Follicle lined by outer root sheath and trichilemmal keratin, with some residual disintegrating grayish inner root sheath in lower part of section (hematoxylin and eosin stain, original magnifi cation 200x). (Right) Upper isthmus, horizontal section: The outer root sheath or trichilemma is lined by trichilemmal keratin (hematoxylin and eosin stain, original magnifi cation 400x). keratinize and project outward and forward to interlock with the inwardly projecting cuticle cells of the inner root sheath (6). The dermal papilla enveloped by the hair matrix cells contains fi broblasts, collagen bundles, fi bronectin, glycosaminoglycans, and small blood vessels. It is continuous with the dermal sheath, which surrounds the hair follicle. The volume of the dermal papilla cells dictates the size of the hair shaft and induces formation of hair follicle (24).

FIGURE 13 The hair bulb is surrounded by the dermal sheath, which is continuous with the dermal papilla, and the hyaline membrane beneath it, which joins the epidermal basement membrane around the dermal papilla. Next is the outer root sheath, followed by the inner root sheath comprising Henle’s layer, Huxley’s layer and the cuticle of the inner root sheath. The central developing hair shaft is largely comprised of hair cortex invested by its cuticle and surrounding the medulla. Source: From Ref. 6. McMichael PTR 01/21/08 Chapter 04

50 Whiting and Dy

FIGURE 14 (Left) Lower bulb, vertical section: Dermal papilla enclosed by hair matrix cells, surrounded by dermal sheath (hematoxylin and eosin stain, original magniﬁ cation 40x). (Right) Lower bulb, horizontal section: Dermal papilla with papillary cells and connective tissue invested by hair matrix cells surrounded by the dermal sheath (hematoxylin and eosin stain, original magniﬁ cation 40x).

Outer Root Sheath The outer root sheath, or trichilemma, has no granular layer and is glycogen rich, accounting for the pale cytoplasm. It appears at the base of the bulb as a thin lining becoming thicker as it extends upward to the level of the isthmus where it shows trichilemmal keratinization (Figs. 15 and 16). The outer root sheath is covered by the hyaline or vitreous membrane, which is continuous with epidermal basement membrane surrounding the dermal papilla. Folds or corrugations of the hyaline membrane are sometimes seen projecting into the underlying trichilemmal layer. The hyaline membrane is surrounded by the ﬁ brous dermal sheath of the hair follicle, which is continuous with the dermal papilla at the base of the hair bulb.

Inner Root Sheath The inner root sheath starts from mid-isthmus extending to the base of the bulb. It comprises three layers: The innermost layer forms the cuticle of the inner root sheath comprising overlapping elongated cells, which slant downward; the middle layer of Huxley, which is composed

FIGURE 15 Vertical sections: Outer hair root sheath shown as thin pale cells present at the level of the hair bulb (center). It expands and thickens as it continues upward (left) and is replaced at the level of the isthmus where it shows trichilemmel keratinization (right). McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 51

FIGURE 16 Horizontal sections: Outer hair root sheath showing varying thickness of the concentric layers. of three to four layers of cuboidal cells; and the outer layer of Henle, which is composed of a single layer of elongated cells. Henle’s layer keratinizes ﬁ rst with the appearance of trichohyaline granules near the hair bulb, forming a distinct pinkish keratinized band higher up from the bulb (Fig. 17). The cuticle of the inner root sheath is the next to keratinize, synchronizing with keratinization of the cuticle of the hair shaft (Fig. 18). Finally, trichohyaline granules appear in Huxley’s layer, signaling impending keratinization (Fig. 19). Keratinization of the inner root sheath is completed halfway up the lower follicle. The keratinized inner root sheath occupies the upper half of the lower follicle (Fig. 20). The inner root sheath is surrounded by one or more layers of cells of the outer root sheath or trichilemma. The potential space between inner and outer root sheaths is named the companion layer and it allows the inner root sheath to slide upward over the outer root sheath during hair growth.

Hair Shaft The hair shaft consists of the cuticle, cortex, and medulla (present in terminal hairs) (Fig. 21). The hair ﬁ ber cortex is cylindrical and consists of keratin ﬁ laments embedded in a sulfur-rich matrix, enclosing the medulla and surrounded by the cuticle of the hair shaft. It also contains

FIGURE 17 (Left) Upper bulb, vertical section: The developing proximal hair shaft shows an emerging central medullary cavity, surrounded by developing cortex, invested by inner and outer root sheaths and the dermal sheath. Henle’s layer, the outermost of the three layers of the inner root sheath, is beginning to keratinize (hematoxylin and eosin stain, original magnifi cation 200x). (Right) Upper bulb, horizontal section: The central developing hair fi ber is surrounded by inner and outer root sheaths and dermal sheath, with commencing keratinization of Henle’s layer, the outermost layer of the inner root sheath (hematoxylin and eosin stain, original magnifi cation 200x). McMichael PTR 01/21/08 Chapter 04

52 Whiting and Dy

FIGURE 18 (Left) Suprabulbar lower follicle, vertical section: Keratinization occurs in the cuticle of the inner root sheath and in the cuticle of the hair shaft (hematoxylin and eosin stain, original magnifi cation 200x). (Right) Suprabulbar lower follicle, horizontal section: The cuticle of the central hair shaft and the cuticle of the inner root sheath are both keratinized (hematoxylin and eosin stain, original magnifi cation 400x). melanin pigment. The hair shaft is generated by transit amplifying matrix cells in the hair bulb, which surround the dermal papilla. The hair fi ber diameter remains uniform during a single growth phase under normal conditions. Cortical fi bers are responsible for the mechanical properties of hair. The hair shaft cuticle is one cell layer thick and binds cortical fi bers together. Hair shaft and inner root sheath cuticles interlock to stabilize the growing hair and to ensure that the inner root sheath and hair shaft grow upward together. A comparative electron microscopic analysis of the cuticular structures of Asian and white hair revealed Asian hair has more cuticlar layers that are thicker and more densely packed than white hair. This may account for susceptibility of white hair to damage during daily grooming (23).

FIGURE 19 (Left) Intermediate lower follicle, vertical section: Keratinization of Huxley’s layer is seen in the lower portion of this section, leading to a fully keratinized inner root sheath higher up (hematoxylin and eosin stain, original magniﬁ cation 200x). (Right) Intermediate lower follicle, horizontal section: Impending keratinization of Huxley’s layer in central layer of inner root sheath is signaled by the red stained keratohyaline granules (hematoxylin and eosin stain, original magniﬁ cation 400x). McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 53

FIGURE 20 (Left) Upper half, lower follicle, vertical section: Hair shaft and inner and outer root sheaths are fully keratinized (hematoxylin and eosin stain, original magniﬁ cation 200x). (Right) Upper half, lower follicle, horizontal section: Hair shaft and inner and outer (trichilemmal) sheaths are fully keratinized (hematoxylin and eosin stain, original magniﬁ cation 400x).

Follicular Units Horizontal sections at the sebaceous duct level show follicular units. Follicular units are roughly hexagonal in shape and are surrounded by a loose network of collagen; they contain several terminal and vellus follicles with sebaceous ducts and glands and arector pili muscles (Figs. 22 and 23) (8). In adults, the mean area of a follicular unit is 1 mm2; thus 12 to 14 follicular units are usually found in a horizontal section of a 4 mm punch biopsy, which has an actual area of 12.57 mm2.

Terminal Anagen Hair Anagen involves the complete regrowth or regeneration of the lower, cycling portion of the follicle. Anagen hair formation begins with the activation of a cluster of epithelial cells present at the outer root sheath keratinocytes of a telogen hair follicle called secondary hair germ (telogen germinal unit), which gives rise to the matrical cells. An exchange of molecular signals causes the secondary germ along with the dermal papilla to migrate downward into the dermis. The

FIGURE 21 (See color insert.) Horizontal section, isthmus level: Terminal hair shaft follicle from innermost to the outermost: the medulla, cortex containing melanin pigment, and cuticle. McMichael PTR 01/21/08 Chapter 04

54 Whiting and Dy

FIGURE 22 Follicular units, horizontal section at upper isthmus level: Somewhat hexagonal packets of terminal and vellus hair, sebaceous glands and ducts and arrector pili muscles enclosed in loose collagen are seen. These represent follicular grouping at the skin surface (hematoxylin and eosin stain, original magniﬁ cation 40x).

FIGURE 23 Terminal anagen hair follicle rooted deep in the subcutaneous tissue. McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 55 dermal papilla signals the matrical cells to actively proliferate and grow in an upward direction differentiating into the internal root sheath and hair shaft. The volume of the dermal papilla dictates the size of the hair shaft (24). The terminal anagen hair follicle penetrates deep into the dermis extending into the subcutaneous tissue.

Terminal Catagen Hair When anagen ends, hair goes into catagen, the intermediate transition stage between growth and rest, for 10 to 14 days. The catagen stage heralds the involution of the hair follicle. This process involves regression of the lower cycling portion of the hair follicle via apoptosis. The catagen stage begins with the lower hair follicle and the dermal papilla retracting upward, leaving behind a collapsed perifollicluar sheath which forms into an angioﬁ brotic streamer or stela, linking the follicle to the site of the former anagen bulb. The hair shaft and inner root sheath slide upward together inside the outer root sheath, leaving an elongated mass of trichilemmal outer root sheath below. Apoptosis of trichilemmal cells produces a marked shrinkage of the outer root sheath. Thickening and wrinkling of the surrounding hyaline layer occurs with this shrinkage of trichilemma (Figs. 24 and 25). As the hair shaft retreats further upward, its base becomes club shaped and is surrounded by a pocket of trichilemmal keratin, with the dermal papilla beneath (8). Failure of the dermal papilla to reach the hair follicle “bulge” during catagen stage will lead to cessation of follicular cycling as seen in patients with congenital papular atrichia. These patients carry a mutation in the hairless gene or vitamin D receptor gene, resulting in permanent disconnection of the dermal papilla from the hair bulge, leading to hair loss (25). In horizontal sections, the catagen hair is generally round or oval and is surrounded by a thickened hyaline membrane, often concertinaed by compression from the ascending hair bulb. The catagen hair usually contains apoptotic cells, which stain reddish with hematoxylin and eosin.

FIGURE 24 (Left) Terminal catagen hair, vertical section: The underlying streamer indicates that this terminal hair rooted in subcutaneous fat is retreating up the follicle. The level of this section shows only a shrinking outer root sheath (trichilemma) which is surrounded by a thickened hyaline membrane, indicating catagen (hematoxylin and eosin stain, original magniﬁ cation 200x). (Right) Terminal catagen hair, horizontal section: The hair shaft and inner root sheath have ascended above the level of this section, which shows central trichilemmal shrinkage, surrounded by a thickened, convoluted hyaline membrane, indicating catagen (hematoxylin and eosin stain, original magniﬁ cation 400x). McMichael PTR 01/21/08 Chapter 04

56 Whiting and Dy

FIGURE 25 (Left) Terminal catagen hair, vertical section: A shrinking trichilemma, with central single-cell apoptosis, with surrounding thickening of the hyaline membrane, indicates a catagen follicle (hematoxylin and eosin stain, original magnifi cation 400x). (Right) Terminal catagen hair, horizontal section: A shrunken trichilemma, below the level of the hair shaft and inner root sheath above it, shows individual cell apoptosis, and is surrounded by a well- defi ned hyaline membrane and compensatory thickening of the dermal sheath (hematoxylin and eosin stain, original magnifi cation 400x).

Terminal Telogen Hair After catagen, the hair follicle enters telogen, where the hair follicle matures into a club hair. The hair follicle retracts to the level of the “bulge” at the site of insertion of the arector pili muscle into the follicle (Fig. 26). Here the resting hair comprises a telogen germinal unit situated below the telogen club. The telogen germinal unit consists of trichilemma, which is somewhat convoluted and surrounded by palisading basaloid cells. The telogen germinal unit has a characteristic appearance and shows no obvious apoptosis (Fig. 27) (7). A telogen club comprises a central mass of trichilemmal keratin, star-shaped in horizontal section, surrounded by trichilemmal and ﬁ brous sheaths, connecting telogen germinal units and hair shafts (Fig. 28). The rec- ognition of terminal, anagen, catagen and telogen hairs is only possible from the examination of the lower follicle below the “bulge” level for the presence of inner root sheath, apoptosis, or trichilemmal club, respectively. In the upper follicle, only a keratinized hair shaft can be seen with no internal root sheath, so discrimination between anagen, catagen, or telogen hairs is not possible at this level. After 2 to 4 months of telogen, the telogen germinal cells envelops the dermal papilla and grows down the existing follicular tract or stela to form an anagen hair (Fig. 28). Subsequent hair cycling will continue throughout life for as long as the hair follicle is viable.

CONCLUSION The primary function of each hair follicle is to produce the shaft. The hair shaft can vary in size, shape, curl, and color. A certain proportion of the hair follicles undergo growth, regression, and rest, continuously and independently. This process involves orchestration of a complex yet delicate interplay of molecular signals. Disruption of the signaling process can lead to hair loss. Scalp biopsy can provide an objective way of assessing the hair follicles. A thorough knowledge of the gross and microscopic follicular anatomy in vertical and horizontal sections is essential for the accurate interpretation of the biopsy, leading to the successful evaluation of the patient with hair disorder. McMichael PTR 01/21/08 Chapter 04

Hair Follicle Anatomy in Human Scalp Biopsies 57

FIGURE 26 The central panel in vertical section shows the resting telogen hair below the point where the clubbed hair shaft root is situated. Source: From Ref. 6.

FIGURE 27 (See color insert.) (Left) Telogen germinal unit, vertical section: Basaloid cell islands with palisaded borders below the upwardly retreating follicle indicate telogen germinal unit (hematoxylin and eosin stain, original magnifi cation 100x). (Middle and right) Telogen germinal unit, horizontal section: Different confi gurations of telogen germinal units are shown here (hematoxylin and eosin stain, original magnifi cation 100x).

FIGURE 28 (Left) Telogen club hairs, vertical section: A central telogen hair is seen, retracted to the top of the lower follicle, with root surrounded by red-staining trichilemmal keratin (hematoxylin and eosin stain, original magnifi cation 40x). (Center) Telogen hair club, horizontal section: Central trichilemmal keratin in a telogen hair club is shown here (hematoxylin and eosin stain, original magnifi cation 400x). (Right) Follicular streamer, stela, or angiofi brotic tract, horizontal section: The angiofi brotic nature of the structure indicates its viability for hair cycling up and down its pathway. Note that total fi brosis without a vascular supply indicates cicatricial alopecia and a lack of ability for further cycling. McMichael PTR 01/21/08 Chapter 04

58 Whiting and Dy

REFERENCES 1. Rook A, Dawber R. Diseases of the Hair and Scalp, 2nd ed. Oxford: Blackwell Scientifi c, 1982; 52–56. 2. Menkart, J, Wolfram, LJ and Mao, I. Hair, Negro Hair and Wool: Similarities and Differences. J Soc of Cosm Chem 1966; 17:769–787. 3. Rook A. Racial and other genetic variations in hair form. BrJ Dermatol, 1975, 92:599–600. 4. Bernard B. Hair shape of curly hair. J Am Acad of Dermatol 2003; 48(6):S120–S126. 5. McMichael, AJ. Ethnic hair update: past and present. J Am Acad of Dermatol 2003; 48(supplement 6):127–133. 6. Whiting DA. The Structure of the Human Hair Follicle: Light Microscopy of Vertical and Horizontal Sections of Scalp Biopsies. Fairfi eld, New Jersey: Canfi eld Publishing, 2004; 1–31. 7. Sperling L. Hair density in African Americans. Arch Dermatol 1999; 135(6):656–658. 8. Headington JT. Transverse microscopic anatomy of the human scalp: a basis for morphometric approach to disorders of the hair follicle. Arch Dermatol 1984; 120:449–456. 9. Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol 2002; 118(2):216–225. 10. Cotsarelis G, Millar SE, Chan EF. Embryology and anatomy of the hair follicle. in Olsen EA (Ed): Disorders of Hair Growth, Diagnosis and Treatment, Second edition. New York, McGraw-Hill 2003; 1–21. 11. Kligman AM. The human hair cycle. J Invest Dermatol 1959; 33:307–316. 12. Stenn KS, Nixon AJ, Jahoda CAB, McKay IA, Paus R. Controversies in experimental dermatology. What controls hair cycling? Exp Dermatol 1999; 8:229–236. 13. Stenn KS, Paus R: Controls of hair follicle cycling. Physiol Rev 2001; 81:449–494. 14. Loussouarn, G, Rawadi, C., and Genaian, G. Diversity of hair growth profi les. Int J Dermatol 2005; 44(Suppl 1):6–9. 15. Cotsarelis G, Sun T, Lavker RM. Label-retaining cells reside in the “bulge” area of pilosebaceous unit: implications for follicular stem cells, hair cycle and skin carcinogenesis. Cell 1990; 61:1329–1337. 16. Chuong, CM. Molecular Biology of Skin Appendage Morphogenesis. Austin, TX: Landes Bioscience Publication, 1998. 17. Whiting DA: Scalp biopsy as a diagnostic and prognostic tool in androgenetic alopecia. Dermatol Ther 1998; 8:24–33. 18. Elston DM, Ferringer, T, Dalton MAJ S et al. A comparison of vertical versus transverse sections in the evaluation of alopecia biopsy specimens. J Amer Acad of Dermatol 2005; 53:2:267–272. 19. Elston, DM, McCullough, M, Angeloni, Maj V. Vertical and Transverse sections of alopecia biopsy specimens: Combining the two to maximize diagnostic yield. J Amer Acad Dermatol 1995; 32:3:454–457. 20. Whiting DA. Chronic telogen effl uvium. J Am Acad Dermatol 1996; 35:899–906. 21. Lee, H J., Ha S J., Kim, J W. et al; Hair counts from scalp biopsy specimens in Asians. J Amer Acad Dermatol 2002; 46;2:218–2214. 22. Whiting DA. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia. Journal of American Academy of Dermatology 1993, 28:755–763. 23. Takahashi T, Hayashi M, Okamoto M et al. Morphology and properties of Asian and Caucasian hair J Cosm Sic 2006; 57:327–338. 24. Elliott K, Stephenson TJ, Messenger AG. Difference is hair follicle dermal papilla volume are due to extracellular matrix volume and cell number: implications for the control of hair follicle size and androgen responses. J Inv Dermatol 1999; 113:873–877. 25. Miller J, Djabali K, Chen T et al. Atrichia caused by mutations in the Vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J Inv Dermatol 2001; 117:612–617. McMichael PTR 01/21/08 Chapter 05

5 Nonmedicated Grooming Products and Beauty Treatments

Zoe Diana Draelos Dermatology Consulting Services, High Point, North Carolina, U.S.A.

INTRODUCTION An understanding of hair cosmetics is valuable when diagnosing and treating hair diseases. Hair cosmetics can be helpful in camouﬂ aging hair loss by optimizing the appearance of existing hair; however, hair cosmetics may also be the cause of hair loss when improperly used or used to excess. The primary goal of this chapter is to help the reader understand how shampoos and conditioners can be incorporated into a treatment algorithm for patients undergoing hair disease treatment. The secondary goal of this chapter is to understand hair loss precipitated by hair coloring, permanent waving, and hair straightening. While these procedures can beautify the hair or appeal to fashion concerns, they can also permanently damage the hair protein and produce premature hair breakage and loss. Haircare is important because damage to the non- living ﬁ ber is permanent until replaced by new growth, which is a time-consuming activity. The prevention of damage in the patient with thinning hair becomes paramount.

SHAMPOOS Our ﬁ rst topic of discussion is the most basic activity of cleansing the hair with a soap developed for the unique needs of the hair, known as a shampoo. Shampoo is designed to remove sebum, eccrine sweat, apocrine sweat, fungal elements, desquamated corneocytes, styling products, and environmental dirt from the scalp and hair (1). Cleansing the hair is actually a complex task, since the average woman has 4 to 8 square meters of hair surface area to clean (2). It is very easy to formulate a shampoo that will remove dirt, but hair that has had all the sebum removed is dull in appearance, coarse to the touch, subject to static electricity, and more difﬁ cult to style (3). Thus, the goal of a shampoo is to maintain scalp hygiene while beautify- ing the hair. A shampoo that has high detergent properties can remove the outer cuticle of the hair shaft rendering it frizzy and dull, while a well-designed conditioning shampoo can impart shine and improve manageability. Proper shampoo selection can be the difference between attractive and unattractive hair. Our discussion thus turns to shampoo formulation.

Shampoo Formulation Shampoos cleanse by utilizing synthetic detergents, also known as surfactants, which are amphiphilic. This means that the detergent molecule possesses both lipophilic, or oil-attracting, and hydrophilic, or water-attracting, sites. The lipophilic site binds to sebum and oil-soluble dirt while the hydrophilic site binds to water allowing removal of the sebum with water rinsing (4). There are four basic categories of shampoo detergents: anionics, cationics, amphoterics, and nonionics (5). Usually, a shampoo is a combination of two to four detergents with various abilities to remove sebum, produce foam, and condition the hair. Creating the perfect balance between hygiene and beautiﬁ cation is the goal of a successful shampoo. Anionic detergents are the most popular cleanser in general purpose shampoos and are named for their negatively charged hydrophilic polar group. Anionic detergents are adept at removing sebum from the scalp, but leave the hair harsh, rough, subject to static electricity, dull, and difﬁ cult to detangle. Common anionic detergents include the lauryl sulfates, laureth sulfates, sarcosines, and sulfosuccinates. The second most popular detergents are the amphoterics, which contain both an anionic and a cationic group. This allows them to behave as cationic McMichael PTR 01/21/08 Chapter 05

60 Draelos detergents at low pH and as anionic detergents at high pH. Within the amphoteric detergent category, there are several subgroups, which include the betaines, sultaines, and imidazo- linium derivatives. Amphoteric detergents such as cocamidopropyl betaine and sodium lau- raminopropionate are found in baby shampoos. These detergents actually numb the tissues of the eyes, which accounts for the non-stinging characteristics of baby shampoo. Amphoteric detergents are also used in shampoos for ﬁ ne and chemically treated hair because they foam moderately well while leaving the hair manageable. The main distinguishing characteristic between a bar cleanser and a shampoo is the addition of a sequestering agent. Sequestering agents function to chelate magnesium and calcium ions thereby preventing the formation of insoluble soaps, known as scum. Without sequestering agents, shampoos would leave a ﬁ lm on the hair, making it appear dull.

Shampoo Diversity Even though all shampoos employ the same basic ingredients, the number of formulations on the market is diverse. This is because there are many different cleansing needs and hair types (Table 1). Shampoos designed for so-called normal hair thoroughly cleanse the scalp in persons with moderate sebum production and are best for chemically untreated hair. These shampoos are popular among men and use lauryl sulfate as the primary detergent, which provides good sebum removal and minimal conditioning. This is in contrast to dry-hair shampoos that provide mild cleansing and excellent conditioning. These products are excellent for mature hair, frequent use, and chemically treated hair since they reduce static electricity and increase manageability. A relatively new shampoo category is the conditioning shampoo, also known as the 2-in-1 shampoo, which cleans and conditions simultaneously (6,7). Detergents used in conditioning shampoos are generally amphoterics and anionics of the sulfosuccinate type, previously discussed. These products are designed for patients with chemically damaged hair or those who prefer to shampoo frequently (8). Hydrolyzed animal protein is one of the ingredients added to conditioning shampoos, since it can minimally penetrate the hair shaft temporarily plugging surface defects, resulting in hair with a smoother feel and more shine. The protein can also temporarily mend split ends. Dimethicone is the other common conditioning shampoo ingredient prized for its ability to create a thin ﬁ lm over the hair shaft increasing shine and manageability. For persons with abundant sebum production, oily-hair shampoos are formulated with excellent cleansing and minimal conditioning properties. These shampoos may use lauryl sulfate or sulfosuccinate detergents and are intended for adolescents or persons with extremely dirty hair. Products with this much detergency can be drying to the hair shaft if used daily in the absence of abundant sebum production. The last major shampoo category contains products speciﬁ cally designed for ethnic populations with tightly kinked hair. These shampoos are known as conditioning shampoos, since they are formulated with both cleaning and conditioning agents, such as wheat germ oil, steart- rimonium hydrolyzed animal protein, lanolin derivatives, or dimethicone. Ethnic shampoos remove sebum from the hair shaft and replace it with a layer of oily conditioner to decrease kinky-hair combing friction (9). These shampoos are a variant of the 2-in-1 shampoos discussed earlier, since their main goal is to increase manageability and add shine. These shampoos are typically used weekly or once every two weeks. Many times an ethnic shampoo is used in conjunction with a conditioner, our next topic of discussion.

TABLE 1 Hair Shampoo Diversity Shampoo type Cleansing beneﬁ ts Conditioning beneﬁ ts Oily hair Maximal Minimal Dry hair Minimal Maximal Baby Minimal, but does not sting eyes due to anesthetic effect Minimal Fine hair Moderate Minimal Chemically treated hair Minimal Maximal Kinky hair Moderate Maximal 2-in-1 Moderate Maximal McMichael PTR 01/21/08 Chapter 05

Nonmedicated Grooming Products and Beauty Treatments 61

CONDITIONERS The need for hair conditioners arose following technological developments in shampoo formulation that allowed superior cleansing of the hair shaft. Frequent shampooing with excessive sebum removal created the need for a synthetic sebum-like substance able to minimize static electricity, increase hair shine, improve hair manageability, and aid in hair styling (10). Thus, hair conditioners were developed to mimic the positive attributes of sebum while avoiding the greasy appearance indicative of dirty hair (Table 2). Conditioners do not damage the hair shaft and can provide protective qualities against heat, combing friction, and trauma. Conditioners are liquids, creams, pastes, or gels that function like sebum, making the hair manageable, glossy, and soft. Conditioners also attempt to recondition hair that has been damaged by chemical or mechanical trauma (11). Common sources of cosmetic trauma include excessive brushing, hot blow-drying, permanent hair waves, hair straightening, and hair bleaching. Damage to the hair shaft can also occur through environmental factors such as exposure to sunlight, air pollution, wind, seawater, and chlorinated swimming pool water (12). This type of hair damage is technically known as “weathering” (13). The conditioner effect is temporary, lasting only until it is removed with shampooing, and it requires reapplication. The primary goal of a hair conditioner is to improve manageability by decreasing static electricity. Static electricity is generated following combing or brushing as the hair shafts become negatively charged. These negatively charged shafts repel one another, preventing the hair from remaining in the desired style. Conditioners deposit positively charged ions on the hair shaft and neutralize the electrical charge and minimize frizzy hair. Conditioners also improve hair manageability by decreasing friction between hair shafts through a smoother cuticle surface. This is accomplished by fi lling in the gaps around and between the cuticular scales. A quality hair conditioner can reduce friction between hair shafts by as much as 50% (14). This reduction in friction also aids disentangling of the hair following shampooing. Other hair conditioner benefi ts include improved hair shine (15). Hair shine is due to hair shaft light refl ection (16–18). The smoother the hair surface, the more light is refl ected (19). Con- ditioners increase hair gloss primarily by increasing adherence of the cuticular scale to the hair shaft. The conditioner can also coat each individual hair shaft with a shiny material, which also increases light refl ection (20). Thus, shiny hair, which is equated with healthy hair, is a combination of the physical structure of the hair shaft and surface-modifying conditioning ingredients. The fi nal role of conditioners is to temporarily mend split ends. Split ends, medically known as trichooptilosis, occur when the cuticle has been removed from the hair shaft and the soft keratin cortex and medulla are exposed to weathering and grooming trauma. The proteins of these structures are unable to withstand the damage and split or fray, much like a damaged textile fi ber (21). Conditioners temporarily reapproximate the frayed remnants of remaining medulla and cortex until subsequent shampooing. This prevents a frizzy appearance to the distal hair shaft and minimizes hair breakage. Many years ago there was concern that conditioners could create a fi lm on the hair shafts that was poorly removed with shampoo. The appearance of this over-conditioned hair was

TABLE 2 Role of Hair Conditioners Hair conditioner benefi t Effect on hair Mechanism of action Decreased static electricity Prevents fl y-away hair Neutralizes negative charge on hair shafts Increased hair shine Creates the appearance of healthy Coats the individual hair shafts with hair a light refl ective material Decreased intershaft hair friction Decreases the ability of the hair to Sticks the loosened cuticular scale tangle to the hair shafts Increased hair manageability Improves the ability of the hair to Fills in surface defects in the hair remain in a desired hairstyle shafts to minimize static electricity Increased hair softness Improves the tactile characteristics Smoothes loosened cuticular scale of the hair shafts to create an even hair surface Temporarily mends split ends Improves the appearance of frayed Sticks the exposed cortex and medulla distal hair shafts together to temporarily mend the protein split McMichael PTR 01/21/08 Chapter 05

62 Draelos labeled “the greasies” by the popular advertising media and represented limp, hard-to-style hair due to waxes and thick oils that were incompletely removed with traditional shampoos. Indeed this condition can still occur with insufﬁ cient shampooing, however the introduction of silicones into hair conditioners to replace waxes and oils has remedied the situation.

Conditioner Formulation Conditioners are available for many different hair types and needs. Typically, a variety of different hair-modifying ingredients are combined to yield the ﬁ nal characteristics of the conditioner. The most common conditioning agents and their functions are listed in Table 3 and include quaternaries, ﬁ lm-formers, proteins, and silicones (22).

Quaternary Conditioners The quaternary conditioning agents, also known as quaternaries or quaternary ammonium compounds or quats, are cationic detergents as discussed previously under hair shampoo detergents (23). These ingredients are found in both conditioning shampoos and hair conditioners (24). They function to neutralize the negative charge found on the hair shafts thus minimizing static electricity (25). It is the attraction of the positively charged conditioner to the negatively charged hair shafts that allows quat conditioners to resist water rinsing (26). This allows the conditioning agent to remain behind on the hair shafts until subsequent shampooing, providing long-lasting hair beautiﬁ cation.

Film-forming Conditioners The second category of conditioning agents is known as fi lm-formers. These function by coating the hair with a thin polymer layer (27). Film-formers contain some of the new lightweight polymers, such as polyvinylpyrrolidone (PVP), and smooth down the cuticular scale to create a smooth, light-refl ective surface (28). This improves hair luster by fi lling in the protein voids within the hair shafts and reduces static electricity by neutralizing any charges present on the hair shafts. Film-forming conditioners are traditionally used following towel drying of the hair and are sometimes incorporated into conditioning hair styling agents.

Protein-Containing Conditioners The third conditioner category is proteins (29). As the cuticular scale is lost through hair damage from combing, brushing, styling, and chemical processing, the hair loses its structural strength. These areas of the hair shaft devoid of the cuticle create sites for deposition of conditioner protein, which is hydrolyzed to a molecular weight 1000 to 10,000 Daltons (30). Voids may also be present in the cuticle due to hair dyeing, which disrupts the cuticle through exposure to hydrogen peroxide and/or ammonia, or hair permanent waving, which disrupts the cuticle due to ammonium thioglycolate exposure. The small molecular weight proteins can penetrate the hair shaft through these voids and increase hair fracture strength by 10%. This strength increase is temporary, however, as

TABLE 3 Hair Conditioner Categories Hair conditioner category Primary ingredient Main advantage Hair grooming beneﬁ t Cationic detergent Quaternary ammonium Smooth cuticle, Excellent to restore compounds decrease static damaged, chemically electricity processed hair Film-former Polymers Fill hair shaft defects, Improve the appearance decrease static electricity, of dry hair, improve improve shine grooming of coarse, kinky hair Protein-containing Hydrolyzed proteins Penetrate hair shaft to Temporarily mend split minimally increase ends strength Silicones Dimethicone, Thin coating placed on hair Decrease static electricity, cyclomethicone, shafts decrease combing amodimethicone friction, add shine Source: From Ref. 73. McMichael PTR 01/21/08 Chapter 05

Nonmedicated Grooming Products and Beauty Treatments 63 the proteins diffuse out with subsequent shampooing. Additional protein-containing conditioner use will replace the proteins, temporarily improving hair strength. The proteins may be derived from animal collagen, keratin, placenta, or egg. The source of the protein is not as important as the size of the protein particle and its ability to enter and remain inside the hair shaft (31,32). The ability of protein-containing conditioners to strengthen the hair shaft depends on contact time. The longer the protein conditioner is left in contact with the hair shaft, the more protein that will diffuse into the shaft. Thus, proteins are used in short-contact instant conditioners applied following shampooing and rinsed for minimal protein penetration and in leave-on conditioners applied prior to shampooing and left on the hair for 30 minutes prior to removal for greater protein penetration. The amount of protein that penetrates the hair shaft determines the ﬁ nal cosmetic appearance of the conditioned hair and its breaking strength characteristics. Reapplication is necessary with each water contact to maintain the effect.

Silicone Conditioners The last major category of conditioning agents is silicone. Silicones have virtually revolution- ized hair conditioning, both from the standpoint of conditioning shampoos and instant hair conditioners (33). Topical silicone is an amazingly safe material from a dermatologic perspective, since it is hypoallergenic, noncomedogenic, and nonacnegenic. Silicone originates from silica, which is found in sand, quartz, and granite. It derives its chemical properties from the alternating silica and oxygen bonds, known as siloxane bonds, which are exceedingly strong (34). The silicone used in topical preparations is an odorless, colorless, nontoxic liquid. Silicone is immiscible and insoluble in water. For this reason it is used in hair conditioners, since it will place a thin ﬁ lm over the hair shaft that resists water rinsing. The most common form of silicone used in hair conditioners is dimethicone, which improves hair manageability by reducing static electricity, minimizes tangles by decreasing friction, and imparts shine by smoothing roughened cuticular scale (35–37). Since silicone can form a thin, nongreasy ﬁ lm on the hair shaft, it does not create the limp appearance characteristic of other hair-conditioning ingredients. Topical silicone is very safe as there have been no reports of problems arising from its use in shampoos, conditioners, moisturizers, or facial cosmetics.

Conditioner Diversity Hair conditioners are available in several types, depending on their intended function and when in the grooming process they are applied (38–40). The major types of hair conditioners are summarized in Table 4, consisting of instant conditioners, deep conditioners, leave-in conditioners, and hair rinses.

Instant Conditioners Instant conditioners are aptly named, since they are applied directly from the bottle to the hair once it has been shampooed and rinsed. They are left in contact with the hair brieﬂ y for 1–5 minutes and then thoroughly rinsed. Due to their short contact time, they provide minimal conditioning and must be used after each shampooing to achieve the desired effect. The need for instant hair conditioners arose after hair shampoo detergents were developed with excellent sebum-removing capabilities. In addition, many of the currently popular hairstyles require frequent shampooing to remove styling gels, mousses, waxes, and sprays. Thus, the hair must be shampooed daily with a strong detergent leaving the hair unmanageable. Instant condition-

TABLE 4 Hair Conditioner Product Type Type Use Indication Instant Apply following shampoo, rinse Minimally damaged hair, aids wet combing Deep Apply 20–30 minutes, shampoo, rinse Chemically damaged hair Leave-in Apply to towel-dried hair, style Prevent hair dryer damage, aids in combing and styling Rinse Apply following shampoo, rinse Aids in disentangling if creamy rinse, remove soap residue if clear rinse Source: From Ref. 73. McMichael PTR 01/21/08 Chapter 05

64 Draelos ers are used by persons who shampoo frequently and who have hair damaged by permanent waving or dyeing chemical processes. Instant conditioners are the most popular type of hair conditioner for both home and salon use, even though they have limited ability to repair damaged hair. They contain water, conditioning agents, lipids, and thickeners. The conditioning agent usually consists of cationic detergent, known as quats.

Deep Conditioners Deep conditioners are generally creams or oils, in contrast to instant conditioners that are generally lotions, designed to remain on the hair for 20–30 minutes prior to shampoo removal. They usually contain higher concentrations of quaternary and protein-containing conditioning agents (41). Deep conditioners for African-American individuals with kinky hair may consist of warm oil applied to the hair shaft. The goal of a deep conditioner is to allow the conditioning agent to more thoroughly coat and penetrate the hair shaft to improve its cosmetic appearance (42). Sometimes heat is used to enhance penetration in the form of a hair dryer or warm towel to cause hair shaft swelling, which allows increased conditioner penetration. These products are intended for extremely damaged hair.

Leave-in Conditioners Leave-in conditioners are applied following towel drying of the hair and are designed to remain on the hair shaft to aid in styling. They are removed with the next shampooing. A large category of leave-in conditioners, known as blow-drying lotions, are designed to coat the hair shaft and protect the hair protein from heat damage during the drying process. The most popular leave-in hair conditioners are designed for persons with curly or kinky hair. These products lubricate and moisturize the hair shaft while aiding in styling. For example, oil sheen sprays and oily pomades help retain water within chemically straightened hair shafts and decrease the combing friction between hair shafts thereby preventing hair breakage. For persons with fi ne, straight hair, the oily leave-in conditioner would render the hair limp and hard to style, but for persons with coarse kinky hair, the oils improve manageability and impart shine. These products typically contain petrolatum, mineral oil, vegetable oils, and silicone and function as a true hair moisturizer. Leave-in conditioners can create a fi lm over the hair shaft that may be diffi cult to remove with shampooing. For individuals with tightly kinked hair, this is advantageous because it allows more frequent shampooing with less hair damage. Certainly for persons with fi ne, straight hair, this conditioner build-up would create the appearance of greasy, unclean hair. It is important to remember that the main purpose of a shampoo is to clean the scalp, not the hair. The amount and type of leave-in conditioner applied depends on degree of curl present in the hair shaft, tightly curled kinky hair requires more conditioning than straight hair.

Hair Rinses Hair rinses are a special category of hair conditioners designed as thin liquids applied like an instant hair conditioner after shampooing and rinsed. They utilize cationic quaternary ammonium compounds, such as stearalkonium chloride and benzalkonium chloride. These products are mainly used to facilitate hair detangling by reducing friction and do little else to condition the hair shaft. They are intended for persons with oily hair who need little conditioning due to abundant sebum production.

HAIR COLORING To this point we have discussed products designed to meet the basic hygiene and grooming needs of the hair, however, modern haircare also involves the use of chemicals designed to change the appearance of the hair. Modern chemical processes can change the color of the hair, either lighter or darker than the natural color, and the conﬁ guration of the hair, making straight hair curly or kinky hair straight. These processes inherently damage the hair shaft, which may precipitate hair breakage. Our discussion begins with hair-coloring techniques (43). McMichael PTR 01/21/08 Chapter 05

Nonmedicated Grooming Products and Beauty Treatments 65

Several different hair dye cosmetics have been developed for use on all different hair types: gradual, temporary, semipermanent, and permanent (Table 5). Approximately 65% of hair-dye purchases are for permanent hair colorings, 20% for semipermanent colorings, and 15% for the remaining types.

Gradual Dyes Gradual hair dyes, also known as metallic or progressive hair dyes, require repeated application to result in gradual darkening of the hair shaft. These products will change the hair color from gray to yellow-brown to black over a period of weeks (44). There is no control over the ﬁ nal color of the hair, only the depth of color. The hair can only be darkened and not lightened with this technique. The most commonly used gradual hair dyes employ water-soluble lead salts, which are deposited on the hair shaft in the form of oxides, suboxides, and sulﬁ des (45). The lead is in an inert form, thus gradual hair dyes pose no threat of lead poisoning. This type of hair coloring is most popular among men who wish to blend their gray hair gradually over time with the surrounding darker hairs. Continued use is necessary to maintain the hair color. Gradual dyes cannot be combined with permanent waving or other hair-coloring techniques. The presence of the lead salts on the hair shaft creates unpredictable results if further chemical processing is undertaken (46). After prolonged use, gradual hair colorings may weaken the hair shaft and precipitate hair breakage.

Temporary Dyes Temporary hair coloring is aptly named since the color is removed in one shampooing (47). These hair dyes are used to add a slight tint, brighten a natural shade, or improve an existing dyed shade. The dye particle size is too large to penetrate through the cuticle, thus the dye only coats the hair shaft accounting for the temporary effect (48). Temporary hair dyes do not damage the hair shaft and are easily removed with moisture from rain or perspiration. These

TABLE 5 Types of Hair Dye Chemical Anticipated end Hair dye type reaction result Duration of effect Advantages Disadvantages Gradual Deposition of Gradual brown Requires continuous Inexpensive, easy Cannot be metal salts hair darkening application to apply combined with other chemical hair processing Temporary Acid textile dyes Blending of hair One shampoo Short-lived, May rub off on tones exposure inexpensive clothing or run with water exposure Semipermanent, Henna with metal Reddish hues to 4–6 shampoo Low incidence of Leaves hair vegetable salts hair exposures allergenicity somewhat harsh Semipermanent, Textile dyes Tone hair, 4–6 shampoo Add color Short-lived color textile minimally exposures highlights cover gray Demipermanent Deeper penetra- Tone hair, 10–12 shampoo Longer lasting Cannot completely ting textile minimally exposures with no obvious cover gray dyes cover gray hair grow-out Permanent Oxidation/ Darken hair color, Permanent Excellent coverage Color is permanent reduction cover gray of gray hair reaction

One-step Oxidation/ Lighten hair color, Permanent Achieve light Damaging to hair bleaching reduction cover gray blonde hair reaction shades Two-step Oxidative alkaline Dramatically Permanent Achieve dramatic Very damaging to bleaching reaction lighten hair color, hair color hair cover gray lightening Source: From Ref. 73. McMichael PTR 01/21/08 Chapter 05

66 Draelos dyes are most popular among mature women who wish to brighten gray hair to a platinum color. This is achieved by adding a blue or purple temporary dye to the hair after shampooing to cover yellow hair hues. Temporary hair dyes contain acid dyes of the same type used to dye wool fabrics. These dyes belong to the azo, anthraquinone, triphenylmethane, phenzainic, xanthenic or benzoquino- neimine classes (49). They are listed on the ingredient disclosure as FDC and DC blues, greens, reds, oranges, yellows, and violets. Some of these dyes may be appropriate for individuals who are sensitive to paraphenylenediamine, a chemical found in most other hair dyes.

Semipermanent Dyes Semipermanent hair dyes are designed for use on natural, unbleached hair to cover gray, add highlights, or rid hair of unwanted tones (50). Semipermanent dyes are longer-lasting than temporary dyes since they are retained in the hair shaft by weak polar and van der Waals attractive forces. A typical semipermanent dye will last through 6–10 shampooings (51). Usually, 10 to 12 dyes are mixed to obtain the desired shade, which must be darker than the natural hair color (52). Thus, in the cosmetic industry, semipermanent dyes are known as suitable for staying “on shade.” There are several different types of semipermanent hair dyes based on the derivation of the dye: textile dyes, vegetable dyes, and synthetic hair stains. Semipermanent hair colorings derived from textile dyes are popular with both men and women. Since human hair is basically a textile, dyes for wool and natural ﬁ ber cloths are well suited for adaptation to hair dyeing. The dyes used include the nitroanilines, nitrophenylenediamines, nitroaminophenols, azos, and anthraquinones (53). Sometimes these dyes are combined with henna, botanically known as Lawsonia alba, to create a “natural” vegetable dye. However, most of the currently marketed vegetable dyes use a small amount of synthetic henna, combined with traditional semipermanent dyes, to achieve the desired hair color. These dyes are commonly available as shampoos and mousses that are applied to wet, freshly shampooed hair and rinsed in 20 to 40 minutes. A newer, longer-lasting form of the semipermanent dye, known as a demipermanent hair coloring, usually lasts through 10–12 shampooings. This is due to enhanced dye penetration into the hair shafts facilitated by the addition of small amounts of ammonia. As might be expected, demipermanent dyes are more damaging to the hair shafts than semipermanent dyes.

Permanent Dyes Permanent hair coloring is the most popular hair-coloring technique used by men and women due the tremendous color variety available. Permanent hair coloring can dye hair both lighter and darker, achieving almost any color desired by the user. The hair color is permanent because the dyestuff penetrates the hair shaft to the cortex and forms large color molecules that cannot be removed by shampooing (54). This type of hair coloring does not contain dyes, but rather colorless dye precursors that chemically react with hydrogen peroxide inside the hair shaft to produce colored molecules (55). The process entails the use of primary intermediates (p-phen- ylenediames, p-toluenediamine, p-aminophenols), which undergo oxidation with hydrogen peroxide. These reactive intermediates are then exposed to couplers (resorcinol, 1-naphthol, m-aminophenol, etc.) to result in a wide variety of indo dyes. These indo dyes can produce shades from blonde to brown to black with highlights of gold to red to orange. Variations in the concentration of hydrogen peroxide and the chemicals selected for the primary intermediates and couplers produce this color selection (56). The form of permanent hair dyeing that leads to hair-color lightening is known as bleaching. This is the most damaging form of hair coloring. Hair color can be bleached with one-step or two-step processing. In one-step processing, the dyeing and lightening procedures are performed as one step, but the hair cannot be dramatically lightened. One-step processing uses the same dyes as discussed previously, except the hydrogen peroxide used in the oxidation dyeing process is used to lighten the existing hair color, a phenomenon known as “lift.” Two-step hair processing involves removing the natural hair pigments followed by dyeing to the desired lighter shade. This technique is used when patients wish to dye their hair much lighter than their natural color or if the hair contains more than 60% gray. Removing of the natural hair McMichael PTR 01/21/08 Chapter 05

Nonmedicated Grooming Products and Beauty Treatments 67 pigments, a process known as hair bleaching, is achieved with an alkaline mixture of hydrogen peroxide and ammonia. This causes swelling of the hair shaft allowing easier penetration of the dye, known as a toner (57). The toner must be used since hair completely stripped of color has an undesirable grayish appearance.

PERMANENT HAIR CURLING Permanent hair curling is used to alter the shape of the hair shaft. Specifi cally, permanent hair curling is used to make straight hair wavy, curly, or kinky. The chemistry of the permanent waving process is based on the 16% cystine incorporated into disulfi de linkages between polypeptide chains in the hair keratin fi lament. These disulfi de linkages are responsible for hair elasticity and can be reformed to change the confi guration of the hair shaft. Permanent waving utilizes three processes: chemical softening, rearranging, and fi xing of the disulfi de bonds (58). The basic chemistry involves the reduction of the disulfi de hair shaft bonds with mercaptans (59,60). The standard permanent waving procedure involves initial shampooing of the hair to remove dirt and sebum. This wetting process with water is the fi rst step in preparing the hair for chemical treatment, since the water enters the hair’s hydrogen bonds and allows increased fl exibility. The hair is then sectioned into 30 to 50 areas, depending on the length and thickness of the hair, and wound on mandrels or rods with holes to allow the permanent waving solution to contact all surfaces of the hair shaft. The size of the rod determines the diameter of the curl with smaller rods producing tighter curls and larger rods producing looser curls. The hair must be wound on the curling rod with suffi cient tension to provide the stress required for bond breaking. After the hair has been completely wrapped on the curling rods, the waving lotion and the activator are mixed (Table 6). The activated waving lotion is applied and left in contact with the hair for 5 to 20 minutes, depending on the condition of the hair. The reducing action of the waving lotion is said to “soften” the hair and contains a disulfi de bond-breaking agent, such as ammonium or calcium thioglycolate, and an antioxidant, such as sodium hydrosulfi te, to prevent the lotion from reacting with air before it reaches the hair. Once the hair has been thoroughly saturated with the waving lotion, the hair is placed under a plastic shower cap. The cap traps the heat of the body, which is used to increase the activity of the permanent wave solution. The cap also traps the smell of sulfur, which is produced as sulfur escapes from the hair when the disulfi de bonds are broken. Once the desired amount of curl has been achieved, the hair disulfi de bonds are reformed with the hair in the new curled conformation around the curling rods. This process is known as neutralization, fi xation, or hardening (Table 7). The neutralizer functions to reform the broken disulfi de bonds and restores the hair to its original condition (61). A permanent wave is designed to last 3 to 4 months. Curl relaxation occurs with time as the hair returns to its original conformation. There are several types of permanent waves depending on the chemistry of the solution employed. The differences between the various types of permanent waves are due to the unique attributes of the waving lotions (Table 8) (62–64). Alkaline permanent waves utilize ammonium

TABLE 6 Permanent Waving Lotion Ingredients Ingredient Chemical examples Function Reducing agent Thioglycolic acid, thiolactic acid, glycerol Break disulfi de bonds monothio-glycolate, sodium sulfi te Alkaline agent Ammonium hydroxide, triethanol-amine Adjust pH Chelating agent Tretrasodium EDTA Remove trace metals Wetting agent Fatty alcohols, sodium lauryl sulfate, disodium Improve hair saturation with laureth sulfosuccinate, sodium laureth sulfate, waving lotion cocoampho-diacetate Antioxidant Tocopherol, tocopherol acetate Preservative Buffer Ammonium carbonate Adjust pH Conditioner Proteins, humectants, quaternium compounds Protect hair during waving process Opacifi er Polyacrylates, polystyrene latex Opacify waving lotion McMichael PTR 01/21/08 Chapter 05

68 Draelos

TABLE 7 Permanent Wave Neutralizer Ingredients Ingredient Chemical example Function Oxidizing agent Hydrogen peroxide, sodium bromate Reform broken disulfi de bonds Acid buffer Citric acid, acetic acid, lactic acid Maintain acidic pH Stabilizer Sodium stannate Prevent hydrogen peroxide breakdown Wetting agent Fatty alcohols Improve hair saturation with neutralizer Conditioner Proteins, humectants, quaternium compounds Improve hair feel Opacifi er Polyacrylates, polystyrene latex Make neutralizer opaque thioglycolate or ethanolamine thioglycolate as the active reducing agent in the waving lotion. The pH of the waving lotion is adjusted to 9–10 since the thioglycolates are not effective at an acidic pH. Alkaline permanent waves produce tight, long-lasting curls very rapidly, but can be damaging to the hair shafts. This has led to the development of buffered alkaline permanent waves, which utilize ammonium bicarbonate as a buffering agent to reduce the pH to 7–8.5. This allows rapid production of a tight, long-lasting curl with less hair damage. Another variation on the permanent wave, known as an exothermic permanent, is designed to increase patient comfort by reducing the chill from the cold waving solution. The heat is produced as a by-product of the chemical reaction when the oxidizing agent, such as hydrogen peroxide, is mixed with the thioglycolate-based waving lotion immediately prior to scalp application. Permanent waves are also available in a self-regulated form, designed to reach a chemical equilibrium such that the disulfi de bond breakage is stopped at a predetermined time. This is accomplished by adding dithioglycolic acid to the thioglycolate-based waving lotion. The advantage is that the hair does not need to be immediately neutralized allowing the beauty operator more leeway in getting the permanent wave solution out of the scalp. There are two other types of permanent waves, known as acid permanent waves and sulfi te permanent waves. Acid permanent waves are designed with an acidic waving lotion at a pH of 6.5–7. They are based on thioglycolate esters, such as glycerol monothioglycolate. The lower pH produces less hair-shaft swelling, thus hair damage is minimized. These products result in a looser, shorter-lasting curl, but leave the hair soft. They are ideal for bleached or color-treated hair. Sulfi te permanent waves are mainly marketed for home use and have not found popularity among salons in the United States. These products differ in that the reducing agent is a sulfi te or bisulfi te, instead of a mercaptan. This accounts for the reduced odor, which is their primary advantage.

TABLE 8 Types of Permanent Waves Type of permanent wave Chemistry pH Advantages Disadvantages Alkaline Ammonium thioglycolate 9–10 Quick processing Harsh on hair shafts or ethanolamine time, tight curls thioglycolate Buffered alkaline Ammonium bicarbonate 7–8.5 Less harsh on hair than Less harsh than alkaline added to alkaline curl alkaline perm perm, but still damaging ingredients Exothermic Thioglycolate and peroxide 6.5–7 Heat produced for patient Must be properly mixed to produce dithio- comfort to prevent hair damage diglycolate Self-regulated Dithioglycolic acid and 6.5–7 Stops processing Not good for hard-to-perm thioglycolate automatically at hair equilibrium Acid Thioglycolate esters, such as glycerol mono- 6.5–7 Less damaging to hair Produces looser, shorter- thioglycolate lasting curl Sulfi te Sulfi te or bisulfi te 6–8 Less odor Long processing time, harsh on hair McMichael PTR 01/21/08 Chapter 05

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TABLE 9 Rationale for Permanent Hair Straightening 1. Hair manageability is improved. 2. The hair can be more easily combed and styled. 3. Hair breakage may be decreased due to less combing friction. 4. Hair shine is improved with a straighter hair shaft. 5. Fashion may dictate the need for straight hair. 6. Versatility in straightening techniques allows multiple styling options: completely straightened, minimally straightened, texturized, or straightened and recurled.

PERMANENT HAIR STRAIGHTENING Hair straightening, also known as lanthionization, is undertaken for many reasons, including those listed in Table 9 (65). It is a chemical process utilizing metal hydroxides, such as sodium, lithium, potassium, or guanidine hydroxide, to change about 35% of the cysteine content of the hair to lanthionine along with minor hydrolysis of the peptide bonds (66). Chemical relaxing can be accomplished with lye-based, lye-free, ammonium thioglycolate, or bisulﬁ te creams (67). Lye-based, or sodium hydroxide straighteners are alkaline creams with a pH of 13. Sodium hydroxide is a caustic substance that can damage hair, produce scalp burns, and cause blindness if exposed to the eye. These products are generally restricted to professional or salon use and may contain up to 3.5% sodium hydroxide (68). Lye relaxers are available in “base” and “no-base” forms. The “base” is usually petrolatum that is applied to the scalp and hairline prior to application of the sodium hydroxide. This prevents scalp irritation and burns. The base relaxers contain between 1.5% and 3.5% sodium hydroxide and therefore require that the scalp and hairline be coated with a petrolatum base prior to application. These higher concentration lye products are necessary for hard-to-straighten hair. “No-base” relaxers, on the other hand, contain 1.5% to 2.5% sodium hydroxide and only require base application to the hairline (69). They are more popular since it is time-consuming for the beautician to apply the base to the scalp and most individuals are re-straightening hair that has already been chemically weakened. Other strong alkali chemicals sometimes used in place of sodium hydroxide are guanidine hydroxide and lithium hydroxide, which are known as “no-lye” chemical hair straighteners. These relaxing kits contain 4% to 7% cream calcium hydroxide and liquid guanidine carbonate. The guanidine carbonate activator is then mixed into the calcium hydroxide cream to produce calcium carbonate and guanidine hydroxide, the active agent. These products do not require basing of either the scalp or the hairline. Table 10 compares the lye and no-lye relaxers in terms of their effect on the hair shaft. Thioglycolate can also be used as an active agent in hair straightening (70). These are the same thioglycolate chemicals that were described as permanent wave solutions, except that they are formulated as thick creams, rather than lotions. The cream adds weight to hair and helps to pull it straight. Also, instead of the hair being wound on mandrels, it is combed straight while the thioglycolate cream is in contact with the hair shaft. Thioglycolate hair straighteners are extremely harsh on the hair and are the least popular of all the relaxing chemicals for this reason. The thioglycolate cream has a pH of 9.0 to 9.5, which removes the protective sebum and

TABLE 10 Comparison of Lye and No-Lye Chemical Relaxers Hair quality Lye chemical relaxer No-lye chemical relaxer Relative strength on scale of 1–3 3 1 (higher # is stronger) Alkaline relaxing agent NaOH or KOH Guanidine hydroxide Chemical agent OH OH pH 12.5–14 12.5–13.5 Hair shaft penetration Faster Slower Processing time Shorter Longer Irritation High Low Drying potential Less drying to hair and scalp More drying to hair and scalp Source: Adapted from Ref. 73. McMichael PTR 01/21/08 Chapter 05

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TABLE 11 Hair Relaxing Steps 1. Do not shampoo. 2. Apply petrolatum base to scalp and hairline. 3. Section hair. 4. Apply cream relaxer from hair root to end beginning at nape of neck. 5. Gently comb hair straight for 10–30 minutes until degree of relaxation is achieved. 6. Rinse thoroughly with water. 7. Apply neutralizer. 8. Shampoo. 9. Apply conditioner. 10. Style. 11. Apply styling conditioner. facilitates hair shaft penetration. Chemical burns can also occur with this variety of chemical hair straightener (71). The least damaging of all hair-straightening chemicals are the ammonium bisulfi te creams. These products contain a mixture of bisulfi te and sulfi te in varying ratios depending on the pH of the lotion. Many of the home chemical straightening products are of this type, but can only produce short-lived straightening. These are very similar to the home sulfi te permanent waves previously discussed, except the hair is combed straight instead of being wound on curling rods. The key to successful hair relaxing is an experienced beautician who can quickly apply and remove the chemicals and determine when the desired degree of disulfi de bond breaking has occurred. The steps involved in hair relaxing are summarized in Table 11. It is estimated that virgin hair loses about 30% of its tensile strength following a properly performed chemical straightening procedure. It also becomes more porous, allowing future relaxing procedures to process more quickly (72). Hair relaxing is a careful balance between achieving the straightening of kinky hair and minimizing irreversible hair-shaft damage.

SUMMARY This chapter has discussed basic hair grooming and cosmetic manipulations of the hair shaft. It goes without saying that virgin hair is the healthiest and strongest. With continued grooming and chemical manipulation the hair loses it protective lipid coating, cuticular scale, elasticity, and strength. Combing, brushing, and shampooing all infl ict damage on the hair shaft that is temporarily partially reversed with conditioners. Semipermanent and permanent dyeing procedures involve the formation of holes within the hair shaft where the color molecules can either penetrate or undergo chemical formation. Once these holes are created through cuticle swelling, they can never be completely closed. This leaves the hair shaft porous and subject to breakage. An even more dramatic physical insult is infl icted with permanent waving and straightening. Here the strong protein backbone of the hair shaft is broken by dissolving and reforming the disulfi de bonds. Hair with an altered physical shape can never be returned to its original confi guration. Individuals with hair and scalp disease, with or without hair loss, will want to beautify their hair with some of the procedures discussed in this chapter. While the physician may be tempted to tell patients to avoid all hair products and procedures except for the most basic shampoos, it is unlikely that this advice will be heeded. The use of hair cosmetics is ubiquitous among men and women of all ages. Thus, a basic working knowledge of the formulation and function of these products must be obtained.

REFERENCES 1. Robbins CR. Interaction of shampoo and creme rinse ingredients with human hair. In: Chemical and Physical Behavior of Human Hair. 2nd ed. New York: Springer-Verlag, 1988:122–167. 2. Bouillon C. Shampoos and hair conditioners. Clinics Dermatol 1988; 6:83–92. 3. Markland WR. Shampoos. In: deNavarre MG, ed. The Chemistry and Manufacture of Cosmetics. 2nd ed. Wheaton, IL: Allured Publishing Corporation, 1988; Vol. IV:1283–1312. 4. Zviak C, Vanlerberghe G. Scalp and hair hygiene. In Zviak C, ed. The Science of Hair Care. New York: Marcel Dekker, 1986:49–86. McMichael PTR 01/21/08 Chapter 05

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5. Tokiwa F, Hayashi S, Okumura T. Hair and surfactants. In: Kobori T, Montagna W, eds. Biology and Disease of the Hair. Baltimore: University Park Press, 1975:631–640. 6. Hunting ALL. Can there be cleaning and conditioning in the same product? Cosmet Toilet 1988; 103:73–78. 7. Gruber J, Lamoureux B, Joshi N, Moral L. The use of x-ray fl uorescent spectroscopy to study the infl uence of cationic polymers on silicone oil deposition from shampoo. J Cosmet Sci 2001; 52:131–136. 8. Lochhead R. Formulating Conditioning Shampoos. Cosmet & Toilet 2001; 116:55–66. 9. Brooks G, Burmeister F. Black hair care ingredients. Cosmet Toilet 1988; 103:93–96. 10. Goldemberg RL. Hair conditioners: the rationale for modern formulations. In: Frost P, Horwitz SN, eds. Principles of Cosmetics for the Dermatologist. St. Louis: CV Mosby Company, 1982:157–159. 11. Swift JA, Brown AC. The critical determination of fi ne change in the surface architecture of human hair due to cosmetic treatment. J Soc Cosmet Chem 1972; 23:675–702. 12. Zviak C, Bouillon C. Hair treatment and hair care products. In: Zviak C, ed. The Science of Hair Care. New York: Marcel Dekker, Inc, 1986:115–116. 13. Rook A. The clinical importance of “weathering” in human hair. Br J Dermatol 1976; 95:111–112. 14. Price VH. The role of hair care products. In: Orfanos CE, Montagna W, Stuttgen G, eds. Hair Research. Berlin: Springer-Verlag, 1981:501–506. 15. McMullen R, Jachowicz J. Optical properties of hair: Effect of treatments on luster as quantifi ed by image analysis. J Cosmet Sci 2003; 54:335–351. 16. Okamoto M, Yakawa R, Mamada A, et al. Infl uence of internal structures of hair fi ber on hair appearance. III. Generation of light-scattering factors in hair cuticles and the infl uence on hair shine. J Cosmet Sci 2003; 54:353–366. 17. Tango Y, Shimmoto K. Development of a device to measure human hair luster. J Cosmet Sci 2001; 52:237–250. 18. Scanavez C, Zoega M, Barbosa A, Joekes I. Measurement of hair luster by diffuse refl ectance spectrophotometry. J Cosmet Sci 2000; 51:289–302. 19. Robinson VNE. A study of damaged hair. J Soc Cosmet Chem 1976; 27:155–161. 20. Zviak C, Bouillon C. Hair treatment and hair care products. In: Zviak C, ed. The Science of Hair Care. New York: Marcel Dekker, Inc, 1986:134–137. 21. Swift J. Mechanism of split-end formation in human head hair. J Soc Cosmet Chem 1997; 48:123–126. 22. Corbett JF. The chemistry of hair-care products. J Soc Dyers Colour 1976; 92:285–303. 23. Allardice A, Gummo G. Hair conditioning: quaternary ammonium compounds on various hair types. Cosmet & Toilet 1993; 108:107–109. 24. Allardice A, Gummo G: Hair conditioning. Cosmet Toilet March 1993; 108:107–109. 25. Ruetsch S, Kamath Y, Weigmann H. The role of cationic conditioning compounds in reinforcement of the cuticula. J Cosmet Sci 2003; 54:63–83. 26. Idson B, Lee W. Update on hair conditioner ingredients. Cosmet Toliet October 1983; 98:41–46. 27. Dalton J, Allen G, Heard P, Hallam K, Elton N, Walker M, Matz G. Advancements in spectroscopic and microscopic techniques for investigating the adsorption of conditioning polymers onto human hair. J Cosmet Sci 2000; 51:275–287. 28. Finkelstein P: Hair conditioners. Cutis 1970; 6:543–544. 29. Griesbach U, Klingels M, Horner V. Proteins: classic additives and actives for skin and hair care. Cosmet & Toilet 1998; 113:69–73. 30. Fox C. An introduction to the formulation of shampoos. Cosmet Toilet March 1988; 103:25–58. 31. Spoor HJ, Lindo SD. Hair processing and conditioning. Cutis 1974; 14:689–694. 32. Swift J, Chahal S, Challoner N, Parfrey J. Investigations on the penetration of hydrolyzed wheat proteins into human hair by confocal laser-scanning fl uorescence microscopy. J Cosmet Sci 2000; 51:193–203. 33. Rosen M. Silicone innovation for hair care. GCI 2002; 37–39. 34. Ruiz M, Hernandez A, Llacer J, Gallardo V. Silicone chemistry. Cosmet & Toilet 2003 1998; 113:57– 62. 35. Berthiaume M, Merrifi eld J, Riccio D. Effects of silicone pretreatment on oxidative hair damage. J Soc Cosmet Chem 1995; 46:231–245. 36. Reeth I, Caprasse V, Postiaux S, Starch M. Hair shine: correlation instrumental and visual methods for measuring the effects of silicones. IFSCC 2001; 4:21–26. 37. Starch M. Screening silicones for hair luster. Cosmet & Toilet 1999; 114:56–60. 38. Klein K. Formulating hair conditioners: hope and hype. Cosmet & Toilet 2003; 118:28–31, 118. 39. Fox C. Hair care. Cosmet & Toilet 1993; 108:29–57. 40. Braida D, Dubief C, Lang G. Ceramide: a new approach to hair protection and conditioning. Cosmet & Toilet 1994; 109:49–57. 41. Bouillon C: Shampoos and hair conditioners. Clinics in Dermatol 1988; 6:83–92. 42. Syed A, Ayoub H. Correlating porosity and tensile strength of chemically modifi ed hair. Cosmet & Toilet 2002; 117:57–62. 43. Casperson S. Men’s hair coloring a review of current technology. Cosmet & Toilet 1994; 109:83–87. McMichael PTR 01/21/08 Chapter 05

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44. Pohl S. The chemistry of hair dyes. Cosmet Toilet 1988; 103:57–66. 45. Spoor HJ. Part II: Metals. Cutis 1977; 19:37–40. 46. Casperson S. Men’s hair coloring. Comet Toilet 1994; 109:83–87. 47. Spoor HJ. Hair dyes: temporary colorings. Cutis 1976; 18:341–344. 48. Corbett JF. Hair coloring. Clin Dermatol 1988; 6:93–101. 49. Wilkinson JB, Moore RJ. Harry’s cosmeticology. 7th ed. New York: Chemical Publishing, 1982:526– 528. 50. Spoor HJ. Semi-permanent hair color. Cutis 1976; 18:506–508. 51. Corbett JF. Hair coloring processes. Cosmet Toilet 1991; 106:53. 52. Robbin CR. Chemical and physical behavior of human hair. 2nd ed. New York: Springer-Verlag, 1988:185–188. 53. Corbett JF. Hair coloring processes. Cosmet Toilet 1991; 106:53. 54. Tucker HH. Formulation of oxidation hair dyes. Am J Perfum Cosmet 1968; 83:69. 55. Corbett JF, Menkart J. Hair coloring. Cutis 1973; 12:190. 56. Zviak C. Oxidation coloring. In: Zviak C, ed. The Science of Hair Care. New York: Marcel Dekker, Inc, 1986:263–286. 57. Spoor HJ. Hair coloring--a resume. Cutis 1977; 20:311–313. 58. Wickett RR. Permanent waving and straightening of hair. Cutis 1987; 39:496–497. 59. Zviak C. Permanent waving and hair straightening. In Zviak C, ed. The Science of Hair Care. New York: Marcel Dekker, 1986:183–209. 60. Cannell DW: Permanent waving and hair straightening. Clinics in Dermatol 1988; 6:71–82. 61. Lee AE, Bozza JB, Huff S, de la Mettrie R. Permanent waves: an overview. Cosmet Toilet 1988; 103:37–56. 62. Ishihara M. The composition of hair preparations and their skin hazards. In: Koboir T, Montagna W, eds. Biology and Disease of the Hair. Baltimore: University Park Press, 1975:603–629. 63. Zviak C: Permanent waving and hair straightening. In: Zviak C, ed. The Science of Hair Care. New York: Marcel Dekker, 1986:183–209. 64. Gershon SD, Goldberg MA, Rieger MM. Permanent waving. In: Balsam MS, Sagarin E, eds. Cosmetics Science and Technology. 2nd ed. New York: Wiley-Interscience, John Wiley & Sons, 1972, Vol. 2:167–250. 65. Syed A, Kuhajda A, Ayoub H, Ahmad K. African-American hair. Cosmet & Toilet 1995; 110: 39–48. 66. Cannell DW. Permanent waving and hair straightening. Clinics in Dermatol 1988; 6:71–82. 67. Syed A. Ethnic hair care: history, trends, and formulation. Cosmet & Toilet 1993; 108: 99–108. 68. Khalil EN. Cosmetic and hair treatments for the black consumer. Cosmet Toilet 1986; 101:51–58. 69. Ogawa S, Fuﬁ i K, Kaneyama K, Arai K, Joko K. A curing method for permanent hair straightening using thioglycolic and dithiodiglycolic acids. J Cosmet Sci 2000; 51: 379–399. 70. Bulengo-Ransby, Bergfeld WF. Chemical and traumatic alopecia from thioglycolate in a black woman. Cutis 1992; 49:99–103. 71. Syed A, Ayoub H. Correlating porosity and tensile strength of chemically modiﬁ ed hair. Cosmet & Toilet 2002; 117:57–62. 72. Obukowho P, Birman M. Hair Curl Relaxers: A discussion of their function, chemistry, and manufacture. Cosmet & Toilet 1995; 110:65–69. 73. Draelos, ZD. Hair Care. NY:Taylor & Francis, 2004. McMichael PTR 01/21/08 Chapter 06

6 Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos

Janet G. Hickman Dermatology Consultants, Inc. and The Education and Research Foundation, Inc., Lynchburg, Virginia, U.S.A.

INTRODUCTION Dandruff is one of the most common scalp disorders and one of the most frequent conditions for which consumers seek and purchase over-the-counter drugs. Within the United States for ﬁ scal year 2005/2006 total sales of antidandruff products were between $450 and $500 million dollars. However, scientiﬁ c attention has only recently been focused on the causes and treatment of dandruff (1).

DEFINITIONS Dandruff is visible fl aking of the scalp. The scalp, like the rest of the skin, is a stratifi ed squamous epithelium continually shedding dead microscopically sized corneocytes from the surface. It is estimated that each person sheds about 4 kg of corneocyte squames per year (2). While bloodhounds may detect these shed fl akes from normal scalps, we are generally only aware of them when they are large enough to see clumped on the scalp, adherent to the hairs, and visible on clothing. Seborrheic dermatitis of the scalp includes both visible fl aking and infl ammation with erythema and, generally, pruritus. The relationship of seborrheic dermatitis and dandruff has been debatable. Now that more is known about the pathophysiology of both conditions, it is reasonable to consider that most dandruff is seborrheic dermatitis with a range of infl ammatory severity from inapparent to severe (1).

CLINICAL PRESENTATION The mildest grade of dandruff shows tiny fl akes at the orifi ce of some hair follicles. At more severe grades, the fl akes are present over more of the scalp, are larger, and accumulate in clumps (Figs. 1 and 2). At its most severe, dandruff fl aking can form a dense mat over the entire scalp surface. With clinically evident seborrheic dermatitis, the fl aking may occur in patches with associated erythema and serous oozing. Seborrheic dermatitis also typically affects other hair-bearing or oily areas such as the eyebrows, sideburns, beard, moustache, alar and nasolabial creases, postauricular creases, glabellar crease, and sternum (Fig. 3). Even the axillae and intertriginous folds in adults and the diaper area of infants may be involved. Patients with seborrheic dermatitis commonly report a positive family history of similar problems, suggesting a genetic predisposition. The tendency to develop seborrheic dermatitis persists life-long but fl uctuates in activity. It may appear as “cradle cap” (thick oily fl aking at the vertex of the scalp) in infancy, remit during childhood, return during adolescence, and appear episodically thereafter (3). Some studies show another increase in activity in the elderly (4). Exacerbating factors include tension, stress, temperature, and humidity. Seborrheic dermatitis may produce hypopigmentation or post-infl ammatory hyperpigmentation, especially noticeable on pigmented skin. The primary symptom is pruritus, although the degree of itching does not necessarily correlate directly with the degree of fl aking. Patients with dandruff report quality-of-life effects such as embarrassment, discomfort, frustration, limitation of hairstyle and clothing choices, and even job discrimination McMichael PTR 01/21/08 Chapter 06

74 Hickman

FIGURE 1 Moderately severe dandruff scale at the hairline.

FIGURE 2 (See color insert.) Moderately severe dandruff scale in the scalp.

FIGURE 3 Seborrheic dermatitis involving the alar crease.

(5). The Scalpdex and other quality-of-life measurement tools are available to assess these effects (6) There is often a discrepancy between the scalp condition severity and the patient’s awareness of it. In studies where subjects are asked to assess their scalp state prior to examination by a trained scalp grader, there is wide variation in the self-reported versus directly observed degree of scalp scale. This may be explained in part by a culturally learned reluctance to admit to “dandruff.” Patients more readily use the term “dry scalp,” but as studies demonstrate, it is sebum and not lack of it that is part of the pathogenesis of dandruff. McMichael PTR 01/21/08 Chapter 06

Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 75

PREVALENCE The prevalence of dandruff varies with the shampooing habits of populations. In the past, it has been estimated that approximately 50% of the population have dandruff at some point in life, with 2–5% having infl ammatory seborrheic dermatitis (7). The prevalence of scalp scale is higher in African American subjects, especially women, related in part to the decreased average shampoo frequency common to African American hairstyles. This was confi rmed in population screening of 1408 Caucasian, African American, and Chinese adults and teenagers studied in Minnesota, Georgia, and China. The prevalence of noticeable fl aking was 81–95% in African Americans, 66–82% in Caucasians, and 30–42% in the Chinese. In the U.S. subjects, higher shampoo frequency was associated with lower dandruff scores. The Chinese subjects, although they had a lower shampoo frequency, had a much higher prevalence of routine antidandruff shampoo use (10–20% in the United States vs 40–52% in the Chinese) which correlated with their overall lower level of fl aking (7,8). Dandruff is not necessarily uniform across the scalp. Micro-environmental factors infl u- ence the distribution of scale on the scalp. Thus, there will usually be increased scale where the scalp creases, under hat bands and eyeglass frames, and under areas where the hair is gathered into a ponytail or twist. Temporary changes in hair care can affect dandruff, such as illness, stroke, or injury to the arm or hand impeding shampooing. There is even a subtle decrease in scale on the side of the dominant hand, presumably because of more effective mechanical scale removal during shampooing and brushing.

Systemic Disease Associations Worsening seborrheic dermatitis is an early and prominent sign in Parkinson’s disease and related neurological conditions (9,10). Similarly, stroke patients have an increased prevalence of seborrheic dermatitis. The reason for this association is not clear, though pooling of sweat where the facial muscles are inactive, inability to remove sweat and sebum, or changes in sebum are postulated (11,12). Seborrheic dermatitis is one of the earliest and most common dermatologic manifestations of HIV infection, reported in 30–83% of patients with AIDS (13). Seborrheic dermatitis in this population has been reported to be more severe, more extensive, and more erythematous and papular than usual in immunocompetent individuals. Even now that highly active antiretroviral therapy (HAART) is available, seborrheic dermatitis in HIV-infected patients is more prevalent (10.6%) than the average and ranked as the third most common dermatologic diagnosis after folliculitis (all forms) and condylomata acuminata in one study (14). The increased prevalence of seborrheic dermatitis in AIDS, the abundance of Malassezia yeast cells in skin samples from these patients and patients’ clinical improvement with oral or topical ketoconazole treatment were all early observations supporting the causative role of Malassezia in seborrheic dermatitis (15–17).

DIFFERENTIAL DIAGNOSIS Other causes of ﬂ aking or scaling scalp include: Psoriasis of the scalp is typically distinguished by sharply demarcated raised erythematous plaques with silvery scale. Diagnosis is facilitated by observation of psoriatic plaques elsewhere on the body or typical nail disease. The therapeutic measures used for dandruff and seborrheic dermatitis are also the ﬁ rst line therapy for scalp psoriasis. Irritant dermatitis of the scalp presents with thin, dry, crackling scale plus symptoms of stinging, burning, or itching. It is most often produced by barrier disruption from strong surfactants in shampoos or chemical treatments for hair styling. Patients with atopic dermatitis are particularly susceptible to such barrier damage. Tinea capitis, particularly Trichophyton tonsurans infection, may mimic dandruff or seborrheic dermatitis. Microscopic examination of scale and plucked hairs plus culture should be performed when tinea capitis is a possibility. Suggestive signs include “dandruff” in pre-pubertal children, hair breakage or loss in affected areas, and cervical or postauricular adenopathy. McMichael PTR 01/21/08 Chapter 06

76 Hickman

Pityriasis amiantacea is also called tinea amiantacea, though not caused by dermatophyte infection. This presents with large masses of scale adherent fi rmly to the hair shafts, especially at the vertex of the scalp. It may be a form or precursor of psoriasis or seborrheic dermatitis. The initial focus of treatment is softening and removal of the matted scale by keratolytic agents. “Silver scalp” is a condition seen primarily in the elderly where thin plaques of erythema and powdery dry silvery scale are present. The scales are fi ner and more tightly adherent to the scalp than in psoriasis. Itching is a common symptom. The posterior scalp is the most frequent site of involvement. This condition is stubbornly resistant to treatment. Other uncommon conditions may also be associated with scalp scaling such as ichthyosis, pityriasis rubra pilaris, zinc defi ciency, Langerhans cell histiocytosis, and Wiskott–Aldrich syndrome (18).

ANTHROPOLOGY OF DANDRUFF Although a theory not widely held by current anthropologists, the Aquatic Ape hypothesis of human evolution offers a possible role for dandruff in human development. The tenets of this hypothesis are that the evolutionary forebears of Homo sapiens were adapted to a warm aquatic environment and that some of those adaptations persist today. Examples include our thick subcutaneous fat layer, lack of fur, stretched hind limbs, voluntary respiration, diving refl exes, and infant swimming. Even the fi nding that omega 3 fatty acids (“fi sh oils”) promote healthy human and ape brain development accords with this hypothesis (19–21). For dermatologic fi ndings, this theory notes hair and sebaceous gland distribution as promoting streamlining for forward swimming in water. Thus, male vertex balding, the growth pattern of nose, ear and chest hair, and sebaceous gland concentration at the scalp, forehead, nose, and shoulders all appear adaptive for swimming. Even dandruff fi ts this hypothesis, as individual scales at the base of hairs are angled to assist in “slicking down” the hairs for decreased water resistance. The Malassezia yeasts that colonize the scalp secrete a UV protectant that may also have been useful to swimming ancestors (22,23).

ETIOLOGY OF DANDRUFF The etiology of dandruff has been debated for centuries. The Greeks Galen and Celsus argued whether the nature of the squames was dry or exudative. Hebra in the nineteenth century considered dandruff a sebaceous disease. In the late nineteenth century, Rivolta, Malassez (24) and Sabouraud described a bottle-shaped fungus (later called Pityrosporum ovale) on scalps with dandruff and considered it the cause of the condition. However, the ﬁ nding of the same organism on normal scalps placed that explanation in doubt (25). By the mid-twentieth century, the theory that dandruff was a hyperproliferative state unrelated to the presence of yeasts was proposed (26,27). Renewed interest in the role of scalp yeasts arose with the ﬁ nding that oral ketoconazole was effective in decreasing seborrheic dermatitis (13,28,29). This advent of more effective antifungal agents and the development of more precise microbiologic techniques have lead to the current appreciation of the role of yeasts in dandruff and seborrheic dermatitis.

Malassezia Malassezia yeasts (previously called Pityrosporum) are a normal part of the skin fl ora. Because they require lipids for growth, they are found on lipid-rich areas of the body, especially the chest, back, face, and scalp. Colonization of the scalp occurs in infancy and is correlated with the age of appearance of “cradle cap” seborrheic fl aking (30,31). Proliferation of Malassezia yeast, and the appearance of easily visible pseudohyphae on KOH microscopic examination, link Malassezia furfur (Pityrosporum ovale, orbiculare) and other Malassezia species to tinea versicolor. In contrast, Malassezia yeast in skin scrapings from dandruff or seborrheic dermatitis are only clearly seen using staining techniques such as periodic acid-Schiff (PAS) on formalin fi xed tissue or Wright–Giemsa, Nile Blue, or neutral red on fresh smears (Fig. 4). Pseudohyphae McMichael PTR 01/21/08 Chapter 06

Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 77

FIGURE 4 Dandruff scalp fl akes stained with Nile Blue stain demonstrating Malassezia yeast. are not present in dandruff scale samples (32). The diffi culty culturing these lipid-dependent (33–35) organisms makes culture unproductive for routine use. Malassezia are present in both normal and dandruff scalps, and constitute the most abundant population in both. The other common microorganisms recovered from sampling the scalp are aerobic cocci and Propionibacterium acnes (36). The role of bacteria in the genesis of dandruff is presumably minor since selective antifungal agents are the most effective therapeutic agents (37). However, those few patients who fail to respond to antifungal shampoos often show especially heavy colonization with bacteria. In these instances, infl ammation may be incited by the bacterial colonization. In especially severe seborrheic dermatitis, secondary infection with Staphyococcus may complicate the scalp infl ammation (36). In general, scalps with dandruff have more yeast than non-dandruff scalps (38), but the quantity and distribution of the yeasts are less important than the host response to their presence. Elimination of the yeasts is associated with clearing of scale. Recolonization is followed by recurrence of fl aking (39). In early childhood, before the sebum production needed for these lipid-dependent organisms has begun at puberty, dandruff is rare (40). In older literature, Pityroporum were classifi ed morphologically as ovale and orbiculare. Now, however, the use of molecular markers has allowed identifi cation of at least ten species of this genus (41): M. globosa, M. restricta, M. obtuse, M. slooffi ae, M. sympodialis, M. furfur, M. nana, M. japonica, M. yamatoensis and M. pachydermatis (3,42–45). Newly described additions to the genus are M. dermatis isolated from atopic dermatitis patients and M. equi from horses. Each species has specifi c biochemical and genetic characteristics. Gupta et al. (46) and others describe culture-based techniques to assay species collected from different body sites and diseases. Gemmer et al. (43) have described a more rapid molecular technique using terminal fragment length polymorphism analysis (tFLP). When applied to samples from non-dandruff and dandruff scalp scales, both groups had similar species present. The scalps with dandruff showed a higher prevalence of each species. The most prevalent species were M. restricta and M. globosa. Only the scalps with the highest dandruff scores showed a very low prevalence of other species: M. slooffi ae and M. obtuse. This is in accordance with visual observation of Nile Blue-stained scalp scales where the predominant yeasts are the bottle-shaped yeast formerly called P. ovale, which correspond to M. restricta, with some scalps showing the more rounded forms of the yeast formerly called P. orbiculare, now corresponding to M. globosa. (As can be seen, the changes in accepted nomenclature can make integration of older literature and reports using other naming systems complex.)

Inﬂ ammation How Malassezia initiate an inﬂ ammatory reaction and the role of host sensitivity are current areas of investigation (47). Humoral immunity is unlikely as a mechanism. IgE levels are not generally elevated nor are total antibody levels (2,48). Some investigators have reported an increase in IgG levels, but McMichael PTR 01/21/08 Chapter 06

78 Hickman this has been refuted by others (2,49–51). Activation of complement in serum by the alternative pathway has been demonstrated for clinical isolates of Malassezia (Pityrosporum ovale) and proposed as a mechanism of non-specifi c immune response (52–57). Toll-like receptor (TLR) activation by Malassezia may lead to cytokine production through the innate immune system. TLR2 has been implicated in reaction to Malassezia furfur with lipid depleted yeast extracts inducing high levels of TNF-α, IL-6, and IL-1β while total yeast extracts did not produce signifi cant levels of infl ammatory cytokines (58). Baroni et al. (59) have reported that human keratinocytes infected with M. furfur demonstrate up-regulation of TRL2, myeloid differentiation factor 88 (MyD88), the antimicrobial peptides human beta- defensin 2 and 3, and interleukin-8 (IL-8) mRMA expression. These effects could be inhibited by anti-TLR2 neutralizing antibodies. The array of cytokines induced varies with the species of Malassezia tested (60), with M. globosa inducing IL-5, IL-10, and IL-13 and M. restricta inducing IL-4 in one study (61). Lipase activity is a likely mechanism linking the Malassezia yeast to the fl aking and infl ammation of dandruff and seborrheic dermatitis (3). Malassezia globosa yeasts incubated with artifi cial sebum change the lipid composition with triglyceride degradation and increased free fatty acids (62). Human sebum from dandruff scalps shows high levels of free unsaturated fatty acids; levels revert to normal after antimicrobial shampoo treatment. Dandruff-like fl aking can be induced on guinea pig skin by the application of the yeast plus a sebum-like lipid source. This has been demonstrated to be from the production of oleic acid by lipase activity. P. acnes, also known to produce lipases that cleave free fatty acids from sebum (62), had a similar though weaker effect in the guinea pig model (63). In a study of humans, application of 7.5% oleic acid solution induced fl aking identical to dandruff both visually and ultrastructurally, but only when applied to scalps of subjects previously identifi ed as having a history of dandruff. Non-dandruff subjects did not have the same response to oleic acid, thus emphasizing the role of both the lipid and the individual susceptibility (64).

Hyperproliferation Several methods have been used to study whether the rate of epidermal proliferation is higher in dandruff compared to non-dandruff scalps. Kligman et al. (26) proposed that dandruff was primarily a hyperproliferative condition. Tritiated thymidine was used to establish labeling indices and migration of scalp epidermal cells from the basal to the cornifi ed layers. Corneo- cytes shed from the scalp were collected and counted. There was considerable overlap in measurements between those scalps graded as dandruff and those without but an increase in the rate of cell production was suggested. Slife et al. (65) also studied stratum corneum turnover and epidermal cell proliferation in eleven subjects with moderate to severe dandruff compared to an equal number with no dandruff. Two subjects with scalp psoriasis served as positive controls. The fl uorescent dye dansyl chloride was used to stain the scalps. Turnover time was measured by observing the disappearance of the dye from the scalp. As expected, the disappearance from the psoriasis scalps was rapid (5 days), but the mean number of days to disappearance from the dandruff (12.9) and non-dandruff (14.6) scalps was not statistically different. In the same study, fresh scalp biopsy specimens were incubated with tritiated thymidine and the incorporation into the basal layer of the epidermis recorded. Again, the results with the dandruff and non-dandruff scalps were nearly equal while the incorporation into psoriatic cells was almost four- fold greater. The current understanding of dandruff is that while some degree of increased cell turnover may contribute to the amount of fl aking, this is not a primary hyperproliferative condition. Rather, any increased cell production is a consequence of infl ammation. Effec- tive treatment occurs with a wide variety of active ingredients that have in common their antifungal activity rather than cytostatic effects. In a study by Marks et al. (66), zinc pyrithione shampoo reduced dandruff without a signifi cant difference in labeling index in scalp biopsies. McMichael PTR 01/21/08 Chapter 06

Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 79

Nature of Flaking Individually shed corneocytes from the scalp surface are too small (approx. 0.04 mm diameter) to be seen. It is only when they are shed as aggregates that they are large enough to be appreciated as dandruff fl akes. Transmission electron microscopy of scalp tape strips has been reported by Warner et al. (67). Abnormalities seen included infi ltration by Malassezia, parakeratosis, lipid droplets within corneocytes, reduced or absent desmosomes, and interdigitated curling membranes. Many of the corneocytes were separated by a thick mass of sebum-like intercellular lipid. Even areas of the dandruff subjects’ scalps with less obvious fl aking still showed similar ultrastructure pathology but tape strips from the lower leg of a subject with severe dandruff were normal. Treatment with zinc pyrithione shampoo effected improvement in the visible dandruff which directly correlated with normalization of the stratum corneum fi ndings. The reduced or absent desmosomes in dandruff scalp samples are in contrast to the fi ndings in dry skin of the legs (winter xerosis), where reduced degradation of corneodesmosomes and their abnormal retention in the superfi cial layers of xerotic stratum corneum underlie reduced desquamation (68,69).

TREATMENT The options for treatment of scalp seborrheic dermatitis and dandruff include products for scale removal, relief of itching, suppression of Malassezia, and reduction of inﬂ ammation (Table 1). The safety, cosmetic acceptability, and ease of use are of concern since these are chronic conditions requiring long-term treatment.

History Humans have long sought a cure for dandruff. Teresi, in Lost Discoveries: the Ancient Roots of Modern Science—From the Babylonians to the Maya (70), reports that the ancient Egyptians con- cocted potions using hippopotamus fat to control dandruff. Schamberg’s A Compend of Diseases of the Skin (71) published in 1905 recommended some treatments still in use today such as salicylic acid and sulphur, but also advised that “Tonics, such as arsenic, iron, strychnin [sic], and quinin [sic] are often indicated.” Fortunately we now have less toxic and better tested approaches!

Effi cacy Testing Methods Most clinical trials to establish effi cacy of antidandruff and anti-seborrheic dermatitis products rely on direct observation of scalp scale (72–74). Typically, test subjects use a standardized non- treatment shampoo for at least two weeks to achieve a baseline state. Further standardization is achieved by specifying an interval, for instance three days, between the last wash-out shampoo use and the clinical grading. The scalp is evaluated by sectioning and parting the hair to visualize the entire scalp. Intense light, angled to increase detection of scale edges, is used. The amount of observed fl aking is graded visually in multiple sections of the scalp, commonly using a 0–10 or 0–4 rating scale. Additional grades for erythema and excoriation may be included. The evaluation of adherent scalp fl aking is more reproducible than evaluation of loose scale, as loose fl akes vary with hair texture and recent scratching, brushing or combing more than adherent scale. Scalp grading is then repeated after use of the products to be tested, commonly at intervals of 2, 4, and 6 weeks. While visual grading is at best semi-quantitative, a trained and experienced grader will demonstrate consistency in duplicate grading tests and reproducible results in clinical trials. Subjective data from subject questioning about pruritus or cosmetic qualities of a product may also be collected. Long-term use studies for safety and effi cacy are performed with subjects using a product frequently (5–10 times per week) over weeks or months of observation. Other measures of dandruff severity such as tape stripping or counting corneocytes collected from scrubbing small areas of the scalp with solvents are useful for physiology studies but not practical for routine effi cacy demonstration. These techniques have the inherent disadvantage of assessing only a small portion of the scalp surface (75). McMichael PTR 01/21/08 Chapter 06

80 Hickman

Other techniques to screen for potentially effective antidandruff preparations include in vitro methods. Minimum inhibitory concentrations (MIC) against Malassezia in culture can predict relative antidandruff potency. In the hair strand test described by Mayser et al. (76), sample hairs are incubated for fi ve minutes with test shampoo formulations, rinsed, dried, and then incorporated into media inoculated with Malassezia with observation of the infl uence on fungal growth. This is intended not only to relate to the MIC but also to refl ect the bioavailability of the antifungal when used as a shampoo.

FDA Monograph The U. S. Food and Drug Administration Monograph on Drug Products for the Control of Dan- druff, Seborrheic Dermatitis, and Psoriasis (77) lists the following active ingredients as “generally recognized as safe and effective” for over-the-counter human use. These ingredients form the basis for most treatment shampoos:

Coal tar 0.5–5% Pyrithione zinc (ZPT) 0.3–2% Salicylic acid 1.8–3% Selenium sulﬁ de 0.6–1% Sulfur 2–5%

Additional over-the-counter or prescription products undergo individual approval processes.

Keratolytics Salicylic acid is still used as it was over one hundred years ago for dandruff. Salicylic acid in a shampoo base is used to loosen scale. Salicylic acid decreases corneocyte to corneocyte adhesion (78). Other agents to remove scale include glycolic acid and urea. P&S Liquid®, a product containing mineral oil, water, glycerin, phenol, and saline that is applied to the scalp, occluded with a shower cap, and left on overnight before shampooing in the morning, can be used for scale that is difﬁ cult to remove, but is messier than simple shampooing. When using a keratolytic shampoo, the patient should allow the lather to stand on the scalp for a few minutes to facilitate loosening of the scale. Oils such as peanut oil or olive oil applied to the scalp under occlusion with a shower cap can soften scale and facilitate removal. However, these need to be removed thoroughly by shampooing. Residual oily products such as pomades left on the scalp promote the growth of Malassezia and aggravate the condition. A soft rubber-toothed scalp brush can mechanically assist scale removal. Patients should be warned against vigorous scratching since electron microscopy conﬁ rms hair shaft damage from excoriation.

Antipruritics By reducing the Malassezia-driven inﬂ ammation of dandruff and seborrheic dermatitis, most effective antimicrobial shampoos are expected to also reduce scalp itch. This has been demonstrated for a pyrithione zinc shampoo (79). Menthol 1.5% added to tar shampoos has been demonstrated to improve short-term itch relief (80).

Anti-Malassezia Agents The majority of effective treatment shampoos have in common their activity against Malassezia yeast. In general, their antidandruff effect parallels their antimicrobial potency (81–83).

Coal Tar Coal tar’s antifungal effect has been demonstrated in vitro against Malassezia strains isolated from dandruff, seborrheic dermatitis, and pityriasis versicolor (84). While it is a weak antifungal, tar has additional antiproliferative (85) and anti-inﬂ ammatory effects making it a ﬁ rst-line choice McMichael PTR 01/21/08 Chapter 06

Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 81 for psoriatic scalp treatment. The efﬁ cacy of tar shampoo formulations may vary considerably in both epidermal DNA synthesis suppression assay and in clinical dandruff testing (86). The disadvantages of tar shampoos limit their use beyond psoriasis. They vary in cosmetic elegance. The odor of tar is objectionable to some patients. Patients with light-colored hair may notice yellow or yellowish-red staining from tar. Safety concerns regarding carcinogenicity exist since coal tar was historically recognized as a carcinogenic agent. Coal tar shampoos are rich in polycyclic aromatic hydrocarbons. Biopsy study of hair follicles following four days of tar shampoo use showed induction of enzyme activity critical to cancer induction (P-450-dependent aryl hydrocarbon hydroxylase) (87). After use of coal tar shampoo, urinary excretion of polycyclic aromatic hydrocarbons metabolites can be detected in humans (88). An epidemiological study in southeastern Arizona showed a slight increase over expected squamous cell skin cancers in users of tar and antidandruff shampoos (89). Regulations in California have required labeling about possible carcinogenic risk for dermatology products containing tar. In normal use, however, tar shampoo contact with the scalp is brief, limiting safety concerns. The FDA monograph regulations include coal tar at 0.5–5% concentration as “generally recognized as safe and effective” and no deﬁ nite evidence of increased cancer from tar shampoos has been recorded despite a long history of use. Tar shampoos remain an important therapeutic choice for scalp psoriasis.

Zinc Pyrithione Shampoos and conditioners containing zinc pyrithione (ZPT), also referred to as pyrithione zinc (PZT), have been available in the United States since the 1960s. Although anti-infl ammatory and cytostatic effects have been suggested for ZPT (90). its primary action in antidandruff products is antimicrobial. Zinc pyrithione interferes with fungal membrane transport and inac- tivates copper-containing enzymes of bacteria and yeasts (91–93). Numerous clinical studies attest to the effectiveness of ZPT in reducing dandruff and eliminating Malassezia from scalp scale (7,28,73,77,94). Electron microscopy of dandruff scalp samples before and after treatment with ZPT shampoo demonstrated improvement in the stratum corneum ultrastructure (67). Formulation is critical to the effectiveness of ZPT products. The compound exists as a dimer of two monomers linked by zinc-oxygen bonds. It is a crystalline solid available in various particle sizes and shapes. The bioavailability rather than simply the percent present determines the effi cacy. Bioavailability is infl uenced by active concentration, particle size, particle shape, uniformity of suspension, and delivery to the scalp. Clinical testing to date has demonstrated that an optimum particle size and shape for distribution and retention on the scalp is a thin platelet with diameter of 2.5µm (95). Larger cuboidal forms of ZPT do not precipitate well on the scalp and smaller particles rinse away too easily rather than being retained on the scalp. Since dandruff is a chronic condition and recolonization with Malassezia occurs readily, the long-term use of treatment shampoos is necessary. Thus, the cosmetic qualities of the shampoo and its effect on hair texture become important compliance issues. ZPT has been demonstrated to inhibit the irritation potential of surfactants (7). Antidandruff shampoos containing ZPT have been formulated with silicones and other conditioners while retaining antidandruff effi cacy (96).

Selenium Sulfi de Selenium sulfi de is also an effective antimicrobial against Malassezia (94). A cytostatic mechanism of action has also been proposed (97). Selenium sulfi de in micronized particles outper- forms higher concentration coarse grade products. The FDA monograph was amended in 1994 to accept micronized selenium sulfi de at 0.6% for the control of dandruff in addition to the previously accepted 1% standard selenium sulfi de (98). The distinctive odor of selenium sulfi de limits its acceptability to some patients. The availability of the 2.5% higher concentration shampoo as a prescription formulation may be an advantage for dandruff inadequately controlled by over-the-counter products.

Ketoconazole Ketoconazole also has both 1% over-the-counter and 2% prescription strengths available. Both effectively eliminate Malassezia from the ﬂ ake samples and improve dandruff and seborrheic McMichael PTR 01/21/08 Chapter 06

82 Hickman dermatitis with the 2% shampoo more effective than the 1% (99–101). The mechanism of action for its antifungal activity is inhibition of cell membrane ergosterol synthesis (102). Ketoconazole has also been shown to have some direct anti-inﬂ ammatory activity separate from its antimicrobial action (103), to inhibit leukotriene biosynthesis (104) and to reduce fungal antigen-induced lymphocyte-mediated immune responses (105). Ketoconazole binds to the keratin of the hair shaft and scalp, allowing persistence of its effect between shampoos (106). Shampooing once weekly as prophylaxis has been demonstrated to be effective after treatment of dandruff and seborrheic dermatitis (107). This is an advantage for patients who because of age, illness, or choice of hairstyle shampoo less frequently. On the other hand, prolonged use with frequent shampooing (5 to 10 times per week) has been demonstrated to be safe with no signiﬁ cant systemic absorption of ketoconazole (108–110).

Ciclopirox Ciclopirox 1% shampoo is a more recent addition to the prescription shampoo choices (111). It is a hydroxypyridone antifungal agent with a broad spectrum of fungicidal activity. There are also anti-inﬂ ammatory (112) and some antibacterial effects. Ciclopirox shampoo is effective in treating seborrheic dermatitis used once or twice a week (113,114) and even showed a decreased relapse rate with prophylactic shampooing every two weeks (115).

Other Other agents active against Malassezia are available as antidandruff shampoos. Tea tree oil (Melaleuca oil) is reported to have broad-spectrum antimicrobial activity and has been used in shampoo base for dandruff (116,117). The action of sulfur-containing shampoos may be partially explained as anti-Malassezia effect (118,119). The antidandruff effect of sulfur is enhanced in formulas containing salicylic acid (120). Sulfur- or sulfacetamide-containing shampoos and lotions may also be helpful where bacterial overgrowth on the scalp is heavy. Climbazole is an effective antimycotic agent available in antidandruff shampoos in Europe but not currently marketed in the United States (121,122).

Shampoo Comparison Studies A few direct comparison studies have been done to compare results with different brands or formulations of shampoos (123–126). Nizoral® 2% ketoconazole shampoo and Selsun® 2.5% selenium sulﬁ de were nearly equal in efﬁ cacy (108–110). Results in comparison studies can vary depending on the exact formulations tested. One comparison demonstrated 2% ketoconazole superior to a 1% ZPT shampoo (127), while a study specifying Nizoral 2% ketoconazole shampoo and Head & Shoulders® antidandruff shampoo with 1% pyrithione zinc found them similarly effective after 4 and 6 weeks of use (128).

Gels, Lotions, Creams When shampoo alone is not suffi cient to clear dandruff or seborrheic dermatitis and in cases where frequent shampooing is not possible or desirable anti-Malassezia leave-on products can be employed. Lotions, creams, and gels with sulfacetamide, ketoconazole (129), tar or ciclopirox (130) are available. Note that propylene glycol, a common vehicle component, is an effective treatment for Malassezia when applied in high concentration (131–135). Thus, gel formulations may be especially effective for seborrheic dermatitis. Gels can substitute for styling pomades in African-American hair or be applied to the scalp prior to using a hair dressing on the ends of the hair. Some gels contain fl ammable vehicles; patients should avoid fi re, fl ame, or smoking during and immediately after application (136). Ketoconazole and ciclopirox creams and gels are also helpful when the seborrheic dermatitis involves other areas of the face or body (137– 139). Benzoyl peroxide is another antimicrobial agent reported to be useful in the treatment of facial seborrheic dermatitis (140–142). Rarely, a patient with severe seborrheic dermatitis may need oral ketoconazole (17) or itraconazole to achieve control.

Dispelling Shampoo Myths Many patients with dandruff and seborrheic dermatitis mistakenly believe the ﬂ aking they notice is “dry scalp”; they need to be encouraged to shampoo regularly and to avoid oily or McMichael PTR 01/21/08 Chapter 06

Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 83 greasy hair products. It is especially important for African-American patients to ﬁ nd suitable non-greasy hair conditioning and styling products. Note also that some patients have heard the myth that dandruff shampoos will cause hair loss. Perhaps the harsher surfactants used decades ago initiated this impression. Modern shampoo vehicles are milder and better tolerated by the hair and scalp. The availability of built-in conditioners (143) or separate antidandruff compatible conditioners may be helpful for patients with dry or damaged hair. Antidandruff shampoos which incorporate dimethicone conditioners would be an especially good choice for African-American patients with easily damaged hair. Contrary to the myth, there are data that shampoos containing ZPT or ketoconazole may actually improve hair density in androgenetic alopecia (144–146).

Anti-Inﬂ ammatory Agents The inﬂ ammatory component of more severe seborrheic dermatitis may require additional treatment. The usual choices are corticosteroids, available in a vast range of potencies and vehicles. Rarely, severe seborrheic dermatitis could require a brief course of oral corticosteroids to initiate control.

Topical Corticosteroids Over-the-counter scalp lotions or solutions containing hydrocortisone and the lowest potency prescription steroids may suffi ce for mild infl ammation and are acceptable for intermittent use on the face as well as scalp (147). More potent corticosteroids are available as shampoos, oil- based pre-shampoo treatments, gels, lotions, solutions, and mousse-like foams. Patients usually fi nd solutions and foams neater and less disruptive to hairstyles (148), but these vehicles may sting because of the scalp barrier disruption (149). Especially severe scalp infl ammation or scalp psoriasis may benefi t from corticosteroid ointment, oil or gel applied under plastic shower cap occlusion several hours or overnight before a shampoo.

Calcineurin Inhibitors Safety concerns limit the use of corticosteroids for seborrheic dermatitis extending to the face. The chronic nature of seborrheic dermatitis makes dependence on corticosteroids inadvisable because of the risks of steroid rosacea, telangiectasia, atrophy, absorption and dyspigmentation (150). At facial sites, the off-label use of the calcineurin inhibitors tacrolimus ointment or pimecrolimus cream has been reported to be helpful without the complication of atrophy or dyspigmentation (151–154). Additionally, both of these calcineurin inhibitors have been demonstrated to have some antifungal effect against Malassezia (155,156).

Combination Therapy Effective individualized therapy of seborrheic dermatitis often utilizes more than one agent (Table 1). For example, for an active person with a short or simple hairstyle and moderate dandruff, simply using an anti-Malassezia shampoo daily may suffi ce to eliminate the symptoms of fl aking and itching. However, a patient with severely infl amed scalp might begin with nightly applications of an oil- or ointment-based steroid under plastic shower cap occlusion washed out in the morning with an anti-Malassezia shampoo until infl ammation was reduced, and then switch to the less messy use of a steroid solution, spray, or foam between shampoos after the scalp barrier improves. Concomitant dermatitis of the ears and face would be treated with ketoconazole or ciclopirox gel or cream, supplemented by topical mupirocin if fi ssures or crusting suggest secondary Staphylococcal infection. Seborrheic dermatitis of the beard or moustache can be treated by using the dandruff shampoo in these areas during showering or a sulfur/sulfacetamide facial wash plus ketoconazole or ciclopirox gel as needed. When hairstyle or general health limits shampooing to once-weekly or less, prescription- strength ketoconazole shampoo is a useful fi rst choice. If the patient depends on a beauty salon for shampooing, she can take the prescription product to the salon and assure personnel that no special precautions are necessary but that the shampoo procedure should be amended to allow the lather to remain on the scalp for up to fi ve minutes before rinsing. Between shampoos, a steroid foam, solution, or spray can relieve itching without interfering with the hairstyle. McMichael PTR 01/21/08 Chapter 06

84 Hickman

TABLE 1 Treatment of Dandruff and Seborrheic Dermatitis General Instructions Shampoo as frequently as hairstyle and health permit (daily if possible) Avoid greasy hair products or pomades First-line therapy: Non-prescription antimicrobial shampoo Ketoconazole 1% Pyrithione zinc (ZPT) 0.3–2% Selenium sulfi de 0.6–1% Coal tar 0.5–5% Sulfur 2–5% Tea tree oil Prescription antimicrobial shampoo Ketoconazole 2% Selenium sulfi de 2.5% Ciclopirox 1% For thick scale, add: Keratolytic agents Salicylic acid shampoo Glycolic acid shampoo Urea 10% shampoo P&S Liquid® with shower cap occlusion For more severe itching, add: Antipruritics Menthol in shampoo Menthol in scalp solution For more severe cases or where frequent shampooing is not possible, add: Antimicrobial topical medications Ketoconazole 2% cream, gel Ciclopirox 0.77% cream, gel, topical suspension Sulfacetamide 10% cream, foam, gel, wash Sulfacetamide/sulfur suspension, cream, emulsion, gel, wash For more severe infl ammation, add: Anti-infl ammatory agents Topical corticosteroids Non-prescription Hydrocortisone 1% scalp solution, cream, lotion, ointment Prescription (numerous choices such as the following) Aclometasone 0.05% cream, ointment Hydrocortisone butyrate 0.1% solution Betamethasone valerate 0.1% cream, lotion, ointment Betamethasone valerate 0.12% foam Mometasone 0.1% lotion Fluocinolone acetonide 0.01% topical oil, solution, ointment Fluocinolone 0.01% shampoo Triamcinolone aerosol Betamethasone dipropionate 0.05% ointment, gel, lotion Clobetasol 0.05% shampoo, lotion, spray, solution, foam Calcineurin inhibitors Prescription (off-label use) Tacrolimus 0.03, 0.1% ointment Pimecrolimus 1% cream

Similarly, African-American hair may not tolerate frequent shampooing unless the hair is worn very short. Labor-intensive hairstyles such as braiding patterns cannot be reasonably undone for medication application. In these settings, ketoconazole 2% shampoo as often as practical is a ﬁ rst step. Steroid solutions, foams, or sprays may be applied without disrupting hairstyling. If hair dressings are usually used, ketoconazole or ciclopirox gel or steroid- containing ointments, gels or oils may be substituted for the cosmetic hair products. McMichael PTR 01/21/08 Chapter 06

Dandruff and Seborrheic Dermatitis: Use of Medicated Shampoos 85

SUMMARY Dandruff, defi ned as visible scalp-fl aking, is a common chronic problem for a signifi cant portion of the population. Dandruff and infl ammatory seborrheic dermatitis of the scalp are of similar origin, differing chiefl y in the degree of visible infl ammation. After centuries of study, the exact pathophysiology is not fully understood, but a genetically and environmentally infl u- enced response to Malassezia yeast and subsequent infl ammation are central features. Thera- peutic choices include a combination of products with antimicrobial, keratolytic, antipruritic, and anti-infl ammatory modes of action. Individualization of treatment requires considering the patient’s hairstyle and lifestyle.

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142. Prestia AE. Topical benzoyl peroxide for the treatment of tinea versicolor. A Am Acad Dermatol 1983; 9(2):177–178. 143. Rushton H, Gummer CL, Flasch H. 2–in-1 shampoo technology: state-of-the-art shampoo and conditioner in one. Skin Pharmacol 1994; 7(1–2):78–83. 144. Berger RS, Fu JL, Smiles KA, et al. The effects of minoxidil, 1% pyrithione zinc and a combination of both on hair density: a randomized controlled trial. Br J Dermatol 2003; 149(2):354–362. 145. Pierard-Franchimont C, De Doncker P, Cauwenbergh G, et al. Ketoconazole shampoo: effect of long-term use in androgenic alopecia. Dermatology 1998; 196(4):474–477. 146. Khandpur S, Suman M, Reddy BS. Comparative efﬁ cacy of various treatment regimens for androgenetic alopecia in men. J Dermatol 2002; 29(8):489–498. 147. Cornell RC. Atrophogenic potential of alclometasone dipropionate ointment 0.05% vs hydrocortisone ointment 1%. Curr Ther Res 1986; 39(2):260–268. 148. Milani M, Molfetta ADS, Gramazio R, et al. Efﬁ cacy of betamethasone valerate 0.1% thermophobic foam in seborrheic dermatitis of the scalp: an open-label, multicenter, prospective trial on 180 patients. Curr Med Res Opin 2003; 19(4):342–345. 149. Harding CR, Moore AE, Rogers JS, et al. Dandruff: a condition characterized by decreased levels of intercellular lipids in scalp stratum corneum and impaired barrier function. Arch Dermatol Res 2002; 294(5):221–230. 150. Gupta AK, Nicol KA. Seborrheic dermatitis of the scalp: etiology and treatment. J Drugs Dermatol 2004; 3(2):155–158. 151. Meshkinpour A, sun J, Weinstein G. An open pilot study using tacrolimus ointment in the treatment of seborrheic dermatitis. J Am Acad Dermatol 2003; 49(1):145–147. 152. Rigopoulos D, Ioannides D, Kalogeromitros D, et al. Pimecrolimus cream 1% vs. betamethasone 17–valerate 0.1% cream in the treatment of seborrheic dermatitis. A randomized open-label clinical trial. Br J Dermatol 2004; 151(5):1071–1075. 153. Firooz A, Solhpour A, Gorouhi F, et al. Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial. Arch Dermatol 2006 142(8):1066–1067. 154. High WA, Pandya AG. Pilot trial of 1% Pimecrolimus cream in the treatment of seborrheic dermatitis in African American adults with associated hypopigmentation. J Am Acad Dermatol 2006 54(6):1083–1088. 155. Sugita T, Tajima M, Ito T, et al. Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species. J Clin Microbiol 2005; 43(6):2824–2829. 156. Sugita T, Tajima M, Tsubuku H, et al. A new calcineurin inhibitor, Pimecrolimus, inhibits the growth of Malassezia spp. Antimicrob Agents Chemother 2006; 50(8):2897–2898. McMichael PTR 01/21/08 Chapter 07

7 Alopecia Areata

Maria K. Hordinsky Department of Dermatology, University of Minnesota, Minneapolis, Minnesota, U.S.A. Ana Paula Avancini Caramori Department of Dermatology, Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, Brazil

INTRODUCTION Alopecia areata (AA) is a complex genetic, immune-mediated non-scarring disease that targets actively growing anagen hair follicles (1). The lifetime risk is estimated to be approximately 2% (2). The disease can affect all ethnic groups and both males and females at all ages. More than 4.5 million people in the United States are estimated to be affected with AA, according to the National Alopecia Areata Foundation. AA typically presents as one of four major patterns:

Round or oval patches of hair loss Loss of all scalp hair (alopecia totalis) Loss of all body hair (alopecia universalis) Ophiasis pattern alopecia areata (Figs. 1–3)

There is not yet a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of this common hair disease. To suppress disease activity, physicians commonly prescribe topical or intralesional corticosteroids and, less commonly, oral steroids. There are also many other treatment approaches and several are currently being evaluated in clinical trials. As the understanding of AA advances, physicians will be able to offer their patients and families more comprehensive information on the epidemiology, pathophysiology, evaluation, and management of this immune-mediated disease.

CLINICAL FEATURES In addition to the common presentations of patchy or extensive hair loss, alopecia areata may present less commonly as reticular alopecia areata, diffuse scalp alopecia areata, or perinevoid alopecia areata. Patients who experience the reticular variant have ongoing disease activity with patches of non-scarring hair loss appearing and disappearing. Those with the diffuse variant of AA may present with a decrease in scalp hair density but no patches. A scalp biopsy obtained from such patients can show patchy focal peribulbar infl ammation. The perinevoid variant is even rarer and is characterized by non-scarring hair loss around nevi. When the AA process is active, hair-pull tests are positive and exclamation-mark hair fi bers can frequently be found. These fi bers have a broader distal segment than the proximal end and when these fi bers grow they taper down proximally to a pencil point and may break easily, similar to what is seen with hair fi bers experiencing anagen arrest as with chemotherapy (Fig. 4). The immune attack on hair follicles tends to spare white fi bers; likewise when hair regrowth occurs, fi bers are frequently white before coming pigmented, indicating that the hair follicle pigment system is still dysfunctional (Fig. 5). It is relatively easy to diagnose alopecia areata, particularly when there are patches of non-scarring hair loss, skin “bare as a baby’s bottom,” and positive hair-pull tests. However, patchy disease may sometimes be mistaken for tinea capitis, traction alopecia, loose anagen syndrome, aplasia cutis congenita, or pseudopelade (3). Nail abnormalities may precede, follow, or occur concurrently with hair-loss activity. The frequency of nail changes has been reported to range from 10–66%, with nail pitting as the most McMichael PTR 01/21/08 Chapter 07

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FIGURE 1 Scalp: Extensive patchy alopecia areata.

FIGURE 2 Scalp: Alopecia totalis. McMichael PTR 01/21/08 Chapter 07

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FIGURE 3 Scalp: Ophiasis pattern alopecia areata. Area of involvement includes the lower occipital scalp and region above both ears.

FIGURE 4 Regrowth of tapered ﬁ bers in a patient with alopecia areata. This is similar to what can be seen following chemotherapy- induced hair loss.

FIGURE 5 Regrowth following an episode of alopecia areata demonstrating that though hair is back, pigment-cell function is not; hence, disease activity is still present. commonly reported nail abnormality. Other abnormalities include koilonychia, longitudinal ridging, brittle nails, onycholysis, onychomadesis, and periungual erythema (4). It has also been suggested that sweat gland function may be altered in patients with AA (5,6). Additional studies are needed to conﬁ rm this observation. AA may occur in otherwise healthy individuals or it may occur associated with other diseases. Common disease associations include atopy (allergic rhinitis, asthma, and atopic dermatitis) up to 40% in some studies, while the prevalence of atopic disease in the population is estimated to be 20% (7). Other common disease associations include thyroid disease and McMichael PTR 01/21/08 Chapter 07

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autoimmune diseases, such as thyroiditis and vitiligo. Up to 30% of patients with autoimmune polyglandular syndrome (APS-1) may express alopecia areata. These patients have chronic hypo- parathyroidism, mucocutaeous candidiasis, and autoimmune adrenal insufﬁ ciency. AA is also seen more frequently in patients with Down’s syndrome and in those with Turner’s syndrome (8,9). Though not a life-threatening disease, AA may have a signiﬁ cant psychological impact on patients, leading to a high lifetime rate of generalized anxiety disorders or even depression (10).

SCOPE OF THE PROBLEM The prevalence of AA in the United States, as determined from the First National Health and Nutrition Examination Survey conducted from 1971 through 1974, was 158 per 100,000 persons, or roughly 0.1 to 0.2% of the population (7,11). Ikeda reviewed the case histories of 1,989 patients with AA at Kyoto University in Japan and assigned them to one of four types (12):

Type I, common type carrying a good prognosis; Type II, round, ophiasis, reticular or type associated with atopy; Type III, the prehypertensive type commonly associated with a reticular pattern of hair loss evolving to alopecia totalis; and Type IV, associated with endocrine-autoimmune diseases.

Other investigators subsequently confi rmed many of her conclusions, but in more recent times this classifi cation system is not commonly used. Muller and Winkelmann conducted a historical review of 736 patients with AA seen at the Mayo Clinic between 1945 and 1954. They ascertained that 30% of patients developed alopecia totalis (54% of children, 24% of adults) and that the proportion of patients presenting with alopecia totalis declined with each decade of life. They concluded that although spontaneous resolution is expected in most patients, a small but signifi cant proportion of cases, approximately 7%, may evolve into severe and chronic hair loss (7). Walker and Rothman studied 230 patients with AA who were seen in the University of Chicago Clinics during the period from 1928 to 1948 (13). They reported that of those patients who developed AA before puberty, 50% eventually developed alopecia totalis. They also reported that the overall incidence of relapse or of experiencing another episode of AA was 86%, but the fi gure reached 100% if patients were followed for 20 years. From such studies and others, the presence of severe nail abnormalities, atopy (asthma, allergic rhinitis, and atopic dermatitis), and onset of extensive disease at less than fi ve years of age have all been implicated as negative prognostic indicators. Alopecia totalis or universalis lasting more than two years, is also believed to have a particularly low chance of spontaneous regrowth and to be less responsive to therapy.

FIGURE 6 Scalp biopsy specimen from a patient with long-standing extensive alopecia areata. Follicles are small, ﬁ bers are dystrophic, and there is minimal perifollicular and peribulbar inﬂ ammation. McMichael PTR 01/21/08 Chapter 07

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FIGURE 7 (See color insert.) Higher magniﬁ cation of a follicular unit emphasizing the small, dystrophic hair ﬁ bers commonly seen in patients with long-standing disease.

More recent surveys of AA have been completed in Kuwait, northern India, Chandigarh, India, Singapore, and Korea. In some, similar prognostic indicators have been reported, but in others different associations have been observed (14–19). In a study completed in Asia, records of all newly diagnosed AA cases seen from May 1998 to April 1999 at the National Skin Center in Singapore were collected with regard to the epidemiology, pattern of alopecia, and disease associations. Two hundred and nineteen new case referrals of AA were examined, representing an incidence of 3.8%. There were 173 Chinese, 35 Indians, and 11 Malays. The male-to-female ratio was 1:1.3. The median age at presentation was 25.2 years. The majority of patients had their fi rst episode before the age of 40 years. Thirty-fi ve percent of such patients presented with extensive AA compared with 5.5% of the patients above the age of 40 years. The authors concluded that their fi ndings were similar to those reported in the Western literature. Similar fi ndings were described from Chandigarh, India, where all new cases of AA were studied during the years 1983–1993. Eight hundred forty-one cases were recorded, including 201 (23.9%) children less than 16 years of age. The male-to-female ratio was 1:1.4 for childhood alopecia areata. The conclusion from this study was that childhood AA in Chandigarh is quite similar to that seen in Western countries. However, an association of atopy with a younger age at onset and severe alopecia was not confi rmed. Different observations were noted in studies from Kuwait and northern India. In Kuwait, 10,000 consecutive new patients were surveyed; 96% of whom were children of Arab descent. A female preponderance (52%) was observed, and infants constituted the largest group (28.7%). A total of 162 dermatoses were recorded. Atopic dermatitis was the most prevalent dermatitis (31.3%). The prevalence of AA was 6.7%. Further study of 215 children revealed that 97% of the children were of Arab ancestry and girls outnumbered boys by a 2.5:1 ratio. The peak age of onset was seen between 2 and 6 years of age with a mean age of onset at 5.7 ± 2.8 years. A majority of the patients had mild disease, and extensive disease was seen in 13% of the children. The age of onset, a positive family history of alopecia areata, and associated atopic disorders were observed to have no infl uence on the extent and severity of the disease. In northern India, a prospective, hospital-based study, which lasted for a decade (1983– 1992), evaluated the epidemiology of alopecia areata, including noting associated diseases and risk factors for development of severe alopecia areata. The study evaluated 880 patients (532 men and 276 women) and 509 controls (307 men and 202 women). The conclusions were that in northern India, AA has preponderance in men (2:1) and the majority of individuals with the disease were 40 years of age or less. Onset in childhood was more frequent in females, but the incidence of severe alopecia was higher in males with onset at an earlier age. Atopy was found to be present in 18% of patients, but its reported association with younger age of onset and severe alopecia was not confi rmed. Risk factors for severe AA were the presence of vitiligo in family members and onset before 20 years of age, especially in males. McMichael PTR 01/21/08 Chapter 07

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The differences between age of onset, gender, and risk factors in different parts of the world is at this point observational information. The reasons for these differences remain to be ascertained. However, in our mobile world, an understanding of these differences may be important in discussions with patients and families.

PATHOPHYSIOLOGY Histology Recent transplantation studies in severe combined immunodefi cent (SCID) mice have established that T-cell immunity plays a crucial role in the pathophysiology of AA (20). Histologically, a hallmark of AA has been the presence of a peribulbar lymphocytic infi ltrate that consists primarily of activated T lymphocytes. Most scalp biopsy specimens from patients with typical oval and round patches of AA will show this classic peribulbar lymphocytic T-cell infi ltrate, but infl ammation may be minimal or absent in long-standing disease, the ophiasis or diffuse forms (21). These changes with disease activity and type are postulated to be associated with different therapeutic responses; for example, it may be that the use of steroids may be more effective in the acute phase as compared to the chronic phase of AA when the infl ammatory infi ltrate is less prominent. If the diagnosis of AA is not straightforward, examination of a 4-mm scalp biopsy specimen may be useful in confi rming the diagnosis as well as assisting with the development of a treatment plan (Fig. 6). The best place to take a biopsy for diagnostic purposes is the active edge of an area of hair loss. This biopsy specimen will typically show the characteristic peribulbar, infl ammatory infi ltrate, in both horizontal and vertical sections, as well as an increased percentage of follicles in telogen. In extensive alopecia areata, examination of both vertical and horizontal scalp biopsy specimens may provide useful information in advising patients about therapy (Fig. 7). A mean follicular count in horizontal sections which is less than one follicle per square millimeter usually indicates little likelihood for good regrowth (21).

Immunology Normal anagen hair-bulb keratinocytes lack expression of major histocompatibility complex class I and class II antigens. However, in alopecia areata, human leukocyte antigen (HLA) A, HLA-B, HLA-C, and HLA-DR are all expressed on anagen hair bulbs. HLA-DR expression has also been found on telogen hair bulbs of AA but to a much lower extent. These observations have led to the concept that immune privilege is lost in AA and that the disease involves T- cell interaction with aberrant HLA-DR antigens expressed by hair follicle keratinocytes (22). Increased, decreased, and normal peripheral blood T and B lymphocyte number and function have all been reported in AA patients and, as noted earlier, the results of transplantation studies in SCID mice have established the importance of T-cell immunity in this disease (1,20).

Genetics Understanding the genetic factors in AA may help deﬁ ne at-risk individuals as well as lead to the design of new treatment strategies. The familial incidence of AA has been reported to range between 10% and 50% and it is now generally accepted that AA is a complex or multifactorial genetic trait (23). This is based on the following:

1. Its prevalence in the population 2. Concordance with twins (55%) 3. A Gaussian distribution of severity 4. A ten-fold increased risk of affected ﬁ rst-degree relatives 5. The aggregation of affected individuals in families, rather than showing a clear Mendelian pattern of inheritance

Until recently, genetic studies were focused on association analyses with candidate genes including particular HLA alleles, interleukin-1 cluster genes, and the MX1 gene. Sig- niﬁ cant associations were reported for severe, extensive alopecia areata, and DQB1*0301 and McMichael PTR 01/21/08 Chapter 07

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DRB1*1104 alleles. The major histocompatiblity complex class I chain-related gene A (MICA) was identiﬁ ed as both a potential candidate gene that could be associated with susceptibility as well as severe, extensive disease. In addition, the gene encoding the lymphoid protein tyrosine phosphatase (PTPN22) was demonstrated to be associated with severe forms of alopecia areata. Other disease associations described with disease severity include the IL-1 receptor antagonist and the IL-1 receptor antagonist homologue. More recently, a genome-wide scan for linkage has revealed evidence for several susceptibility loci for AA on chromosomes 6, 10, 16, and 18. Interestingly, the major locus on chromosome 18 was found to coincide with a previously reported locus for psoriasis as well as hereditary hypotrichosis simplex, suggesting this region may harbor genes involved in a number of different skin and hair disorders (23).

Nerves Many AA patients experience occasional itching, tingling, formication, or slight local pain during combing, touching, or tension on their hair. Alterations in neuropeptide and neurotrophin expression in animal models of AA as well as humans have been reported, suggesting a role for the neurocutaneous immune system in AA (24,25). More recently, peripheral nerve function in the C2 and V1 dermatomes, both of which innervate scalp skin, was found to be abnormal as compared to controls (70). Stressful life events and psychiatric disorders have been studied as they relate to both the onset and the progression of alopecia areata. In one study, scalp-hair regrowth was analyzed in 21 patients, nine with alopecia totalis or alopecia universalis and 12 with extensive AA during a fi ve-year period. After hypnotherapy treatment, all patients had a signifi cantly lower score for anxiety and depression and scalp-hair growth of 75% to 100% was seen in 12 patients after three to eight sessions. Clearly more patients need to be studied, but the fi ndings suggest hypnotherapy may enhance the mental well-being of patients and may improve clinical outcome, perhaps through an effect on the peripheral nervous and immune systems (26).

TREATMENTS There is no “best” treatment for AA and at this time there is no FDA-approved drug for the treatment of AA (27). It is believed that the available treatments at best only suppress the underlying process. Most of the published studies on the treatment of AA have focused on correlating therapy with clinical outcome as well as disease extent, disease duration, and historical factors such as previous treatment or history of atopy. Treatment for AA also needs to be considered in light of the normal course of the disease. To facilitate comparison of data and the sharing of patient-derived tissue alopecia areata, guidelines were published in 1999 and then updated in 2004 (28,29). These guidelines are now routinely used in clinical trials and can be adapted to direct patient care. The following represent the guideline recommendations for data collection on the extent of scalp and body hair loss as well as nail abnormalities:

_____ S0 = no scalp hair loss _____ S1 = <=25% hair loss _____ S2 = 26–50% hair loss _____ S3 = 51–75% hair loss _____ S4 = 76–99% hair loss _____ a = 76–95% hair loss _____ b = 96–99% hair loss _____ S5 = 100% hair loss S: scalp hair loss

_____ B0 = no body hair loss _____ B1 = some body hair loss _____ B2 = 100% body (excluding scalp) hair loss B: body hair loss McMichael PTR 01/21/08 Chapter 07

98 Hordinsky and Caramori

_____ N0 = no nail involvement _____ N1 = some nail involvement _____ 20 nail dystrophy/trachyonychia (must be all 20 nails) N: nail involvement

Sacket deﬁ ned evidence-based medicine as “the integration of individual clinical expertise with the best available external clinical evidence of systematic research” (30). In the last 30 years there have been several publications on the treatment of AA and those utilizing evidence- based criteria have been interpreted to have the following (31):

Placebo-controlled with statistically signiﬁ cant results or unilateral treatment Majority of patients with alopecia areata totalis, universalis, or extensive patchy (>25%) hair loss Patients with a disease duration of more than three months End result of cosmetically acceptable hair regrowth Not associated with serious side effects

Review of the literature indicates that in contrast to other treatments, contact sensitizers such as diphencyprone or squaric acid dibutylester have been used in studies in a manner that fulﬁ lls these criteria. However, there are questions and concerns regarding the use of these chemicals as neither preparations nor shelf-life are standardized. Long-term controlled safety studies are not available.

Topical Sensitizers Diphenycyprone is the most commonly used topical sensitizer. Patients are normally sensitized to a 2% solution within a two-week time period. Weekly applications ranging from 1.0, 0.5, 0.1, 0.05, 0.01, or 0.001 to 0.0001 follows. The goal is to choose a concentration capable of producing a mild allergic contact dermatitis. Cosmetically acceptable hair regrowth may require up to two years of treatment. Sensitization, if usually performed on the scalp, and weekly applications are targeted to produce a mild eczematous reaction. Initial hair regrowth may be visible after 8–12 weeks and may be discontinued once hair regrowth occurs; likewise, treatment can be reinsti- tuted if a relapse occurs. Desired reactions include the development of a mild eczematous dermatitis and enlargement of retroauricular lymph nodes. Undesired side effects noted in 2–5% of patients include vesicular or bullous reactions, dissemination of allergic contact dermatitis, urticarial or erythema multiforme-like reactions, as well as alterations in skin pigmentation (32,33).

Steroids: Topical, Intralesional, Oral The minimum and maximum strengths or classes of topical steroids for the treatment of AA have not yet been determined. A retrospective review suggests that patients with more than 50% hair loss may achieve signifi cant hair regrowth with a class I–IV topical steroid and a response has also been demonstrated in patients with severe, refractory AA applying 0.05% clobetasol propionate under occlusion (34,35). The use of 0.05% betamethasone dipropionate cream, 0.05% clobetasol propionate, and 0.2% fl uocinolone acetonide cream have all also been associated with hair regrowth with the time to regrowth averaging three months (35–38). Primary complications from the use of topical steroids include the development of skin atrophy, folliculitis, and telangiectasias, all of which are reversible adverse experiences if drug therapy is discontinued. Little is known about adrenal suppression with the use of topical steroids to intact scalp skin for an extended period of time. Because of these well-known side effects of topical steroid use, implementation of shampoos containing mid or higher strength steroids is particularly appealing as direct contact is shorter and theoretically should be associated with fewer side effects. The effi cacy of the use of shampoo products containing steroids in the management of AA remains to be confi rmed. Intralesional steroids, including triamcinolone acetonide or triamcinolone hexaceton- ide are commonly used to treat patients with less than 50% scalp involvement (39). Eyebrow McMichael PTR 01/21/08 Chapter 07

Alopecia Areata 99 regions may also be injected; rarely is this technique used to treat eyelash alopecia areata. Con- centrations typically used range from 3 to 10 mg/cc. In some practices, up to 40 mg will be injected intralesionally per session with sessions spaced apart by 6- to 8-week intervals. To be successful, it is important to inject just below the epidermis where the miniaturized follicles are, not into the fat, as this may lead to atrophy and a poor response. Children and adolescents and some adults may benefi t from application of a topical anesthetic prior to therapy. Compli- cations include atrophy, which again is reversible if treatment is discontinued. The National Alopecia Areata Foundation is currently sponsoring a clinical trial examining adrenal-gland suppression with this treatment modality. Oral steroids may be of benefi t to patients with active disease. Various dosing regimens have been used successfully and reported in the literature. In one study, the critical threshold to stimulate hair growth was 0.8 mg/kg daily. A six-week tapering dose of oral prednisone beginning at 40 mg/day tapering by 5 mg/day weekly over 4 weeks and then by 5 mg/day every three days resulted in 15 of 32 patients having at least 25% regrowth and 8 of the 15 experiencing more than 75% regrowth (40). An oral monthly pulse of 300 mg prednisolone for a minimum of four doses has also been reported to result in complete or cosmetically acceptable hair regrowth (41). In other studies, children with extensive, recent-onset alopecia areata benefi ted from intravenous methylprednisoone (5 mg/kg twice a day) as did patients with exensive multifocal AA or severe AA of recent onset (42,43). Side effects of using oral or intravenous steroids for the treatment of AA deserve attention. Adverse experiences include weight gain, osteoporosis, hypertension, psychological changes, suppression of the adrenal cortical axis, striae, acne, hypertrichosis, and purpura. To counter the development of osteoporosis, calcium, vitamin D, or even drugs such as Fosamax® [adlendronate sodium (Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.)], may be prescribed. Most disheartening to patients however, is either not responding to this treatment approach or experiencing excellent hair regrowth only to see the recurrence of AA once treatment is discontinued. Patients need to be coached in advance about potential adverse experiences and expectations.

Minoxidil: Topical and Oral The safety profi le of this drug is appealing but evidence-based medicine using the criteria mentioned earlier does not support its use in the management of AA (31). However, patients with patchy AA have been reported to achieve cosmetically acceptable regrowth with 2% topical minoxidil and in one study it was suggested that patients with severe disease may benefi t from 5 mg of oral minoxidil administered every 12 hours with a mean time of approximately 35 weeks to attain cosmetically acceptable hair regrowth (44,45). Patients receiving this therapy need to be on a 2-gram sodium diet, as fl uid retention may be an adverse experience. Topical minoxidil, either the 2% or 5% concentrations, can be benefi cial in AA when the focus is on promoting follicle differentiation, early anagen to late anagen.

Anthralin Anthralin is postulated to target mitochondria and interact with the electron transport chain on the inner mitochondrial membrane, ultimately resulting in a decrease in adenosine triphophos- phate synthesis. It also generates oxygen radicals in situ via auto-oxidation. How these mechanisms of action are associated with hair regrowth in AA patients is unknown. Concentrations used in the management of AA must be sufﬁ cient to elicit mild irritation and may range from 0.2% to 1.0% (46). However, just as with minoxidil, the use of this drug in published studied has not fulﬁ lled the criteria of evidence-based treatment described earlier (31).

Light Therapy (UVA, NBUVB, UVB, Laser) The use of psoralen-ultraviolet A (PUVA) light has resulted in complete hair regrowth for some patients with either patchy or extensive AA. Although complete hair regrowth has been achieved with 50 to 80 treatment sessions, averaging three per week, hair loss is commonly seen following discontinuation (47). An additional concern is in regard to increased risk of malignant melanoma with more than 250 treatments reported in psoriasis patients treated with PUVA McMichael PTR 01/21/08 Chapter 07

100 Hordinsky and Caramori

(48). UVB light treatment has also resulted in complete hair and beard regrowth although hair loss may occur following discontinuation of treatment (49,50). In contrast, a study examining the role of photodynamic therapy in AA found no signiﬁ cant hair regrowth after 20 twice- weekly treatment options (51). The 308-nm excimer laser has been used to successfully treat AA in small studies. The results look promising, particularly for eyebrow/eyelash AA, but more studies are needed (52).

Biologics Given the involvement of T cells in the pathogenesis of AA, agents specifi cally targeted against T cells have been studied. By blocking CD11a, Efalizumab (Raptiva®, Genentech, Inc., San Francisco, California, U.S.A.) blocks several T–cell-dependent functions, including adhesion of T cells to keratinocytes, traffi cking, and activation and has been approved by the U.S. FDA for the treatment of moderate-to-severe chronic plaque psoriasis. Surprisingly, after 12 weeks of treatment, in a double-blind, placebo-controlled study, patients with extensive, active disease treated with efalizumab only had an approximately 8% hair regrowth response rate (71). Use of other biologics in AA has been studied but in smaller numbers of patients and with varying results. Etanercept, a tumor necrosis factor (TNF) inhibitor, was tested in an open-label study in the treatment of moderate to severe AA, totalis or universlais, in 17 patients. Signifi - cant hair regrowth was not demonstrated in any of the treated subjects after 8 to 24 weeks of treatment with 50 mg of etanercept given subcutaneously twice weekly (53). The development of AA in a patient receiving infl iximab, a chimeric monoclonal antibody to TNF-alpha, suggests, but does not prove, that the immune signals responsible for the onset of hair loss in AA are not dependent on TNF-alpha (54,55). A clinical trial supported by the National Alopecia Areata Foundation with the biologic alefacept (Amevive®, Astellas Pharma U.S., Inc., Deerfi eld, Illinois, U.S.A.) has recently been completed. The focus of this study is to examine the safety and effi cacy of alefacept, a human fusion protein, in the management of AA. Alefacept binds to CD2, inhibiting antigen- presenting cell interaction with T cells and selectively reducing CD45RO+ cells. This biologic is known to kill activated memory T cells, reversibly lowering the T-cell count. Treatment of AA with alefacept may be a reasonable option if effi cacy can be demonstrated in clinical trials. (Additional information on ongoing clinical trials in AA can be found on www.clinicaltrials.gov.)

COMBINATION THERAPIES Combination therapies have been tested in the management of AA but in small numbers of patients and no combination has fulﬁ lled the criteria of evidence-based treatment described earlier. The use of methotrexate in association with low-dose prednisone for the treatment of AA is the latest combination that has caught the attention of clinicians faced with challenging AA patients (56). Examples of this and other combination therapies include the following:

1. Topical minoxidil and oral prednisone (40). This was a 6-week study examining a tapering dose of oral prednisone (starting at 40 mg/day) followed by 2% topical minoxidil applied daily for up to 14 weeks. Results: Use of topical minoxidil limited post-steroid hair loss in AA patients. 2. Topical minoxidil and bethamethasone dipropionate (57). In this study, patients applied 5% topical minoxidil twice daily, followed 30 minutes later by 0.05% beta-methasone dipropionate cream. Results: Fifty-six percent of patients with severe, treatment-resistant AA attained fair to good regrowth after 16 weeks of therapy. 3. Topical minoxidil and anthralin (58). In this study, patients applied 1 mL 5% topical minoxidil twice daily, followed by an overnight application of anthralin. Anthralin was applied two hours after the evening application of topical minoxidil. Results: Terminal hair regrowth was observed in 39 of 50 patients with severe, treatment-resistant AA by week 12. At week 24, 5 of 24 patients had achieved cosmetically acceptable regrowth. McMichael PTR 01/21/08 Chapter 07

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4. Methotrexate alone or with low doses of prednisone (56). Patients received oral prednisone at 10 to 20 mg/day; methotrexate was given at an initial weekly dose of 15 mg, 20 mg or 25 mg. Results: Sixty-four percent achieved a total recovery including 3 of 6 patients treated with methotrexate alone and 11 of 16 who had combined treatment.

Other Treatments Many other treatments have been examined for AA. Some, such as tacrolimus, nitrogen mustard and cyclosporine, were tested in small numbers of human subjects based on their success in rodent animal models (59–61). Eleven patients with AA affecting 10% to 75% of the scalp, average duration of 6 years, participated in a study examining the effi cacy of topical tacrolimus. No terminal hair growth was seen in response to this drug and the investigators postulated one reason for this poor response could be related to insuffi cient depth of penetration of the ointment formulation. Results with the use of oral cyclosporine have been mixed, and like some other treatments for AA, patients may relapse after the drug is discontinued. In a bilateral comparison 16-week study of topical nitrogen mustard, a benefi t was seen in one of six patients; four did not complete the trial. Other drugs that have been tested in small numbers of AA patients include sulfasalazine, isoprinosine, thymopentin, azathioprine, and imiquimod (62–65). Thalidomide has been suggested as a potential treatment but its controversial history makes it a diffi cult to conduct experimental trials (66). Glatiramer acetate, a drug that is growing in popularity in treating multiple sclerosis and one which induces a shift of the cytokine profi le from Th1 to Th2 cells has also been suggested (67).

Potential Future Medical Treatments Future therapies may include improved immunosuppressive, immunomodulatory, or anti- inﬂ ammatory formulations as well as the incorporation of agents into liposomes for improved drug delivery, inhibition of the Fas-FasL system, induction of tolerance, or inhibition of lymphocyte homing as well as potential interference with neurotrophins, neuropeptides, or their receptors (31). To facilitate the development of ﬁ nding a cure for AA, the National Alopecia Areata Foun- dation supports testing drug combinations in the C3H/HeJ AA mouse model. Initial screenings are being done that utilize compounds that have had known positive responses based on route of administration. The goal is to target compounds that will be tested for up to 16 weeks and then advanced to human studies based on the results.

Alopecia Areata Registry The Alopecia Areata Registry was established with grant support from the National Institutes of Health’s Institute of Arthritis, Musculoskeletal and Skin Diseases. The overall goal is to better understand the genetics and immunology of AA, to understand the complexity of the hair follicle, and to use this knowledge to devise safe and effective treatments. Registrants must have a diagnosis of AA from a dermatologist and be a resident of the United States. Initial information is captured on line (www.AlopeciaAreataRegistry.org), or by completing a paper questionnaire that captures age, sex, ethnicity, age of onset, severity, record of duration, and associated conditions, with a focus on autoimmune diseases. Patients are also asked to complete a quality-of-life questionnaire. Second-tier registration is limited and is focused on collecting information from:

Families with 3 or more members with alopecia areata Patients with severe forms of AA Twins or siblings who have AA, as well as their parents Patients with transient or patchy AA

Second-tier registration includes a 33-page form and a physical exam by a dermatologist. Registry participation as of December 31, 2007 is shown in Table 1. McMichael PTR 01/21/08 Chapter 07

102 Hordinsky and Caramori

TABLE 1 Alopecia Areata Registry Participation as of December 31, 2007 American Hawaiian/ African Indian/Alaska Paciﬁ c Gender Total White American Hispanic Asian Native Islander Mixed Other Unknown Female 4082 3167 196 217 146 18 14 186 39 99 Male 1931 1485 57 119 75 7 2 84 32 70 Total 6013 4652 253 336 221 25 16 270 71 169

Investigators can apply for use of registry samples. This is done by simply completing a form and requesting approval by the steering committee. Current investigations using registry samples include a genetic linkage project, a candidate gene search, and a cytokine proﬁ ling study. In the interim, efforts continue to increase minority participation as well as increasing the number of multiplex families, affected children, and controls. The results of clinical and basic science research using registry samples will undoubtedly enhance our understanding of the pathophysiology of AA and, subsequently, its treatment.

TREATMENT OF ALOPECIA AREATA: OUR APPROACH Patchy Disease In addition to obtaining the standard hair-loss history and performing a good physical examination including examination of all hair-bearing areas and nails, particular attention is paid to any scalp symptoms the patient may report such as burning, itching, or pain with hair loss. It is possible that early treatment of symptoms may be associated with decreased or minimal hair loss. The authors’ preference is to use a shampoo containing a mid- or high-potency steroid or a steroid foam preparation. If scalp dermatitis is present, this should be treated with anti-seborrheic shampoos as there is no need to have two types of scalp infl ammation. Whether or not treating the entire scalp of a patient with patchy disease is benefi cial is not known, but we do know that when normal-appearing scalp skin in a patient with patchy disease is biopsied, it will show abnormalities (68). If one postulates the entire head region should be treated formulations such as Clobex® (clobetasol propionate 0.05%, Galderma R&D Inc., Cranbury, New Jersey, U.S.A.) or Capex® (fl uocinolone acetonide 0.01%, Galderma) can be prescribed. When using Capex shampoo, patients are instructed to apply the shampoo, to lather the product and leave on for 3–5 minutes before rinsing. Patients prescribed Clobex are instructed to apply the product to a dry scalp for 15 minutes, then to lather and rinse off the product. Double-blind, controlled studies examining the effi cacy of this approach in preventing as well as treating patchy AA remain to me done. For the management of patchy disease, the authors suggest the use of intralesional corticosteroids, particularly Kenalog® (triamcinolone acetonide at a concentration of 10 mg/cc). Multiple sites are injected using approximately 0.1 cc per site; up to 4 cc are injected per session with the interval between sessions being on average 6 weeks. This is done concurrently with the shampoos mentioned previously, using each approximately three times per week on an alternate day basis. Shampoos recommended on other days include any anti-seborrheic shampoo the patient prefers. The same concentration is used to treat eyebrow AA with usually 0.3 cc administered per eyebrow region.

Extensive Disease Since the scalps of patients with alopecia totalis or alopecia universalis look similar as there is no hair, performing a scalp biopsy may be of benefi t in assessing the hair cycle and degree of infl ammation. Based on the information from the analysis of both vertical and horizontal sections, treatment plans may be developed that are patient-specifi c. Information that can be quantitated includes number of anagen, telogen, and catagen follicles, terminal-to-vellus ratio, degree, type and localization of infl ammation, as well as the presence of follicular plugging or presence of bacteria or yeast in the epidermis. McMichael PTR 01/21/08 Chapter 07

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AA reportedly goes through three stages: acute, subacute, and chronic. In the acute stage, infl ammatory infi ltrates are present in the classical peribulbar location; in the subacute stage, the numbers of anagen follicles are decreased and there are increased numbers of catagen and telogen follicles. In the chronic stage, decreased terminal follicles and increased miniaturized follicles are found, rather than the normal 7:1 terminal:vellus ratio. More commonly a 1:1 ratio is seen. Patients with recurrent episodes will have a mixture of these fi ndings with the chronic cycling preventing full anagen follicle differentiation. Of note is the observation that if the follicular count in horizontal sections is less than 1 follicle/mm3, the prognosis for regrowth is considered poor (69). The author’s choice of therapy for the patient with extensive disease is based on the histology. If there is a prominence of telogen follicles, Rogaine® (McNeil-Ppc Inc., Fort Washing- ton, Pennsylvania, U.S.A.) 5% in the foam preparation is prescribed. If signifi cant peribulbar infl ammation is noted, steroids are recommended and in some cases where there is both a shift to telogen and signifi cant infl ammation present, combination therapy is recommended. The choice of steroid formulation is based on safety fi rst with the fi rst attempt to decrease disease activity utilizing topical steroids, then advancing to intralesional or oral as indicated. The above described approaches work well for many patients but require frequent clinic visits to monitor effi cacy and adverse experiences. There are of course patients who do not respond to this approach, requiring a reevaluation and introduction of other treatments as reviewed earlier. Finally, whenever possible, patients are offered the opportunity to participate in the Alo- pecia Areata Registry or in a clinical trial. Patients are also informed of ongoing research and the direction of research in this disease and are referred to the Alopecia Areata Foundation.

REFERENCES 1. Hordinsky M, Ericson E. Autoimmunity: alopecia areata. J Invest Dermatol 2004; 9:73–38. 2. Safavi K. Prevalence of alopecia areata in the First National Health and Nutrition Examination Survey. Arch Dermatol 1992; 128:702. 3. Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol 2000; 42:549–566. 4. Orecchia G, Doubille H, Marelli MA. Nail changes and alopecia areata. Ital Gen Rev Dermatol 1988; 25:179–184. 5. Elieff D, Sundby S, Kennedy W, Hordinsky M. Decreased sweat-gland number and function in patients with alopecia areata. Br J Dermatol 1991; 125:130–135. 6. de Berker D, Rees JL. Normal sweat secretion rate in patients with alopecia areata. Br J Dermatol 1995; 132:402–404. 7. Muller SA, Winkelmann RK. Alopecia areata. Arch Dermatol 1963; 88:290–297. 8. Carter DM, Jegasothy BV. Alopecia areata and Down syndrome. Arch Dermatol 1976; 112:1397–1399. 9. Van Daele, C. Down’s anomaly [21 trisomy] and Turner’s syndrome [46 Xxqi] in the same sib ship. Helv Paediatr Acta 1982; 25:412–420. 10. Colon EA, et al. Lifetime prevalence of psychiatric disorders in patients with alopecia areata. Compr Psychiatry 1991; 32:245–251. 11. Safavi KH, Muller SA, Suman VJ, et al. Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 1995; 70:628–633. 12. Ikeda T. A new classifi cation of alopecia areata. Dermatologica 1968; 131:421–445. 13. Walker SA, Rothman S. Alopecia areata: a statistical study and consideration of endocrine infl uences. J Invest Dermatol 1950; 14: 403–413. 14. Nanda A, Al-Hasawi F, Alsaleh QA. A prospective survey of pediatric dermatology clinic patients in Kuwait: an analysis of 10,000 cases. Pediatr Dermatol 1999; 16:6–11. 15. Sharma VK, Dawn G, Kumar B. Profi le of alopecia areata in Northern India. Int J Dermatol 1996; 35:22–27. 16. Sharma VK, Kumar B, Dawn G. A clinical study of childhood alopecia areata in Chandigarh, India. Pediatr Dermatol 1996; 13:372–377. 17. Xiao FL, Yang S, Lui JB, et al. The epidemiology of childhood alopecia areata in China: a study of 226 patients. Pediatr Dermatol 2006; 23:13–18. 18. Tan E, Tay YK, Goh CL, Giam C. The pattern and profi le of alopecia areata in Singapore – a study of 219 patients. Int J Dermatol 2002; 41:748–753. 19. Ro BI. Alopecia areata in Korea (1982–1994). J Dermatol 1995; 22:858–864. 20. Gilhar A, Ullmann Y, Berkutzki T, et al. Alopecia areata transferred to human scalp explants on SCID mice with T-lymphyocyte injections. J Clin Invest 1998; 101:62–67. 21. Whiting DA. Histopathologic features of alopecia areata: a new look. Arch Dermatol 2003; 139: 1555–1559. McMichael PTR 01/21/08 Chapter 07

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22. Ito T, Ito N, Betterman A, et al. Collapse and restoration of MHC class-1-dependent immune privilege; exploiting the human hair follicle as a model. Am J Pathol 2004; 164:623–634. 23. Martinez-Mir A, Zlotogorski A, Gordon D, et al. Genome-wide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet 2007; 80:316–328. 24. Paus R, Peters EMJ, Eichmuller S, Botchkarev VA. Neural mechanisms of hair growth control. J Invest Dermatol 1997; 2:61–68. 25. Peters EMJ, Ericson M, Hosi J, et al. Neuropeptide control mechanisms in cutaneous biopsy: physiological mechanisms and clinical signifi cance. J Invest Dermatol 2006; 126:1937–1947. 26. Willemsen R, Vanderlinden J, Deconinck A, Roseuw D. Hypnotherapeutic management of alopecia areata. J Am Acad Dermatol 2006; 55:233–237. 27. Epstein E. Evidence-based treatment of alopecia areata. J Am Acad Dermatol 2001; 45:640–641. 28. Olsen E, Hordinsky M, McDonald-Hull S, et al. Alopecia areata investigational guidelines. J Am Acad Dermatol 1999; 40:242–246. 29. Olsen EA, Hordinsky M, Price VH, et al. Alopecia areata investigational guidelines – Part II. J Am Acad Dermatol 2004; 51:440–447. 30. Sackett DL. Evidence based medicine. What it is and what it isn’t. BMJ 1996; 312:71–72. 31. Freyschmidt-Paul P, Happle R, McElwee KJ, Hoffmann R. Alopecia areata: treatment of today and tomorrow. J Investig Dermatol Symp Proc 2003; 8:12–17. 32. Wiseman MC, Shapiro J, MacDonald N, Lui H. Predictive model for immunotherapy of alopecia areata with diphencyprone. Arch Dermatol 2002; 138:112–113. 33. Hoffmann R, Happle R. Topical immunotherapy in alopecia areata: what; how; and why? Dermatol Clin 1996; 14:739–744. 34. Olson E. Topical and systemic corticosteroids in alopecia areata. Aust Dermatol 1997; 38:20 (abstract). 35. Tosti A, Piracinni BM, Pazzaglia M, Vincenzi C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J Am Acad Dermatol 2003; 49:96–98. 36. Fiedler VC. Alopecia areata. A review of therapy, effi cacy, safety, and mechanism. Arch Dermatol 1992; 128:1519–1929. 37. Pascher F, Kurtin S, Andrade R. Assay of 0.2 percent fl uocinolone acetonide cream for alopecia areata and totalis. Effi cacy and side effects including histologic study of the ensuing localized acneform response. Dermatologica 1970; 141:193–202. 38. Montes LF. Topical halcinonide in alopecia areata and in alopecia totalis. J Cutan Pathol 1977; 4:47–50. 39. Abell E, Munro DD. Intralesional treatment of alopecia areata with triamcinolone acetonide by jet injector. Br J Dermatol 1973; 88:55–59. 40. Olsen EA, Carson SC, Turney EA. Systemic steroids with or without 2% topical minoxidil in the treatment of alopecia areata. Arch Dermatol 1992; 128:1467–1473. 41. Seiter S, Ugurel S, Tilgen W, Reinhold U. High-dose pulse corticosteroid therapy in the treatment of severe alopecia areata. Dermatology 2001; 202:230–204. 42. Friedli A, Labarth MP, Engelhardt E, Feldmann R, Salomon D, Saurat JH. Pulse methylprednisolone therapy for severe alopecia areata: an open prospective study of 45 patients. J Am Acad Dermatol 1998; 39:597–602. 43. Kiesch N, Stene JJ, Goens J, Vanhooteghem O, Song M. Pulse steroid therapy for children’s severe alopecia areata. Dermatology 1997; 194:395–397. 44. Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol 1987; 16:745–748. 45. Fiedler-Weiss VC, Rumsfi eld J, Buys CM, West DP, Wendrow A. Evaluation of oral minoxidil in the treatment of alopecia areata. Arch Dermatolg 1987; 123:1488–1490. 46. Schmoeckel C, Weissman, I, Plewig G, Braun-Falco O. Treatment of alopecia areata by anthralin- induced dermatitis. Arch Dermatol 1979; 115:1254–1255. 47. Taylor CR, Hawk JL. PUVA treatment of alopecia areata partialis, totalis and universalis: audit of 10 years’ experience at St. John’s Institute of Dermatology. Br J Dermatol 1995; 133:914–918. 48. Stern R, Nichols K, Vakeva L. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). N Engl J Med 1997; 336:1041–1045. 49. Krook G. Treatment of alopecia areata with Kromayer’s ultraviolet lamp. Acta Derm Venereol 1961; 41:178–181. 50. Jury CS, McHenry P, Burden AD, et al. Narrowband ultraviolet B (UVB) phototherapy in children. Clin Exp Dermatol 2006; 31:196–199. 51. Bissonnette R, Shapiro J, Zeng H, McLean DI, Lui H. Topical photodynamic therapy with 5- aminolaevulinic acid does not induce hair growth in patients with extensive alopecia areata. Br J Dermatol 2000; 143:1032–1035. 52. Zakaria W, Passeron T, Ostovari N, Lacour J-P. 308-nm excimer laser therapy in alopecia areata. J Am Acad Dermatol 2004; 51:837–838. 53. Strober BE, Siu K, Alexis AF, Washenik K, Sinha A, Shupack JL. Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study. J Am Acad Dermatol 2005; 52:1082–1084. McMichael PTR 01/21/08 Chapter 07

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54. Ettefagh L, Nedorost S, Mirmirani P. Alopecia areata in a patient using infl iximab: new insights into the role of tumor necrosis factor on human hair follicles. Arch Dermatol 2006; 140:1012. 55. Bartels G, et al. Development of alopecia areata universalis in a patient receiving adalimumab. Arch Dermatol 2006; 142:1653–1654. 56. Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol 2006; 55:632–636. 57. Ferry JJ, Fiedler VC. Pilot study to evaluate the effect of topical betamethasone dipropionate on the percutaneous absorption of minoxidil from 5% topical solution. J Invest Dermatol 1990; 94:524 (Abstract). 58. Fiedler VC, Wendrow A, Szpunar GJ, Metzler C, DeVillez RL. Treatment-resistant alopecia areata. Response to combination therapy with minoxidil plus anthralin. Arch Dermatol 1990; 126:756–759. 59. Price VH, Willey A, Chen BK. Topical tacrolimus in alopecia areata. J Am Acad Dermatol 2005; 52:138–139. 60. Bernardo O, Tang L, Lui H, Shaprio J. Topical nitrogen mustard in the treatment of alopecia areata: a bilateral comparison study. J Am Acad Dermatol 2003; 49:291–294. 61. Shapiro J, Lui H, Tron V, Ho V. Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: a clinical and immunopathologic evaluation. J Am Acad Dermatol 1997; 36:114–117. 62. Ellis CN, Brown MF, Voorhees JJ. Sulfasalazine for alopecia areata. J Am Acad Dermatol 2002; 46:541–544. 63. Sasmaz S, Arican O. Comparison of azelaic acid and anthralin for the therapy of patchy alopecia areata: a pilot study. Am J Clin Dermatol 2005; 6:403–406. 64. Tosti A, Manuzzi P, Gasponi A. Thymopentin in the treatment of severe alopecia areata. Dermatologica 1988; 177:170–174. 65. Goddard CIR, August PJ, Whorwell PJ. Alopecia totalis in a patient with Crohns disease and its treatment with azathioprine. Postgrad Med 1989; 65:188–189. 66. Namazi MR. The potential effi cacy of thalidomide in the treatment of recalcitrant alopecia areata. Med Hypotheses 2003; 60:513–514. 67. Farina C, Weber MS, Meinl E, Wekerle H, Hohlfeld R. Glatiramer acetate in multiple sclerosis: update on potential mechanisms of action. Lancet Neurol 2005; 4:567–575. 68. McDonald-Hull SP, et al. Immunohistologic and ultrastructural comparison of the dermal papilla and hair follicle bulb from “active” and “normal” areas of alopecia areata. J Invest Dermatol 1991; 96:673–681. 69. Whiting DA. Histopathologic features of alopecia areata: a new look. Arch Dermatol 2003; 139:1555– 1559. 70. Society for Investigative Dermatology meeting. Poster presentation, 2007. 71. Price VH, Hordinsky, MK, Olsen E, et al. Effi cacy and safety results of a clinical study of efalizumab in patients with alopecia areata. J Am Acad Derm (submitted). McMichael PTR 01/21/08 Chapter 07 McMichael PTR 01/21/08 Chapter 08

8 Androgenetic Alopecia

Andrew G. Messenger Department of Dermatology, Royal Hallamshire Hospital, Shefﬁ eld, U.K.

INTRODUCTION The term androgenetic alopecia describes a form of scalp-hair loss in which there is a decline in production of hair, which may eventually lead to balding. It affects both sexes and all ethnic groups although the severity and frequency are greater in men and there are racial differences in prevalence. Male androgenetic alopecia is a trait rather than a disease, predominantly determined by genetic factors. The same is true of androgenetic alopecia in most women. However, female androgenetic alopecia may also be a manifestation of signiﬁ cant androgen excess due to an underlying endocrine disorder. The pathology appears identical in men and women although the pattern of hair loss tends to differ between the sexes and there is some controversy over whether male and female androgenetic alopecia share the same etiology. Very few people enjoy losing their hair and it is probably true that a simple, cheap, nontoxic and effective one-off treatment would be widely taken up. Until this ideal is realized many men, though not all, are content to accept their lot. This is rather less true of women, in whom loss of hair has a greater adverse effect on quality of life. In this article the treatments currently available for androgenetic alopecia are reviewed, together with a brief consideration of the etiology and epidemiology.

CLINICAL FEATURES Male Androgenetic Alopecia Male androgenetic alopecia (male balding, male-pattern hair loss) is a common androgen- dependent trait that can start at any age after puberty. In the majority of men balding is patterned, in which the two major components are fronto-temporal recession and loss of hair over the vertex. Hairs become shorter and may, although not always, become fi ner in caliber. Ulti- mately this may lead to complete hair loss except at the lateral and posterior margins of the scalp where hair is retained. In elderly men, hair may also be lost in these parts of the scalp. A small proportion of men show a diffuse pattern of hair loss over the crown and frontal scalp with retention of the frontal hair line, similar to female-pattern hair loss (FPHL). Hamilton classifi ed male balding into several stages (1) and the revision of his classifi cation by Norwood is still widely used (2).

Female Androgenetic Alopecia Most women with androgenetic alopecia (also known as FPHL) present with a history of gradual thinning of scalp hair, often over a period of several years (3). The hair loss can start at any age from puberty onwards. There is sometimes a history of excessive hair shedding, which may predate a clinically obvious reduction in hair density. Examination of the scalp shows a widening of the central parting with a diffuse reduction in hair density mainly affecting the frontal scalp and crown. In some women the hair loss may affect a quite small area of the frontal scalp whereas in others the entire scalp is involved, including the parietal and occipital regions. The frontal hairline is typically retained although many women develop a minor degree of post-pubertal recession at the temples (equivalent to a Norwood-Hamilton II frontal hairline), whether or not they have diffuse hair loss. Some women have more pronounced temporal recession although this usually manifests as thinning rather than the complete loss of temporal hair as seen in men. McMichael PTR 01/21/08 Chapter 08

108 Messenger

PATHOLOGY The follicular changes in androgenetic alopecia, in both men and women, comprise a gradual reduction in the duration of anagen, a prolongation of the “latent phase” of the hair cycle and progressive miniaturization of hair follicles (4–6). The latent phase, also termed kenogen, refers to the interval between shedding of the telogen hair and reentry into anagen. This has been demonstrated in aging male scalp hair follicles (7) and there is some evidence that it also occurs in women (8). Miniaturization may eventually lead to deletion of hair follicles (6). There is little evidence that medical treatments are able to reverse follicular miniaturization; it follows, therefore, that preservation of terminal hair density is best achieved by treatment at an early stage in the development of hair loss. A modest degree of chronic infl ammation around the upper part of hair follicles, sometimes associated with perifollicular fi brosis, is a common feature of the histopathology (4,9). Whether infl ammation is important in the pathogenesis of the hair loss is unknown.

ETIOLOGY Androgens Male balding is an androgen-dependent trait. The American anatomist James Hamilton observed that men castrated before puberty do not go bald unless treated with testosterone (10). Testosterone is the major circulating androgen in men. However, there is compel- ling evidence that dihydrotestosterone (DHT), the 5α-reduced metabolite of testosterone, is responsible for hair loss. The conversion of testosterone to DHT is catalyzed by the enzyme 5α-reductase. There are two isoforms of 5α-reductase that are encoded by different genes (11,12). Although both enzymes catalyze the conversion of testosterone to DHT, they differ in their pH optima, substrate affi nities and tissue distributions. Type 1 5α-reductase is widely distributed in the skin (13), but expression of the type 2 isoform is limited to certain androgen target tissues such as the prostate, the epididymis, and hair follicles in certain regions of the skin. The role of DHT in hair growth was fi rst recognized through the observation that men with a genetic defi ciency of type 2 5α-reductase (Type II pseudohermaphroditism, pseudovaginal perineoscrotal hypospadias) do not go bald (14). These observations were extended by the demonstration that treatment with a 5α-reductase inhibitor prevented the development of balding (15) or increased scalp hair growth (16) in macaques, a primate that reliably develops androgen-dependent hair loss. Confi rmation of the importance of DHT in humans came from the results of large clinical trials showing that fi nasteride, an inhibitor of type 2 5α-reductase, prevents progression of balding in most men and stimulates some recovery of hair growth in about two-thirds (17). This latter fi nding also shows that, contrary to Hamilton’s conclusions from his observations in eunuchs, male balding is partially reversible. A role for androgens in the etiology of male balding is incontrovertible. Nevertheless, other factors are clearly involved as not all men develop balding despite similar androgen levels to those that do. The role of androgens in female androgenetic alopecia is less clear-cut than it is in men. Scalp hair loss is undoubtedly a feature of hyperandrogenism in women (although it is much less frequent than hirsutism). Indeed, loss of hair was reported in women with androgen-secreting tumors prior to Hamilton’s observations in men (18,19). Several investigators have noted that women with hair loss are more likely to have elevated androgen levels or show an increased frequency of other features of androgen excess than women without hair loss. Futterweit and colleagues studied 109 women with hair loss and reported that 38.5% showed clinical or biochemical evidence of androgen excess (20). In a series of 187 women with hair loss, Vexiau et al. reported abnormal hormonal profi les, mostly of minor degree, in 67% of women with hair loss alone and in 84% of women who were also hirsute (21). In a recent series of 89 women presenting to a trichology clinic with hair loss, 67% showed ultrasound evidence of polycystic ovaries compared to 27% in a control group of 73 women, and 21% were signifi cantly hirsute compared to 4% of controls (22). However, other investigators have failed to fi nd evidence of raised androgen levels in women with FPHL (23) and in McMichael PTR 01/21/08 Chapter 08

Androgenetic Alopecia 109 all studies there is a variable proportion of women with hair loss who do not show clinical or biochemical signs of androgen excess. The results of clinical trials of anti-androgens have also questioned whether female androgenetic alopecia is necessarily androgen-dependent and consequently the less committal term “female pattern hair loss” is preferred by some clinicians.

Genetics Twin studies have demonstrated that the predisposition to male balding is predominantly due to genetic factors (24–26). Published concordance rates for monozygotic twins are around 80– 90%, with consistently lower rates in dyzogotic twins. Several studies have shown there is a high frequency of balding in the fathers of bald men. For example, Ellis and colleagues reported that 32 of 54 bald men (59.3%) had fathers with a greater degree of baldness whereas only one of 65 sons of 50 non-bald controls had type III baldness or greater (27). In a study involving 572 men aged 16–91, there was a signifi cant increase in the risk of balding in young men with a balding father over those with a non-bald father [odds ratio (OR) 5.5, 95% CI 1.26–23.99] which fell with increasing subject age to approach unity in elderly men (28). The opposite trend was seen in non-bald men where the risk of non-balding in men with a non-bald father increased with age (OR 3.2, 95% CI 1.82–5.58 in subjects aged 70 and over). Androgenetic alopecia is probably a polygenic trait (29). So far, attempts to identify the relevant genes have been limited to a small number of candidate gene studies. No associations have been found with 5α-reductase genes (27,30) or the insulin gene (31). However, three independent studies have found signifi cant associations, both positive (32,33) and negative (34), with variant regions of the androgen receptor (AR) gene. The AR gene is located on the X chromosome and men inherit it from their mother. This fi nding therefore confi rms there is a mater- nal infl uence on male balding but does not explain the genetic contribution from the father. As yet there are no published genotyping studies in female androgenetic alopecia.

Prevalence Population frequency and severity of androgenetic alopecia in both sexes increase with age. Almost all Caucasian men develop some recession of the frontal hairline at the temples during their teens. Deep frontal recession and/or vertex balding may also start shortly after puberty although in most men the onset is later. Hair loss progresses to a bald scalp in 50–60% of men by the age of 70. A small proportion of men (15–20%) do not show balding, apart from post-pubertal temporal recession, even in old age. Some authorities have suggested that scalp hair loss in elderly men may develop independently of androgens (senescent alopecia) but this remains to be veriﬁ ed (35). Balding is less common in Asian men although there is quite a wide variation in published frequencies. Two recent studies from Thailand and Singapore found prevalence rates not far short of those in Caucasian men (36,37). Takashima et al. reported the male balding starts approximately one decade later in Japanese men than in Caucasians and the prevalence is about 1.4 times lower in each decade group (38). In Korean men the frequency is 20–40% lower than in Caucasian men in the 40–70 age group although the difference becomes less pronounced with advancing age (39). Preservation of the frontal hairline was a common feature in the series reported from Korea and 11.1% of Korean men with androgenetic alopecia showed a “female” pattern of hair loss. There is less published information on the frequency of balding in African men. One early study reported that balding is four times less common in African- American men than in Caucasians (40). The frequency and severity of androgenetic alopecia is lower in women than in men but it still affects a sizeable proportion of the population. Two studies in Caucasian women in the United Kingdom and the United States reported prevalence rates of 3–6% in women aged under 30, increasing to 29–42% in women aged 70 and over (41,42). As in men, androgenetic alopecia is less common and appears to start later in life in Asian women, although nearly 25% of Korean women over 70 years of age show evidence of hair loss (39). There are no published data on the prevalence of androgenetic alopecia in African women although clinical experience suggests that its frequency is similar to that in other racial groups. McMichael PTR 01/21/08 Chapter 08

110 Messenger

MANAGEMENT Male balding is a biologically normal process. Under normal circumstances it has no adverse effect on physical well-being apart from increasing the risk of chronic photodamage to unpro- tected scalp skin. Under exceptional conditions a full head of hair may also contribute to thermoregulation. The French military surgeon Dominique-Jean Larrey observed that the bald men (and men without hats) were the ﬁ rst to die during the Russian campaign in the winter of 1812. Yet balding still has a powerful effect on the human psyche, to the extent that few men would choose to go bald were the choice available. Many men accept loss of their hair and prefer to let nature take its course. However, for some men balding is important enough for them to seek treatment and, for a few, concern about hair loss reaches the level of a body dysmorphic disorder. Men in the latter group are important to recognize as treatment aimed at addressing the perceived hair problem is unlikely to be successful. A number of studies have shown that male balding has an adverse effect on quality of life (though this is almost inevitable in those seeking professional advice) (43). Nevertheless, balding is often seen as a trivial issue (mainly by non-sufferers) which may make men reluctant to approach their physician as they perceive, rightly or wrongly, that they will not receive a sympathetic response. In most women androgenetic alopecia is also a physiological trait. In contrast to the prevailing attitude to male balding, however, society generally regards it as abnormal for women to lose their hair. Consequently the adverse effect of balding on quality of life tends be more severe in women than in men. As a group, women seeking medical advice for hair loss experience more negative body-image feelings, more social anxiety, poorer self-esteem, and psychosocial well-being than control subjects with nonvisible skin disease, as well as dissatisfaction with their hair. In quality-of-life studies, individual responses were more related to self-perception of hair loss than to objective or clinical ratings and those women most distressed by hair loss were more poorly adjusted and had a greater investment in their appearance (44,45). The physician needs to be alert and sensitive to these issues and needs counseling and psychotherapeutic skills that go beyond merely prescribing treatment.

Diagnosis The diagnosis of androgenetic alopecia in men rarely causes diffi culties. In cases presenting with general thinning, other causes of diffuse hair loss should be considered, particularly when the hair loss progresses quickly. This situation is perhaps most likely to be seen in teenage boys brought along by worried parents. The diagnosis of female androgenetic alopecia may be more challenging although it can usually be made on clinical grounds. Rapidly progressive hair loss with a strongly positive “tug test” should raise the possibility of diffuse alopecia areata. Loss of body hair, eyebrows, or eyelashes, and nail changes will support the diagnosis but it is sometimes necessary to obtain histology. Other causes of diffuse hair loss include systemic lupus erythematosus and thyroid disease and the relevant investigations should be performed where indicated by the overall clinical picture. Occasionally, scarring alopecia presents in a diffuse pattern and here a biopsy will usually be necessary. The most common clinical dilemma is the diagnosis of women presenting with chronic excessive hair shedding in whom hair density appears normal, often referred to as chronic telogen effl uvium. If known causes of telogen effl uvium are excluded, about 60% of these women show histological evidence of early androgenetic alopecia on biopsy (46). The cause of increased hair shedding in the remaining 40% is usually obscure, although it may simply be due to age-related shortening of the hair cycle. It should also be remembered that androgenetic alopecia may be a sign of hyperandrogenism. There are usually at least some other clinical features of androgen excess, e.g., hirsutism, oligomenorrhoea, and infertility. Some hyperandrogenic women show a male or, more commonly, a partially male pattern of hair loss but, in the author’s experience, the pattern of hair loss is not a reliable indicator of androgen status. Investigations are unnecessary in women with typical androgenetic alopecia and no other evidence of androgen excess, although most authorities recommend checking a full blood count, serum ferritin and thyroid function. In the author’s experience, abnormalities of thyroid function are not particularly common in women presenting with diffuse hair loss, possibly no more McMichael PTR 01/21/08 Chapter 08

Androgenetic Alopecia 111 common than in the population at large, but formal data are lacking. Whether, and how far, to investigate women with evidence of hyperandrogenism depends on a variety of factors, such as the time course of the complaint, age of the patient, and the presence of associated features. The most important cause, albeit rare, is an androgen-secreting ovarian or adrenal tumor. Viriliza- tion typically progresses rapidly in these patients. A serum testosterone is a useful screening test; a level in excess of 5nmol/l should prompt further endocrinologic investigation. A normal serum testosterone virtually excludes an androgen secreting tumor.

Counseling Those seeking medical advice for androgenetic alopecia, both male and female, fall roughly into three groups (which may overlap): (i) those who wish to ensure their hair loss is not a manifestation of an underlying serious disease, (ii) those who wish to be treated, and (iii) those with a body image problem. For all groups counseling should include an explanation of the nature of the condition and its natural history. For those interested in preventing further progression or improving their hair status, the treatment options, together with a realistic explanation of what can be achieved by treatment, will also need to be discussed. For those with a body dysmorphic disorder involvement of a clinical psychologist or psychiatrist should be explored. Hair loss is an emotional issue and sufferers are vulnerable to exploitation by the unscrupulous. Patients should be advised against parting with large sums of money on unproven and valueless remedies.

Treatment Men At present only two medical treatments, minoxidil and ﬁ nasteride are licensed for the treatment of male balding. Both drugs will stimulate some regrowth of hair in some men but are perhaps better regarded as preventative treatments. Neither will regrow hair on completely bald scalp and continued treatment is necessary to maintain the response. Both drugs have a good safety record, a consideration of paramount importance when treating hair-growth disorders. Surgery is the only method that will produce coverage on bald scalp. Good results require a skilled surgeon and careful patient selection (Table 1).

Minoxidil Minoxidil was licensed as an oral drug to treat hypertension in the early 1970s. It soon became apparent that a high proportion of those taking minoxidil tablets developed signiﬁ cant hypertrichosis, a side effect that has almost eliminated its use as an anti-hypertensive agent. Following a report of increased hair growth on the scalp of a balding man taking minoxidil tablets (47), extem- poraneous formulations of minoxidil solution were developed for topical application in the treatment of hair loss (initial reports concentrated mainly on alopecia areata). A 2% formulation of minoxidil solution was subsequently licensed by the U. S. Food and Drug Administration for the treatment of male balding and marketed by the Upjohn Company in 1986. A 5% formulation was marketed in 1993. The recommended dose is 1ml twice daily (for both 2% and 5% formulations). The mechanism of action of minoxidil on hair growth is uncertain (48). There is convincing evidence that its vaso-relaxant activity is due to opening of ATP-sensitive potassium channels (KATP channels) in the sarcolemma of vascular smooth muscle cells. There is circumstan- tial evidence that its effect on hair growth is also due to opening of KATP channels but direct proof is lacking and it is unclear how this action modulates hair growth. The rapid response of hair growth to minoxidil suggests that the drug acts mainly to promote entry into anagen of follicles in a latent stage of the hair cycle. There is no convincing evidence that minoxidil reverses follicular miniaturization although it may prevent or delay it. Clinical trials using various endpoints including hair counts, hair weight, and global photography have conﬁ rmed improvement in male balding with the use of minoxidil solution (49,50). The mean increase in target area hair counts is about 8% with 2% minoxidil solution and 10–12% with the 5% formulation. When assessed by global photography, nearly 60% of men show improvement with 5% minoxidil solution and 40% with 2%, compared to 23% with placebo. The response to minoxidil in terms of increased hair counts and hair weight is rapid and peaks by 16 weeks although the cosmetic response may take longer to become apparent. McMichael PTR 01/21/08 Chapter 08

112 Messenger

TABLE 1 Treatment of Androgenetic Alopecia General points Counseling vital Manage expectations of treatment outcome Explain expected time course of response Positive response of medical intervention may be prevention or slowing of progression rather than signiﬁ cant increase in hair density Monitor treatment response, e.g., standardized clinical photographs If using minoxidil lotion, 2 ml once daily rather than 1 ml twice daily is more convenient for the patient. Clinical experience suggests the former regimen is equally effective but is unlicensed and unsupported by clinical trial data Treatment options for men Mild/moderate vertex balding 2–5% minoxidil solution Finasteride 1 mg daily Mild/moderate frontal balding Finasteride 1 mg daily Advanced frontal and/or vertex balding Surgery Prosthesis Treatment options for women Mild/moderate hair loss 2% minoxidil solution (5% more effective but unlicensed) If clinical or biochemical signs of androgen excess consider: Oral anti-androgen, e.g., spironolactone 100–200 mg daily (unlicensed). Concomitant contraceptive measures needed in fertile women Severe hair loss Medical treatment as above may help to prevent progression Surgery Prosthesis

Trials continued for up to 2 years suggest the improvement is sustained providing treatment is maintained. Any positive effect on hair growth is lost within 4–6 months of stopping treatment (49,51). Adverse effects of minoxidil are mainly dermatological. Constituents of the vehicle occasionally cause scalp irritation, more commonly with the 5% formulation. Allergic reactions to minoxidil or propylene glycol (a component of the vehicle) are rare but necessitate stopping treatment. Some patients notice an increase in hair shedding 2–8 weeks after starting treatment. This is self-limiting and patients should be forewarned not to stop treatment if this happens.

Finasteride Finasteride is a competitive inhibitor of type II 5α-reductase. Taken orally it reduces DHT levels in serum and in scalp by up to 70% (52). Large, long-term placebo-controlled studies using hair count and global photographic technology show that fi nasteride 1mg daily prevents or slows the progression of male balding in most men and about two-thirds experience some improvement (17). The improvement peaks at around 12 months and, on average, there is some decline after two years. However, after fi ve years those on placebo continued to lose hair more rapidly than those on fi nasteride (53). Similar results were obtained in a trial where the treatment response was assessed using hair weight as the primary endpoint. Clinical trials have shown a small increase in sexual dysfunction (e.g., impotence) in men taking fi nasteride for male balding [4.2% versus 2.2% for placebo in young men (17), 8.7% versus 5.1% in older men (52)]. These side effects resolve on discontinuation of the drug. The level of fi nasteride in semen is very low and poses no risk to a male fetus in a pregnant sexual partner. Data from a long-term trial in 18,882 men aged over 54 taking 5mg fi nasteride daily or McMichael PTR 01/21/08 Chapter 08

Androgenetic Alopecia 113 placebo showed a 25% overall reduction in the incidence of prostatic cancer in those taking ﬁ n- asteride but a small increase in the frequency of high-grade prostatic cancer (54). The relevance of this ﬁ nding to men taking 1 mg daily for male balding is unknown but it is advisable to warn patients of this uncertainty.

Minoxidil versus Finasteride There are no blinded controlled trials comparing the response of male balding to minoxidil solution and oral fi nasteride, although one open study reported a greater degree of improvement in men taking fi nasteride compared to those using 5% minoxidil solution (55). In practice the decision comes down to patient preference. Minoxidil is a little cheaper and it has been in use for longer so more is known about long-term safety. On the other hand, it is more convenient to take a single tablet of fi nasteride daily than apply a solution twice daily to the scalp. We do not know whether the combination of minoxidil and fi nasteride confers any advantage over either drug used singly. The mechanisms of action are different so, on a superfi cial level, one might expect at least a partially additive effect. However, the outcome in terms of their effect on the dynamics of hair growth is probably the same.

Dutasteride This drug inhibits both type I and type II 5α-reductase and suppresses serum and scalp DHT to a greater degree than fi nasteride. In a controlled trial comparing various doses of dutasteride with fi nasteride 5 mg daily, the highest dose of dutasteride (2.5 mg daily) produced a signifi - cantly greater degree of hair growth in men with androgenetic alopecia than fi nasteride after 24 weeks treatment (56). The drug was well-tolerated although reduced libido was more common in the dutasteride-treated subjects. Dutasteride is licensed for treating benign prostatic hypertrophy; it is unlikely the manufacturer will seek a license for treating male balding.

Surgery Surgical treatment of male balding involves the redistribution of terminal hair to cover balding scalp; the number of terminal hair follicles on the scalp remains the same. In most cases this means transplanting hair follicles from the occipital scalp to the balding areas. Other techniques, such as excising the balding skin (scalp reduction) and rotational ﬂ aps are now less widely used. Surgical treatment can achieve very satisfactory results but careful patient selection and surgical skill allied to the aesthetics of scalp hair growth are essential. A detailed review of the indications and techniques of hair surgery is beyond the scope of this article. However, key considerations include the following (57):

There should be an adequate donor area, i.e., good hair density in the occipital scalp. The predictive value for men aged <25 is very uncertain. Surgery in young men may result in misplaced hairlines or an unnatural appearance 20–30 years later as balding progresses. Correction of established frontal hair loss is more effective than vertex balding which tends to progress with time. Thicker hair shafts give better coverage than fi ne-caliber hair. In Caucasians, fair hair gives a more natural appearance than dark hair (which exaggerates the contrast with the color of scalp skin). Experienced surgical teams can give signifi cant improvement after 1–2 sessions. The fi nal results take 5–6 months to become apparent.

Complications of surgery include scalp erythema and crusting, and facial edema. Less common problems include infection, post-operative bleeding, scarring, and arterio-venous ﬁ s- tula formation.

Cosmesis Hairstyling is perhaps the simplest approach to modifying the cosmetic impact of male balding. Currently fashionable short hair styles are particularly effective in minimizing the contrast between balding and non-balding regions of the scalp. Some men resort to wigs or toupees. While these give an instant result, a natural appearance demands skilled professional input. McMichael PTR 01/21/08 Chapter 08

114 Messenger

Women Some women are content to be reassured that their hair loss is not a manifestation of a serious disease and that it is very unlikely that they will go bald. For those who are keen to be treated there are two medical options: minoxidil solution and antiandrogens. In both cases it should be stressed that treatment will, at best, produce only a modest increase in hair density and that it is not possible to fully reverse hair loss. Furthermore, in those who respond, treatment has to be continued to maintain the response. As in men, surgery is the only method capable of restoring the appearance in the presence of severe hair loss.

Minoxidil Minoxidil solution 2% is licensed for the treatment of female androgenetic alopecia in most countries. The 5% formulation is not currently licensed for use in women. Clinical trials in the early 1990s using hair counts as a primary endpoint reported a mean increase in hair growth of 15–33% in the minoxidil-treated groups compared with 9–14% in the vehicle control groups (58–60). One small study using hair weight as the endpoint found an increase of 42.5% in hair weights in the minoxidil group compared to 1.9% in the controls (61). In the investigator and subject assessments minoxidil was superior to the vehicle, but about 40% of subjects appeared not to respond to minoxidil (58,60). A more recent trial comparing 5% and 2% minoxidil solution found increases of 18% and 14% respectively in mean non-vellus hair counts after 48 weeks of treatment, compared to a 7% increase in the placebo group. As in men the increase in hair counts following treatment with minoxidil solution is noticeable within 8 weeks and has peaked after 16 weeks, suggesting that minoxidil acts primarily on the hair cycle. Minoxidil is a safe treatment. Some patients complain that it leaves unsightly deposits on the hair. Occasionally it causes scalp irritation that may be severe enough to cause a temporary increase in hair shedding and patients should be warned about this. Irritant reactions are more common with higher concentrations of minoxidil. Hypertrichosis on the face and on more remote sites has been reported, particularly when higher concentrations of minoxidil are used (62). This resolves if treatment is stopped. In the authors’ experience minoxidil solution is more reliably effective and better tolerated than anti-androgen treatment. Nevertheless, the gains are modest and it is helpful to have an objective measure, such as serial standardized clinical photographs, to convince the patient (and the physician) of the response. Although the recommended dosing schedule is 1 mL twice daily, 2 mL once daily is more convenient and, from clinical experience, appears to be as effective. Once a full response has been obtained (e.g., after 6–12 months), some patients are able to reduce the frequency of minoxidil application, as low as once or twice a week, without an obvious loss of hair density.

Antiandrogens The antiandrogens cyproterone acetate, spironolactone and fl utamide have all been used to treat female androgenetic alopecia, as has the 5α-reductase inhibitor fi nasteride, although none is licensed for this purpose and there is little clinical trial evidence of effi cacy for any of them. Cyproterone acetate acts by blocking androgen receptors. It also has progestational activity and suppresses the production of gonadotrophins. It is not available in the United States but is widely used in Europe, usually in a cyclical regimen in combination with the oral contraceptive Dianette™. In a randomized controlled trial in 66 women with female androgenetic alopecia cyproterone acetate 52mg daily plus a combined oral contraceptive was compared with minoxidil solution 2% (63). After 12 months treatment non-vellus hair density increased signifi cantly in the minoxidil-treated group but fell in the cyproterone acetate group. However, sub-group analysis showed a small improvement in hair density in women with menstrual irregularities receiving cyproterone actetate. This study suggests that antiandrogens may be benefi cial in women with evidence of androgen excess but not in those without, a conclusion in keeping with personal experience of the author. Spironolactone is a competitive inhibitor of aldosterone receptors. It also blocks androgen receptors and increases metabolic clearance of testosterone. It has been widely used to treat hirsutism. There are no controlled trials of its use in female androgenetic alopecia. Rushton and colleagues reported that women treated for 12 months with spironolactone showed less hair McMichael PTR 01/21/08 Chapter 08

Androgenetic Alopecia 115 loss than an untreated group (64). In an open uncontrolled case series of 80 women treated for one year with spironolactone (200 mg daily), or cyproterone acetate, 35 (44%) showed improvement in hair growth as assessed by standardized photography (65). Flutamide is a pure androgen receptor blocker. A randomized trial from Italy compared fl utamide 250 mg daily with cyproterone acetate and fi nasteride in the treatment of 48 hyperandrogenic women with androgenetic alopecia. Those treated with fl utamide showed a modest improvement in hair growth whereas those treated with cyproterone acetate or fi nasteride did not (66). The study appears not to have been blinded and the method of assessment, using the Ludwig grading system, was relatively crude. In a large randomized controlled trial in post-menopausal women with androgenetic alopecia fi nasteride 1 mg daily proved ineffective in preventing hair loss (67). Improvement has been reported, however, in a small cases series of hyperandrogenic women (68) and in a larger series of 37 pre-menopausal women treated for one year with fi nasteride 2.5 mg daily (69). In the latter study 62% showed some improvement as assessed by global photography. Antiandrogen treatment is not without problems. As with minoxidil treatment has to be continued to maintain a response and women taking antiandrogens should not become pregnant because of the risks of feminizing a male fetus. Dose-related side effects of cyproterone acetate, including weight gain, fatigue, loss of libido, mastodynia, nausea, headaches and depression, are common. There is a signifi cant risk of hepatotoxicity with fl utamide and cyproterone acetate is also potentially hepatotoxic in high doses. Spironolactone may cause breast soreness and menstrual irregularities but is probably the safest option and is the personal preference of the author. Finasteride is well tolerated and is worth considering in post-menopausal and infertile women.

Surgery Hair transplantation is less widely used in women than in men but can give good results in selected cases (57). It is most appropriate in women with pronounced hair loss of limited extent who retain good hair density in the donor site. Those with a mild degree of hair loss are less suitable as are those with involvement of the occipital region.

Iron The idea that body iron stores, usually measured as serum ferritin, are important in hair growth is controversial and as yet unsubstantiated in a randomized controlled clinical trial (70). In an open trial of cyclical treatment with cyproterone acetate in women with serum ferritin levels above and below 40µg/l (10 subjects in each group) hair densities increased by about 15% in the high ferritin group after one year of treatment but were unchanged in the low ferritin group (71). Hair densities in an untreated control group fell by about 7%. However, there are no peer-reviewed trials that have tested the effect of iron supplementation on hair growth. Unfortunately, such trials are expensive and unlikely to be supported by the pharmaceutical industry in view of the lack of commercial potential. In the absence of more conclusive data it seems reasonable to check the serum ferritin and advise dietary supplementation with iron in those with a level below 40µg/L. Patients should be advised that iron treatment alone will not halt or reverse hair loss but it may improve the response to speciﬁ c treatments.

Treatment of Non-Caucasians The principles of managing androgenetic alopecia in non-Caucasians are generally the same as in Caucasians although there is relatively little published trial data. A large controlled study from Japan found that ﬁ nasteride 1mg stimulated hair growth in nearly 60% of men with androgenetic alopecia (i.e., similar to the results obtained in U.S. and European studies). This study also included a group taking a lower dose of ﬁ nasteride (0.2 mg daily). Improvement in hair growth in these men was almost as good as in those taking the higher dose (72). In a controlled trial of 1% minoxdil solution in the treatment of 280 Japanese women with androgenetic alopecia 29.2% of the minoxidil-treated group showed improvement after 24 weeks compared to 11.8% in the placebo group (73). Issues around the management of androgenetic alopecia in African women, including detailed consideration of surgical treatment, are discussed in a recent review (74). Topical minoxidil remains the mainstay of treatment in this group but patients should be warned that McMichael PTR 01/21/08 Chapter 08

116 Messenger the use of a solution-based product can return straightened hair to its natural curly state. Min- oxidil in an ointment base can be used if this is a problem. In the author’s experience minoxidil solution is more likely to cause hypertrichosis in women from the Indian subcontinent and the Middle East than in Europeans, particularly in the fronto-temporal and sideburn regions. For many patients this is an acceptable side effect but they should be advised about it before starting treatment.

SUMMARY Whether or not one regards androgenetic alopecia as a medical condition worthy of treatment (75), there is little doubt that it can have a signifi cant adverse effect on quality of life. The emotional aspect of hair loss means that it is not necessarily a trivial issue for the sufferer and, consequently, managing the patient with androgenetic alopecia can be diffi cult and time-consuming for the physician (the same is true of other hair loss disorders). Nevertheless, it can be rewarding to manage patients with androgenetic alopecia and, despite their limitations, current treatments can be of signifi cant benefi t providing the patient is fully aware of what can be achieved. What does the future hold? Our knowledge of hair biology is expanding rapidly and we are making progress in understanding the genetic and molecular basis of androgenetic alopecia. It is unlikely, however, that medical treatments to reverse follicular miniaturization will be forthcom- ing in the foreseeable future and perhaps the best prospect for a more effective treatment will come from the clinical application of hair-follicle cell culture methods (76). The other approach is for there to be a sea change in cultural and societal attitudes toward hair loss. This may seem a bizarre and unlikely prospect but one that is not beyond the bounds of possibility if a few more “celebrities” could be persuaded to fl aunt their hair loss rather than advertise fi ctitious remedies.

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17. Kaufman KD, Olsen EA, Whiting D, et al. Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol 1998; 39(4 Pt 1):578–589. 18. Baldwin LG, Gafford JA. Arrhenoblastoma case report. Endocrinology 1936; 20:373–382. 19. Kantner AE, Ragins AB. Arrhenoblastoma of the ovary. Am J Obstet Gynecol 1941; 42:1061–1066. 20. Futterweit W, Dunaif A, Yeh HC, Kingsley P. The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. J Am Acad Dermatol 1988; 19(5 Pt 1):831–836. 21. Vexiau P, Chaspoux C, Boudou P, et al. Role of androgens in female-pattern androgenetic alopecia, either alone or associated with other symptoms of hyperandrogenism. Arch Dermatol Res 2000; 292(12):598–604. 22. Cela E, Robertson C, Rush K, et al. Prevalence of polycystic ovaries in women with androgenic alopecia. Eur J Endocrinol 2003; 149(5):439–442. 23. Schmidt JB, Lindmaier A, Trenz A, Schurz B, Spona J. Hormone studies in females with androgenic hair loss. Gynecol Obstet Invest 1991; 31:235–239. 24. Hayakawa K, Shimizu T, Ohba Y, et al. Intrapair differences of physical aging and longevity in identical twins. Acta Genet Med Gemellol (Roma) 1998; 41:177–185. 25. Nyholt DR, Gillespie NA, Heath AC, Martin NG. Genetic basis of male pattern balding. J Invest Dermatol 2003; 121:1561–1564. 26. Rexbye H, Petersen I, Iachina M, et al. Hair loss among elderly men: etiology and impact on perceived age. J Gerontol A Biol Sci Med Sci 2005; 60(8):1077–1082. 27. Ellis JA, Stebbing M, Harrap SB. Genetic analysis of male pattern baldness and the 5α-reductase genes. J Invest Dermatol 1998; 110:849–853. 28. Birch MP, Messenger AG. Genetic factors predispose to balding and non-balding in men. Eur J Dermatol 2001; 11:309–314. 29. Kuster W, Happle R. The inheritance of common baldness: Two B or not two B? J Am Acad Dermatol 1984; 11:921–926. 30. Sreekumar GP, Pardinas J, Wong CQ, et al. Serum androgens and genetic linkage analysis in early onset androgenetic alopecia. J Invest Dermatol 1999; 113(2):277–279. 31. Ellis JA, Stebbing M, Harrap SB. Insulin gene polymorphism and premature male pattern baldness in the general population. Clin Sci 1999; 96(6):659–662. 32. Ellis JA, Stebbing M, Harrap SB. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol 2001; 116(3):452–455. 33. Hillmer AM, Hanneken S, Ritzmann S, et al. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet 2005; 77(1):140–148. 34. Hayes VM, Severi G, Eggleton SA, et al. The E211 G>A androgen receptor polymorphism is associated with a decreased risk of metastatic prostate cancer and androgenetic alopecia. Cancer Epidemiol Biomarkers Prev 2005; 14(4):993–996. 35. Kligman AM. The comparative histopathology of male-pattern baldness and senescent baldness. Clin Dermatol 1988; 6(4):108–118. 36. Pathomvanich D, Pongratananukul S, Thienthaworn P, Manoshai S. A random study of Asian male androgenetic alopecia in Bangkok, Thailand. Dermatol Surg 2002; 28(9):804–807. 37. Tang PH, Chia HP, Cheong LL, Koh D. A community study of male androgenetic alopecia in Bishan, Singapore. Singapore Med J 2000; 41(5):202–205. 38. Takashima I, Iju M, Sudo M. Alopecia androgenetica - its incidence in Japanese and associated conditions. In: Orfanos CE, Montagna W, Stuttgen G, eds. Hair Research Status and Future Aspects. Berlin: Springer-Verlag; 1981:287–302. 39. Paik JH, Yoon JB, Sim WY, Kim BS, Kim NI. The prevalence and types of androgenetic alopecia in Korean men and women. Br J Dermatol 2001; 145(1):95–99. 40. Setty LR. Hair patterns of scalp of white and Negro males. Am J Phys Anthropol 1970; 33(1):49–55. 41. Birch MP, Messenger JF, Messenger AG. Hair density, hair diameter and the prevalence of female pattern hair loss. Br J Dermatol 2001; 144:297–304. 42. Norwood OT. Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg 2001; 27(1):53–54. 43. Cash TF. The psychosocial consequences of androgenetic alopecia: a review of the research literature. Br J Dermatol 1999; 141(3):398–405. 44. Cash TF, Price VH, Savin RC. Psychological effects of androgenetic alopecia on women: comparisons with balding men and with female control subjects. J Am Acad Dermatol 1993; 29(4):568–575. 45. van der Donk J, Passchier J, Knegt-Junk C, et al. Psychological characteristics of women with androgenetic alopecia: a controlled study. Br J Dermatol 1991; 125(3):248–252. 46. Sinclair R, Jolley D, Mallari R, Magee J. The reliability of horizontally sectioned scalp biopsies in the diagnosis of chronic diffuse telogen hair loss in women. J Am Acad Dermatol 2004; 51(2):189–199. 47. Zappacosta AR. Reversal of baldness in patient receiving minoxidil for hypertension. N Engl J Med 1980; 303(25):1480–1481. 48. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol 2004; 150(2):186–194. McMichael PTR 01/21/08 Chapter 08

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49. Price VH, Menefee E, Strauss PC. Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and2% topical minoxidil, placebo or no treatment. J Am Acad Dermatol 1999; 41:717–721. 50. Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2002; 47(3):377–385. 51. Olsen EA, Weiner MS, Amara IA, DeLong ER. Five-year follow-up of men with androgenetic alopecia treated with topical minoxidil. J Am Acad Dermatol 1990; 22(4):643–646. 52. Drake L, Hordinsky M, Fiedler V, et al. The effects of fi nasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol 1999; 41(4):550–554. 53. Shapiro J, Kaufman KD. Use of fi nasteride in the treatment of men with androgenetic alopecia (male pattern hair loss). Journal of Investigative Dermatology Symposium Proceedings 2003; 8(1):20–23. 54. Thompson IM, Goodman PJ, Tangen CM, et al. The infl uence of fi nasteride on the development of prostate cancer. N Engl J Med 2003; 349(3):215–224. 55. Arca E, Acikgoz G, Tastan HB, Kose O, Kurumlu Z. An open, randomized, comparative study of oral fi nasteride and 5% topical minoxidil in male androgenetic alopecia. Dermatology 2004; 209(2):117–125. 56. Olsen EA, Hordinsky M, Whiting D, et al. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus fi nasteride. J Am Acad Dermatol 2006; 55(6):1014–1023. 57. Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol 2005; 52(2):301–311. 58. Whiting DA, Jacobson C. Treatment of female androgenetic alopecia with minoxidil 2%. Int J Dermatol 1992; 31(11):800–804. 59. Olsen EA. Topical minoxidil in the treatment of androgenetic alopecia in women. Cutis 1991; 48(3):243–248. 60. Jacobs JP, Szpunar CA, Warner ML. Use of topical minoxidil therapy for androgenetic alopecia in women. Int J Dermatol 1993; 32(10):758–762. 61. Price VH, Menefee E. Quantitative estimation of hair growth. I. androgenetic alopecia in women: effect of minoxidil. J Invest Dermatol 1990; 95(6):683–687. 62. Peluso AM, Misciali C, Vincenzi C, Tosti A. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol 1997; 136(1):118–120. 63. Vexiau P, Chaspoux C, Boudou P, et al. Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized trial. Br J Dermatol 2002; 146(6):992–999. 64. Rushton DH, Futterweit W, Kingsley D, Kingsley P, Norris MJ. Quantitative assessment of spironolactone treatment in women with diffuse androgen-dependent alopecia. J Soc Cosmet Chem 1991; 42:317–325. 65. Sinclair R, Wewerinke M, Jolley D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol 2005; 152(3):466–473. 66. Carmina E, Lobo RA. Treatment of hyperandrogenic alopecia in women. Fertil Steril 2003; 79(1):91–95. 67. Price VH, Roberts JL, Hordinsky M, et al. Lack of effi cacy of fi nasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol 2000; 43(5):768–776. 68. Shum KW, Cullen DR, Messenger AG. Hair loss in women with hyperandrogenism: four cases responding to fi nasteride. J Am Acad Dermatol 2002; 47(5):733–739. 69. Iorizzo M, Vincenzi C, Voudouris S, Piraccini BM, Tosti A. Finasteride treatment of female pattern hair loss. Arch Dermatol 2006; 142(3):298–302. 70. Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron defi ciency and its potential relationship to hair loss. J Am Acad Dermatol 2006; 54(5):824–844. 71. Rushton DH, Ramsay ID. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethinyl oestradiol treatment of diffuse androgen-dependent alopecia in women. Clin Endocrinol (Oxf) 1992; 36(4):421–427. 72. Kawashima M, Hayashi N, Igarashi A, et al. Finasteride in the treatment of Japanese men with male pattern hair loss. Eur J Dermatol 2004; 14(4):247–254. 73. Tsuboi R, Tanaka T, Nishikawa T, et al. A randomized, placebo-controlled trial of 1% topical minoxidil solution in the treatment of androgenetic alopecia in Japanese women. Eur J Dermatol 2007; 17(1):37–44. 74. Callender VD, McMichael AJ, Cohen GF. Medical and surgical therapies for alopecias in black women. Dermatol Ther 2004; 17(2):164–176. 75. Moynihan R, Heath I, Henry D. Selling sickness: the pharmaceutical industry and disease mongering. BMJ 2002; 324(7342):886–891. 76. Cooley J. Follicular cell implantation: an update on „hair follicle cloning“. Facial Plast Surg Clin North Am 2004; 12(2):219–224. McMichael PTR 01/21/08 Chapter 09

9 Telogen Efﬂ uvium

Wilma F. Bergfeld Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland, Ohio, U.S.A.

INTRODUCTION Telogen effl uvium (TE) is the most common hair-loss condition that presents to the dermatologist and it is seen in all races and ethnic groups (Table 1). Patients present with a complaint of increased shedding over normal levels and associated diffuse alopecia. The excessive shedding is the result of alterations of the hair-growth cycle with premature conversion of anagen follicles to telogen follicles, which represents a shift of 7–25% of anagen follicles to telogen (Fig. 1). Clinically TE has been described as having at least three different clinical scenarios. It presents as acute (<4 months), chronic (>4 months), and chronic-repetitive (Fig. 2). In chronic TE, the anagen cycle gradually shortens and the hair fi bers become thinner and shorter. In acute and repetitive TE, follicular regeneration is common. Only in rare situations is there diminished regeneration (follicular dropout). The primary insult is to the dermal papillae of the anagen follicle, which induces an early shunt to telogen. Regeneration of the follicle is determined by the bulge area, so any damage, stress, or infl ammation that involves the bulge will affect regeneration (Fig. 3). At the onset of TE, the patient presents with a perceived loss greater than 25% scalp hair density. The shedding results in a diffuse loss with a more prominent central and frontal scalp loss. The patient usually relates loss of body hair and a diminished rate of hair growth, especially of leg hair. Since TE is a medical sign rather than ultimate diagnosis, it is important to explore the possible trigger(s) (Fig. 4). An important trigger is the TE seen with the onset of androgenetic alopecia (AGA), also known as male-pattern or female-pattern hair loss (MPHL and FPHL respectively). In African Americans, AGA should be distinguished from central centrifugal cicatricial alopecia. Other triggers include hormonal fl uctuations or abnormalities, endocrine disorders, postpartum, physiological, and metabolic stress, drugs, weight loss, nutritional defi - ciencies, systemic acute and chronic illnesses, surgeries, and scalp infl ammation (Table 2). When a trigger is identifi ed and removed or treated, the patient experiences diminished shedding and later regrowth of hair (Table 3). On occasion the TE will unmask an underlying androgenetic alopecia, autoimmune disease, or other disorders.

DIAGNOSIS OF TE The diagnosis of TE is based on the clinical presentation and the confi rmation of excess of shedding of telogen hair. The specifi c time of onset is important to establish. TE can begin 2 weeks after a trigger but peaks between 6–8 weeks and then tapers off in about 6–8 weeks if the trigger is removed or treated. Regrowth is not appreciated for several months, usually 4–6 months (Figure 4). Frequently, patients have multiple triggers that occur concomitantly, sequentially, chronic-repetitive, or chronic. Repetitive, multiple concomitant/sequential triggers, can prolong the TE and be mistaken for chronic TE. Prolonged or repetitive TE can also lead to diminished regrowth and a chronic diffuse alopecia. The differential diagnosis of diffuse alopecia includes androgenetic alopecia, diffuse alopecia areata, and an infl ammatory alopecia such as central centrifugal cicatricial alopecia and lichen planopilaris, especially when the primary loss involves the central scalp. The evaluation of TE should include a review of the following:

Careful history of the hair loss Review of systems McMichael PTR 01/21/08 Chapter 09

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TABLE 1 Common Hair-Loss Disorders Telogen efﬂ uviums Numerous triggers Pattern hair loss: androgenetic alopecia Androgen-excess syndromes SAHA Alopecia areata Inﬂ ammatory and scarring alopecia End-stage alopecia Abbreviation: SAHA, seborrhea, acne, hirsutism, and alopecia.

Recent, chronic and past medical illnesses or surgeries Personal and family medical and hair-loss disorders Prescription and nonprescription drugs, supplements, herbals/botanicals, and chemicals Dietary history with particular attention to “the healthy diet” Recent and chronic illnesses Menstrual and reproductive history in women Hair care Psychological stress

Since the diagnosis of TE is dependent on demonstrating increased telogen hair loss (greater then 7%), there are a number of diagnostic techniques to assist in this assessment. They include hair collections, hair pull, hair clipping, hair pluck, and a scalp biopsy (Table 4). In a laboratory setting a trichogram can be done. A light hair pull will extract loose hair, which can be then examined under 2x magnifi cation. Evaluation and presence of excessive telogen hairs supports a diagnosis of TE. If there are numerous dystrophic anagen hairs, the diagnosis is an anagen effl uvium. Anagen effl uviums are the result of severe insult to the dermal papillae, which produces 80% loss of scalp hair. A telogen effl uvium represents a minor insult to some anagen dermal papillae with 7–25% loss of scalp hair. An anagen effl uvium is observed in alopecia areata and as a result of a cytotoxic drug therapy. A pitfall in the diagnosis of TE is false-negative hair pull due to a recent shampooing or vigorous hair grooming. Also, a false-positive hair pull will be noted if the patient has not shampooed or combed for several days. If a trichodystrophy is suspected, a hair clipping will best display the hair shaft abnormalities. Dependent on the portion of the hair needed for examination, the hair clipping can

TE Shunt 7-25%

FIGURE 1 Hair growth cycle and shedding. McMichael PTR 01/21/08 Chapter 09

Telogen Efﬂ uvium 121

SHEDDING Telogen shed (common) Anagen shed (rare): > 80% loss > 7–30% loss

Acute: < 4 months; chronic: > 4 months

FIGURE 2 Shedding in telogen efﬂ uvium. include the entire visible hair or the distal ends. The complaint that the rate of hair growth is slow with a normal scalp hair density would initiate the hair clipping assessment. Acquired trichodystrophies are commonly observed as a result of grooming and haircare procedures and chemicals, and is especially common in African-American females, due to there frequent haircare straightening procedures, and in Caucasian females, who engage in excess permanent hair coloring, permanent waves, and straightening procedures. A hair pluck of about ﬁ fty hairs, using a rubber-tipped hemostat, can give the physician additional information, such as hair diameters and the anagen–telogen ratio. If trichodystrophy is suspected, a hair pull or clipping will be more helpful. A 2-week hair collection represents a snapshot of daily shedding numbers. The hair is collected daily and put into dated envelopes with a notation of the shampoo day. A morning

Influences Androgens: increase circulation and local metabolism Growth factors: cytokines, inflammation Other: genes, enzymes, proteins, receptors

Growth centers

Bulge

Dermal papillae

FIGURE 3 Hair follicle growth and inﬂ uence. McMichael PTR 01/21/08 Chapter 09

122 Bergfeld

Triggers Genes Inflammation Stromal Metabolic Endocrine Acute versus chronic telogen effluvium (shedding) Hormones Androgens Drugs Systemic disease Stress

Acute

Repetitive Chronic

FIGURE 4 (See color insert.) Shedding patterns and triggers. collection done during hair grooming is usually simplest. These collections can be repeated intermittently and compared. Similar and repetitive collections can be done only on shampoo days. The results of both techniques can be interpreted as follows: daily hair collections of greater than 100 hairs per day represent an effl uvium; if there are primarily telogen hairs (club hairs), it is a telogen effl uvium; if collected hairs are less then 3 cm and present with distal taper, the telogen effl uvium represents an androgenetic alopecia and TE; if the same collection is less than 100 hairs per day, the diagnosis is androgenetic alopecia; if the hair has an adherent epithelial envelope, it is an early telogen hair; if the collection contains dystrophic telogen hair with adherent epithelial envelope, it is probably secondary to a cytoxic drug or alopecia areata; if the telogen hair normal or dystrophic hair has an adherent epithelial envelope, it may represent an infl ammatory alopecia such as lichen planopilaris, discoid lupus erythematosus, central centrifugal cicatricial alopecia, or tinea capitis. In tinea capitis, spores and hyphae can be observed with a contrast stain, for example PAS and methylene blue stain. A scalp biopsy can also be helpful. The actual technique for biopsy differs in the African American because of the helical hair and diagonal hair follicle. In this situation, the biopsy punch should be slightly angled and follow the hair direction while in the Caucasian, non-helical curly hair, the biopsy would be a routine vertical punch biopsy without angling the biopsy instrument. The dermatopathologist interpretation should include comments on the hair follicle, sebaceous glands, infl ammation, fi brous tracts, miniaturization of follicles, and the stromal changes. In a telogen effl uvium, there is an increase in telogen and a decrease of anagen follicle density, and a reversal of the tissue’s anagen–telogen ratio. The sebaceous glands may be hypertrophied especially in AGA. The reversal of the anagen–telogen ratio is a common fi nding in androgenetic

TABLE 2 Telogen Effl uvium Triggers Scalp infl ammation Endocrine disorders Seborrheic dermatitis Hormonal changes Nutritional defi ciencies Poor health/illness Iron storage anemia, low zinc Drugs Physiological stress Surgery Metabolic stress Heredity McMichael PTR 01/21/08 Chapter 09

Telogen Efﬂ uvium 123

TABLE 3 Telogen Shed: Removing Triggers Find and remove Rx triggers Oftentimes multiple triggers Follow-up important alopecia. A primary increase in telogen follicles with a reversal of anagen–telogen ratio is common of acute TE. In alopecia areata, the most common fi nding is peribulbar infl ammation around anagen bulbs and increased catagen follicles. In diffuse alopecia areata, the patient will have diffuse reduction of follicular density and size, and a TE. While a resolving acute TE will have regeneration of terminal follicles, regeneration of hair follicles with diminished diameters could represent androgenetic alopecia, chronic TE, or alopecia areata. The presence of a perifollicular or interstitial infl ammatory infi ltrate is common to the cicatricial alopecias. Suppurative follicular and interstitial infl ammation is common to the folliculitis decalvans group of disorders. Combined vertical and transverse sections of the biopsy are the most rewarding for an assessment of follicular density, assessment of anagen–telogen ratios, miniaturization, infl ammation, and scarring. Examination of the patient includes specifi c examination of the scalp and body hair. It is important to grade the density, distribution of scalp hair, and the skin changes. Follicular density loss greater than 25% favors a diagnosis of diffuse alopecia. An important observation in diffuse alopecia is excessive or chronic shedding, with progressive diffuse alopecia. Comparison of several scalp hair sites such as the frontal, M recession, temples, parietal, vertex and, posterior scalp is helpful and informative. In both males and females, the central scalp is most commonly affected; therefore a central-part evaluation is important. Males characteristically have a more severe alopecia when the TE is associated with an evolving androgenetic alopecia.

SCALP EXAMINATION Examination of the scalp skin is also essential. The identifi cation of infl ammation, infection, or nonspecifi c dermatitis is important, since infl ammation reduces hair growth, follicular diameters, and density. Often it is necessary to examine the scalp with additional light sources, such as a Woods light, which allow for identifi cation scaling and presence of pitysporium organisms (which fl uoresce orange due to porphyrins). Dermoscopy can be helpful in assessing the scalp’s surface changes such as scaling, perifollicular scales, and follicular pustules. Using different light sources to examine the scalp skin is especially helpful in viewing scaling, perfollicular scaling, and post-infl ammatory pigmentation in all skin types and especially in darker-skinned individuals. The new videodermoscopy offers an added dimension to the evaluation. Nail changes can be helpful in establishing the time of the triggering event or onset of the TE. Beau’s lines, especially on the thumb and great toenail, can indicate a thinning of the nail plate in response to a body stress such as medical illness, fever, and surgery. It allows for determination of an approximate date of the stress. The presence of pitting and distal oncyholysis can assist in diagnosis of alopecia areata. Nail thickening, convex nails, and onchyolysis can be seen in thyroid disease.

TABLE 4 Telogen Efﬂ uvium Diagnostic Techniques Clinical inspection Visual Woods light Dermoscopy Demonstration of TE Hair collection Hair pull Hair clipping Hair pluck Scalp biopsy McMichael PTR 01/21/08 Chapter 09

124 Bergfeld

SCREENING LABORATORY TESTS The patient’s history and clinical presentation are helpful in guiding the laboratory evaluation. Screening tests include complete bload count, CMP, thyroid screen (TSH, T4 and microsomal antibodies), ferritin, zinc, testosterone, free and total, dehydroepiandrosterne sulfate (DHEAS), and dihydrotestosterone (DHT). Additional tests depend on clinical history and results of the screening tests (Table 5). Obese patients have greater incidence of clinical and laboratory ﬁ ndings of androgen excess, such as metabolic syndrome, dysmetabolic syndrome, or syndrome X).

TRIGGERS OF TE Androgens Androgenetic alopecia (MPHL or FPHL), is one the most common alopecic disorders. In Cau- casians, normal male-pattern hair loss is noticeable in about 20% of males by the age of 20 and increases with time, so that all males in their nineties have at least some degree of hair loss. Similar fi ndings are seen in women but are less well-documented. Similar fi ndings are also seen in other races and ethnic groups that are not well-documented. Genetics play a major role in the development of androgenetic alopecia. In males, it is due to a polygenic autosomal dominant phenotype, while in females it is an autosomal recessive phenotype. The onset occurs near or at puberty when there is a natural elevation of the adrenal androgen DHEAS and other androgens. The heralding event can be a TE. The pattern of hair loss in males and females in all races differs mainly in severity. The central scalp has decreased density, miniaturization of hair, and increased sebum production. The fi nal pathway is follicular miniaturization with progressive reduction of anagen cycle and prolongation of latent period of the hair cycle. FPHL is generally less severe than MPHL with mild-to-severe central scalp alopecia, with retention of the frontal hair line in a Christmas- tree pattern. In females with androgen excess or metabolic syndrome, a MPHL pattern can be observed. Females and males have a similar frequency of occurrence and increase in severity of hair loss with age. The role of androgens is not as strong for females as males. At least a third of the women with FPML have signs of androgen excess such as seborrhea, acne, hirsutism, and alopecia (SAHA). Signs of polycystic ovarian syndrome, adrenal hyperplasia, and postmenopausal androgen excess may be present. In females, a post-menopausal androgen excess disorder is recognized and may be refl ected as elevations of total or free testosterone or DHEAS. Males with MPHL have been shown to be at risk for benign prostatic hyperplasia, coronary artery disease, hyperinsulinemia, and insulin-resistance associated disorders such as obesity, hypertension, dyslipedemia, and prostate cancer. Early onset of MPHL has been marker of carrier state of the gene for polycystic ovarian disease. Females with FPHL are also at risk for androgen excess or metabolic syndrome with increased frequency of obesity, hypertension, insulin resistance, type 2 diabetes, hyperlidpe- mia, coronary artery disease, and possibly endometrial cancer. A great mimicker of AGA and even central alopecia areata is central centrifugal cicatricial scarring alopecia which is most prominent in African-American female and less common

TABLE 5 Telogen Efﬂ uvium: Laboratory Evaluation Basic CBC CMP Ferritin > 70 TSH, T4, Antimicrosomal ab Zinc Extended Androgen excess screen Others dependent on personal and family history Abbreviations: CBC, complete blood count; CMP, comprehensive metabolic panel. McMichael PTR 01/21/08 Chapter 09

Telogen Efﬂ uvium 125 in African-American males, Caucasians, and Asian Indians. Frequently, these patients represent with combination hair loss, TE, trichodystrophy, and inﬂ ammatory follicular papules and abscesses. Careful history and examination and a skin biopsy are necessary to determine the etiology of the alopecic condition. Many times the clinical picture is mixed with the patient displaying changes of PHL, TE, and trichodystrophy.

Hormones and TE In some females, TE is experienced within 6 weeks or less after any of the following: the discontinuation of oral contraceptives; taking of oral contraceptives with androgenic progesterones, testosterone, or depoprogesterone; hormonal replacement therapy with high-dose progesterones; and postpartum state. Loss of 30–40% scalp hair density has been noted. Those rare individuals that have increased TE during hormonal replacement may have increased free testosterone with the decrease in sex hormone-binding globulin. If there is consideration of hormonal therapy, a combination estradiol and non-androgenic progesterone is highly recommended. The least androgenic progesterones include norestimate, and desogestrel and dirospirenone, while the most androgenic progesterone is levonorgestrel. The botanical, phytoestrogens, and progesterone therapies are not effective. Postpartum TE is well recognized and occurs usually 4–6 weeks after delivery unless the female prolongs breast feeding. During pregnancy, there is synchronization of anagen growth cycle, with quick conversion to telogen (24–65%) on delivery with a TE within the 2 months postpartum. Within 6 months, the majority of patients note reduced hair loss and regrowth. A postpartum TE can unmask androgenetic alopecia or metabolic syndrome. Chronic TE has been clinically observed with prolonged breast feeding. It has been associated with major reduction in estrogen levels, elevated prolactin, blood loss/anemia, nutritional deﬁ ciencies of iron, zinc, fatty acids, biotin, etc. If breast feeding is prolonged, it is important to take multivitamin and an iron supplements.

Thyroid Both hypo- and hyperthyroidism can induce TE and diffuse alopecia in 18–50% of women. Thyroid screening (TSH, T4, and microsomal antibody and antithyroid antibodies) is important in patients with TE and diffuse alopecia. Diagnosis of the thyroid disorder and treatment can reverse the TE. The treatment of hyperthyroidism initially will induce a profound TE. On occasion, a TE secondary to a change in the type of thyroid medication has been noted, for an example a switch from levothyroxine (T4) to liothyronine (T3) or the reverse.

Senescent Alopecia Senescent alopecia is described as diffuse hair thinning of scalp and body hair which occurs at 50 years or greater with a negative history of familial hair loss. The scalp hair loss is diffuse with a more prominent central scalp loss and associated fi ner hair fi bers. A scalp biopsy refl ects these clinical fi ndings with diminished follicular density and size. These fi ndings can mimic androgenetic alopecia. Senescent alopecia occurs at the same time that the patient is experiencing an increased prevalence of disease, increase in drug therapies, and the general aging of all organ systems. This all adds to the complicated puzzle of events that can inhibit healthy hair regeneration.

Nutritional Infl uences Unusual diets, altered eating habits, body dysmorphia, certain diseases, prolonged breast feeding, and parenteral alimentation to name a few infl uences, have led to many nutritional defi ciencies in developed countries. Weight-loss diets as well as vegetarian and vegan diets also lead to nutritional defi ciencies, which result in not only low body fat but TE and diffuse alopecia. About 4–6 months after initiation of such a diet, a TE is frequently noted. The TE has been associated with iron storage anemia, caloric deprivation (starvation diets), negative nitrogen-balance ketosis, vitamin, mineral, and protein defi ciencies, and rapid weight loss. McMichael PTR 01/21/08 Chapter 09

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Anemia and TE Iron defi ciency is the world’s most common nutritional defi ciency. It has been associated with developmental delay, impaired behavior, diminished intellectual performance, decreased resistance to infection, and generalized pruritus. In young women the most common causes are diet and excessive menses, and in young men the most common cause is diet. In premenopausal and menopausal women the most common cause is menorrhagia. Hemoglobin concentration can be used to screen for iron defi ciency and ferritin can be used to confi rm iron storage defi ciency. Elevated ferritin can be attributed to infectious, infl ammatory, and neoplastic conditions. Other tests used to defi ne iron defi ciency include erythro- cyte zinc protoporphyrin concentration, transferring concentration, serum iron concentration and transferring saturation. If the cause of iron defi ciency is not attributed to diet or excessive menstruation, other causes should be investigated. Several published studies suggest a relationship between iron defi ciency and hair loss. These studies involve primarily women but a few studies have been reported in males. Hair loss secondary to iron storage defi ciency and iron defi ciency has been observed in a number of hair disorders such as telogen effl uvium, diffuse pattern hair loss, and alopecia areata. In these disorders, an evaluation of hemoglobin and ferritin can be helpful in the management of these chronic disorders. Iron supplements and a review of diet with the addition of iron-containing foods have been a helpful adjuvant therapy. If iron supplements are added, recommend monitoring the iron studies, namely hemoglobin and ferritin initially every 6–8 weeks and then every 6 months. In vegetarians, vegans, or in patients with chronic menorrhagia, chronic iron supplement may be necessary. According to the National Institute of Medicine, the upper limit of iron intake for men and pregnant and nonpregnant women of 18 years of age or older is 45 mg/d. The United States recommended daily allowance (U.S. RDA) for iron is 18 mg/day for adults, children, pregnant and lactating females, and children under 4 years old 10 mg/day and for infants 15 mg /day. The major side effect is iron overload, which results in tissue damage and fi brosis. It can also exacerbate hemochromatosis, especially in hereditary hemochromatosis, which manifests itself in the fourth and fi fth decade with fatigue, depression arthralgias, and late fi ndings of skin pigmentation, hepatomegaly with failure and late liver cancer, cardiomyopathy, diabetes, and hypothalamic or pituitary failure.

Zinc Defi ciency and TE Zinc defi ciency can present as alopecia, TE, dermatitis, diarrhea, frequent infections, altered cellular immunity, anorexia, growth retardation, and neurological disturbances. Zinc defi ciency can be acquired or hereditary. The acquired zinc defi ciency is mainly due to dietary restriction, parenteral alimentation, excessive iron supplementation, and vitamin A defi ciency. The diagnosis is made by demonstrating low levels of serum zinc. It is hypothesized that low levels of zinc can be associated with reduced absorption of unsaturated fatty acids and impaired metabolism. This could be a hereditary abnormality or secondary to diet restriction. Acquired zinc defi ciency has been described in parenteral alimentation, GIT bypass surgery, chronic colitis, nephropathy, and prolonged breast feeding without supplementation. In zinc defi ciency, zinc supplementation is the therapy of choice. Oral zinc supplements have other important attributes. They act as anti-infl ammatories and assist iron absorption and antiandrogen activity. Zinc levels should be monitored to avoid levels above normal values that can result in copper, iron, and calcium defi ciencies and gastrointestinal reactions, headaches and drowsiness. The late fi ndings of copper defi ciency include a peripheral neuropathy. In children the U.S. RDA for zinc is 5–8 mg/day. For adults and lactating females it is 15 mg/day. In zinc defi ciency the recommended dose in children and infants is 0.5–1 mg of elemental zinc/kg/day and in adults 25–50 mg/day of elemental zinc.

Vitamin A Deﬁ ciency and TE Vitamin A is an essential vitamin that plays an important role in cell maturation and differentiation and in the immune system. Vitamin A deﬁ ciency can be seen in restricted diets and McMichael PTR 01/21/08 Chapter 09

Telogen Efﬂ uvium 127 excess alcohol ingestion, and is frequently associated with zinc, fatty acid, protein, and caloric deﬁ ciencies. It has also been reported in patients with Celiac disease, Crohn’s disease, pancreatic disorders, and hair loss. Hypervitaminosis A can lead to toxic symptoms, which include birth defects, liver abnormalities, reduced bone density, and central nervous system disorders, while the provitamin A and carotenoids are considered safe. The recommended upper limit of tolerable intake of Vitamin A by the National Institute of Medicine is less than 2000 IU/day for children and less than 10,000 IU/day for adults and pregnant and lactating females.

Biotin Defi ciency and TE Biotin is an essential vitamin that complements hair and nail growth. Biotin defi ciency is rare but has been noted primarily as a congenital disorder and can result in alopecia. It has been associated with pregnancy, prolonged breast feeding, parenteral alimentation, excessive raw egg white ingestion, and dietary defi ciencies. Biotin supplementation is rapidly metabolized and excreted and has low toxicity potential. The recommended U. S. RDA daily dosing in children and infants is 0.05–0.3 mg/day and in adults and lactating females it is 0.3 mg/day. In biotin-defi cient adults, 1–5 mg of biotin is recommended. The common recommendation for treatment in the alopecic disorders is biotin 3–5 mg per day. When used with zinc supplementation there is a complimentary hair growth effect.

Vitamin D and TE In animal models a low vitamin D3, 1,25-dihydroxyvitamin D3 can induce follicular cycling alteration and produce a TE. D3 blood levels could be helpful and, if found defi cient, supplementation could be an adjunctive therapy for TE. In animal models vitamin D, 1, 25-dihyroxyvitamin D3 is involved with not only maintenance of mineral ion homeostasis and skeletal integrity but in hair follicle cycling, blood pressure regulation, and mammary development. Vitamin D3 supplements initiate hair follicle cycling and stimulates hair growth in mice. Assessment of vitamin D3 defi ciency could theoretically produce a TE especially in patients on restricted diets or older patients. Vitamin D3 supplementation could be a supportive adjunctive therapy. In a recent study, topical calcipotriol did not reduce the telogen effl uvium or the atrophic telogen hair induced by chemotherapy. The recommended U. S. RDA is 400 IU/day for children, adults, and pregnant females. The recommended calcium daily doses are 1 gm for adults and children, 0.8 g for children under age 4, and 0.6 g for children under 12 months and 1.3 g for pregnant women.

Protein and Restricted Calories and TE Protein and caloric defi ciencies have induced a TE, alopecia, low body fat, weight loss, and many disorders related to malnutrition. Initially there is a TE and later diminished size and density of hair follicles and ultimately thinner, fi ner hairs (reduced hair diameters). Most of the relevant studies have been reported from the prison camps of World War II and from patients with Marasmus and Kwashiorkor diseases. Chronic defi ciencies result it trichodystrophies described as sparse, fragile, fi ne, and light-colored short hair. Protein supplements and supportive calories will improve the quality of hair and promote growth. Amino acid support has clinically been used to enhance hair regeneration and growth. L-cystine, supplement in a double-blind, placebo-controlled, 4-month study that revealed an improved trichogram and increased hair fi ber diameters with no adverse reactions.

Fatty Acids Fatty acid defi ciencies as other defi ciencies can be congenital or acquired. The skin and hair changes are similar with dry, fragile, light-colored hair with a signifi cant TE. In the acquired FFA defi ciency, diet defi ciencies are the most common causes even though parenteral alimentation, chronic illnesses, and absorption disorders have been reported. Approximately 2–4 months after onset of the defi ciency, a TE occurs. It can be associated with dermatitis especially of the scalp and eyebrows. Fatty acid supplements or foods have reversed TE and diffuse alopecia. McMichael PTR 01/21/08 Chapter 09

128 Bergfeld

SYSTEMIC DISORDERS AND TE Many illnesses and their therapies have associated TE. TE has been reported in autoimmune diseases, acute and chronic systemic infections, inﬂ ammatory bowel disease, gastrointestinal disorders, febrile episodes, acute and chronic illnesses, and lymphoproliferative disorders.

SURGERY AND TE The etiology of postoperative TE is multifactorial and includes the surgery procedure, surgical events, drugs, hypotension, and metabolic stress. A speciﬁ c relationship to the surgical event(s) has not been established and therefore the physician can only assess the timely association.

DRUGS AND BOTANICAL SUPPLEMENTS Many drugs and some herbal supplements have been reported to induce alopecia and TE. Clin- ically, all drugs should be suspect in a patient with TE. Careful histories allow for documentation of the drug initiation, time of discontinuation or change in dosage. A change in dose can initiate a TE. Like other causes of TE, once initiated, it can unmask underlying disorders such as androgenetic alopecia (Table 6). If the initiating drug is discontinued, a reversal of the TE is expected. Androgens such as testosterone, hormonal therapies with androgenic progesterones or testosterone, DHEAS, and anabolic steroids can induce TE and alopecia.

Anticoagulants such as coumadin, heparin, heparinoids, and enoxaparin can produce a TE. Anticonvalsants such as carbamazepine and valproic acid have been reported to occasionally induce a TE. The suggested mechanism is altered or reduced zinc and selenium levels. Antidepressants such as amphetamines, imipramine, desipramine, fl uoxetine, sertaline, and dixyrazine can produce a TE. Lithium induces hypothyroidism and can result in TE and alopecia. Antifungal drugs such as fl uconazole and ketoconazole in high doses have induced reversible TE. Antiinfl ammatory drugs such as chronic nonsteroidal antiinfl ammatory drugs (NSAID’s) have induced a reversible TE. Antimitotic drugs used in cancer or as an immunosuppressant can produce an anagen effl uvium (acute loss of 80% scalp hair) and at lower dose can induce a TE. Angiotensin-converting enzyme inhibitors such as captopril and enalapril can induce TE. The mechanism appears to be the binding of zinc and is reversible with zinc supplements. B-blockers such as systemic and topical ophthalmologic proparanol, and metroprolol can induce a chronic TE and diffuse alopecia. Estrogen antagonists such as tamoxifen, selected estrogen receptor modifi ers, and botanical phytoestrogens can induce a TE and diffuse alopecia. These are estrogen-competitive receptor inhibitors that inhibit estrogen action on the dermal papilla. Heavy metals such as gold have induced severe alopecia. Hypervitaminosis A can induce alopecia and TE. Vitamin A derivatives to monitor include mega- multivitamins, vitamin A supplements, and the oral retinoids.

TABLE 6 Drug for Treatment of Telogen Effl uvium Allopurinol Beta blockers Androgens Ergots Anticholesterol-statins Dopa Anticoagulants Immunomodulators Anticonvulsants Retinoids, vitamin A Antifungals Psychotropics Antihistamines H2 Minoxidil Antiinfl ammatory Heavy metals, i.e., gold Antimitotic SERMs and phytoestrogens Antithyroid Abbreviation: SERMs, selected estrogen receptor modifi ers. McMichael PTR 01/21/08 Chapter 09

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Minoxidil given orally can induce hirsutism while when applied topically it can initiate a TE that usually resolves in several months. Statins such as clofi brfate, triparanol, and cholestyramine can produce TE that may be dose- related. Sulfasalizine and infl ammatory bowel disease can induce a TE. At times it is diffi cult to separate the drug activity from disease to determine which has induced the TE and diffuse alopecia.

SCALP INFLAMMATION AND TE Seborrheic dermatitis, psoriasis and contact dermatitis of the scalp all have been known to induce a TE. Other noted changes include trichodystrophies and follicular miniaturization. The severity of seborrheic dermatitis correlates with the severity of the TE. Treatment with antidandruff shampoos, topical creams, solutions, gels, and shampoos are helpful in reversing the TE. Antidandruff shampoos with active ingredients such as ketoconazole, zinc pyrithione, selenium sulfi de, imidazoles, or ciclopirox olamine and low-potency topical corticosteroids represent the most common therapeutic agents. In addition, ketoconazole and zinc pyrithione can partially reverse a telogen effl uvium and enhance hair growth. This hair growth is noted to be less than the minoxidil response. Other reported effective therapies have included the calcineurin inhibitors such as pimecrolimus 1% cream, oral fl uconazole 50 mg/day for 2 weeks, and oral terbinafi ne 250 mg/day for 6 weeks.

CONCOMITANT TREATMENTS The topical treatment of TE includes use of antiseborrheic and antiandrogen shampoos such as ketoconazole or pyrithione zinc; topical corticosteroids, nutrient support and minoxidil; hormonal support and antiandrogens (Table 7).

Minoxidil Minoxidil 2% and 5% is FDA approved for use in males and 2% in females older than 18 years. Minoxidil works by prolonging the anagen hair cycle, which ultimately enlarges miniaturized follicles. Its precise mechanism is unknown but it is considered to be a potassium-channel opener, vasodilator, and an inhibitor apoptosis. Clinically the 5% is superior to the 2% when used twice a day (60% versus 41% regrowth at one year). The major side effects are irritation, dryness, scaling, itching or redness. In females, facial and distal hirsutism is noted especially with the 5%. In 2006, Rogaine® foam 5% was FDA approved for men as an over-the-counter product. African-Ameri- can patients tend to tolerate minoxidil solution better than the alcohol-based foam. In all, chronic use of minoxidil can induce in some patients a “dry scalp” that is pruritic and scaly. Allergy to the minoxidil product is less common. This irritation can be treated with an intermittent topical steroid solution or ointment dependent on the patient’s preference.

Antiandrogens Androgen excess is diagnosed by elevated circulating androgens or secondary signs and symptoms of androgen excess, such as SAHA. Females are freguently treated with combined thera- pics of antiandrogens and estrogen combinations (estradiol with nonandrogenic progesterone)

TABLE 7 Telogen Effl uvium and Alopecia Treatments Anti-infl ammatory Nutrients Immune modulators Antioxidants Antimicrobial Vitamins Hormonal Minerals Estrogen/progesterone Fatty acids Antiandrogen Protein Hair-growth promoters; minoxidil Camoufl age Weight loss Surgery McMichael PTR 01/21/08 Chapter 09

130 Bergfeld and/or spironlactone, low-dose corticosteroids hs and insulin resistance therapies. The preferred male treatment is similar with the exception of estrogen therapy. Weight loss in the obese can reduce circulating testosterone by diminishing insulin levels, which in turn reduces the production of testosterone.

Finasteride Finasteride 1 mg is FDA approved only for males. It is an inhibitor of type 2 enzyme of 5-alpha- reductase, an important enzyme in the conversion of testosterone to DHT. In clinical studies of postmenopausal females there was no improvement of hair growth. The ﬁ ve-year follow-up ﬁ n- asteride studies show continued clinical improvement after one year of treatment but this appears secondary to thicker hair. Adverse events have been minimal. In clinical studies, the incidence of prostate cancer is less but when present it is more aggressive. Finasteride has been used successfully in females with androgen excess. All antiandrogen therapies in females are potentially fetal teratogens, and therefore necessitate the use of birth control while under treatment.

Dutasteride Recently, dutasteride 2.5 mg has been found to be superior to fi nasteride in the treatment of MPHL in a randomized placebo-controlled study. It is a dual inhibitor 5-alpha-reductase and inhibits both type 1 and type 2 enzymes of 5-alpha-reductase. The adverse effects are similar to fi nasteride, and include a rare sexual dysfunction. The safety profi le dutasteride differs from fi n- asteride due to its longer half-life of 4 weeks as compared to the 6–8-hour half-life of fi nasteride. Currently, dutasteride is only FDA approved for benign prostate enlargement 0.5 mg. If this drug is considered for androgenetic alopecia or androgen excess, it should be used with caution. In females of reproductive age, pregnancy prevention is essential.

Estrogen The mechanism of estrogen induction of hair growth is not well understood. In the clinical setting, estrogens lengthen the anagen growth cycle and decrease transition to telogen. The mechanism appears to be a modiﬁ cation of androgen metabolism in the anagen dermal papillae, with the resultant decrease in local DHT due to an increase in aromatase. The increase in aromatase increases the conversion of testosterone to estrogen. Characteristically, in pregnancy the hair grows well with an increase and synchronization of anagen follicles. In the postpartum state, a TE can be anticipated because of the plummet- ing down of the markedly elevated estrogen that is elevated in pregnancy. In females, combined estrogen therapies and hormone replacement can stabilize or reverse a TE. In addition, the estrogen antagonists are well-recognized to induce hair loss and induce a diffuse alopecia. Clinical studies are needed to conﬁ rm these observations.

Botanicals with DHT Inhibition Some of the over-the-counter, botanical hair promoters incorporate minoxidil as an active ingredient, shcu as Nioxin® Intensive Therapy Follicle Booster and Scalp Med® Vitadil-5A and Vitadil-2A. The majority of botanical DHT inhibitors contain combinations of botanicals with or without minoxidil. Some of the botanicals used include saw palmetto, liposterolic extract of sere- nona repens, and beta-siterosterol, azelaic acid, zinc, B6, linoleic acid, and polyphenols. Some available products are Avacor®, Procede®, Provillus®, and Rivivogen® (Table 8).

Botanical Nutrients Many botanical haircare and hair growth-promoter products include a multitude of vitamins, antioxidants, amino acids, proteins, and fatty acids. The antioxidants and vitamins ingredients claim to induce vasodilatation, and angiogenesis growth, and reduce inﬂ ammation. Some of these ingredients are vitamin E, vitamin C, vitamin A, niacin, amino acids, fatty acids, and polyphenols. McMichael PTR 01/21/08 Chapter 09

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TABLE 8 5-Alpha-Reductase Inhibitors and Competitive Receptor Agonist Estrogen Progesterones Finasteride Spironolactone Corticosteroids Zinc Minerals and vitamins Botanical antiandrogens Ketoconazole

CAMOUFLAGE AND COSMETIC AIDS The use of cosmetic approaches to camoufl age diffuse alopecia include a variety of methods, such as hairstyling, styling agents, coloring, camoufl age prostheses such as wigs, hair pieces, and hair extensions, and scalp coloring products such as tints, powders, lotions, and sprays. Surgical approaches for androgenetic alopecia or chronic diffuse alopecia include hair transplantation. With the newer methods of hair transplantation, a natural look can be achieved. Advanced and combined surgical procedures of hair transplantation, scalp reduction, fl aps, and tissue expansion can be employed when necessary.

FUTURE The advances of molecular technology have opened up the investigation of the molecular and genetic basis of hair growth, hair disorders and the aging process. The discovery of potential pharmacological follicular targets and an effective follicular delivery system will become com- monplace for maintenance and treatment of hair and scalp disorders. With these new techniques, active ingredients such as nutrients, melanins, dyes, genes, hair promoters, hormones, antiandrogens, and other needed elements for hair growth will be delivered directly to the follicle. The development of follicular augmentation, using the patient’s follicles to develop an in vitro ampliﬁ cation of the individuals follicles and then return the ampliﬁ ed population via hair transplantation to the patient, is another exciting option.

CONCLUSION The treatment of TE is directed by the clinical evaluation and the identiﬁ cation of triggering events. The physician’s primary focus is to remove and to treat or inhibit the trigger(s) of the TE. On return visits, a follow-up history of the TE activity, an assessment of the TE and state of alopecia, review of hair care, therapeutic regimen, and a medical update are necessary. The expected results of any therapy should be diminished TE after 2 months, evidence of regrowth at 4–6 months, and recovery or plateau of the therapeutic beneﬁ t of the treatment regimen at 12 months. A patient health calendar that includes the recorded levels of shedding, medical events, drugs (new or changes in dose), and psychological stress is very helpful in monitoring the patient’s status. This chapter has attempted to distill the current concepts, to offer a diagnostic and therapeutic approach, and to expand the therapeutic options.

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Headington JT. Telogen effl uvium. New concepts and review Arch Dermatol 1992; 130(2):256–263. Paus R. Principals of hair cycle control. J Dermatol 1998; 25(12):793–802. Pierard-Franchimont C, Pierard GE. Teloptosis, a turning point in hair shedding biorhythms. Dermatol 2001; 203(2):115–117. Trueb RM. Idiopathic chronic telogen effl uvium in the woman (review). Hautar4zt 2000; 51(12):899–905. Rebora A, Guarreara M, Baldari M, Vecchio F. Distinguishing Androgenetic alopecia from chronic telogen effl uvium when association in the same patient: a simple noninvasive method. Arch Dermatol 2005; 141(10):1243–1245. Stenn KS, Paus R. Controls of hair follicle cycling (a review). Physiological reviews 2001; 81(1):449–494. Sinclair R. Chronic telogen effl uvium or early Androgenetic alopecia? Int J Dermatol 2004; 43(11): 842–843. Trueb RM. Idiopathic chronic telogen effl uvium in the women (Review). Hautarzt 2000; 51(12):899–905. Whiting DA. Chronic telogen effl uvium: increased scalp hair shedding in middle aged women. JAAD 1996; 35(6):899–906. Whiting DA. Update chronic telogen effl uvium. Exp Dermatol 1999; 135(9):1123–1124.

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Drugs Gollnick H, Blume U, Orfanos CE. Adverse drug reactions on hair. Z Hautkr 1990; 65(12):1128–1134. Tosti A, Misciali C, Piraccini BM, Peluso AM, Bardazzi F. Drug induced hair loss and hair growth. Incidence, management and avoidance. Drug Saf 1994; 10(4):310–317. Kimyai-Asadi A, Harris JC, Nousare HC. Critical review: adverse cutaneous reactions to psychotropic medications. J Clin Psychiatry 1999; 60(10):714–725. Bleiker TO, Nicolaou N, Traulsen J, Hutchinson PE. “Atrophic telogen efﬂ uvium” from cytotoxic drugs and a randomized controlled trial to investigate the possible protective effect of pretreatment with a topical vitamin D analogue in humans. Br J Dermatol 2005; 153(1):103–112. Tosi A, Misciali C, Piraccini BM, Peluso AM, Bardazzi F. Drug-induced hair loss and hair growth. Incidence, management and avoidance. Drug Saf 1994; 10(4):310–317.

Androgens Orfanos CE, Adlesr YD, Zouboulis CC. The SAHA syndrome. Horm Res 2000; 54 (5–6):251–258. Vexiau P, Basperyras M, Chaspoux C, Foin N Allaert, Abramovici Y. Acne in adult women: data from a national study on the relationship between type of acne and markers of clinical hyperandrogenism. Ann Dermatol Venereol 2002; 129(2):174–178.

Hormones Foitzik K, Krause K, Nixon AJ, et al. Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen. Am J Pathol 2003; 162(5):1611–1621. Moverare S, Lindberg MK, Faergemann J et al. Estrogen receptor alpha, but not estrogen receptor beta, is involved in the regulation of the hair follicle cycling as well as the thickness of the epidermis in male mice. J Investig Dermatol 2002; 119(5):1053–1058. Chanda S, Robinette CL, Couse JF, Smart RC. 17 beta-estradiol and ICI-182780 regulate the hair follicle cyclin in mice through an estrogen receptor-alpha pathway. Am J Physiology-Endocrinol & metabolism 2000; 287(2):E202–E210. McMichael PTR 01/21/08 Chapter 09

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Hoffman R, Rot A, Niiyama S, Billich A. Steroid sulfatase in the human hair follicle concentrates in the dermal papilla. J Investig Dermatol 2001; 117(6):1342–1348. Verdier-Serain S, Bonte F, Gilchrest B. Biology of estrogen in skin: implications for skin aging. Exp Dermatol 2006; 15:83–94. Niiyama R, Happle R, Hoffman R. Inﬂ uence of estrogens on the androgen metabolism in different subunits of human hair follicles. Eur J Dermatol 2001; 11(3):165–168. Hoffman R, Niiyama S, Huth A, Kissling S, Happle R. 17 alpha-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo. Exp Dermatol 2002; 11(4):376–380.

Nutrients Aburjai T, Natsheh FM. Plants used in cosmetics. Phytotherapy Res 2003; 17:987–1000 (www.interscience.wiley.com). FDA U.S. RDA information retrieved January 15, 2007 from http://fda.gov/ora/inspect_ref/igs/ nleaattc.html National Institute of Health, Dietary Supplement Fact Sheet, retrieved January 17,2007; (Review of vitamins and minerals)from http://ods.od.nih.gov/factsheets/vitamina.asp National Library of Medicine, (drug and natural formulations information) retrieved January 17, 2007 from http://wwsw.nlm.nlm.gov/medlineplus/druginfo/natural National Institute of Health, MidlinePlus Drug information (Review of Nutrients) retrieved January 17, 2006 from http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202374.html

Diet Goette DK, Odom RB. Alopecia and crash dieters. JAMA 1976; 235(24):2622–2623. Strumia R. Dermatologic signs in patients with eating disorders. Am J Clin Dermatol 2005; 6(3):165–173. Skolochenko M. Crash dieting associated with telogen efﬂ uvium. Geriatrics 2000; 55(7):16.

Iron Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron defi ciency and its potential relationship to hair loss. JAAD 2006; 54:824–844. Olsen EA. Iron defi ciency and hair loss: the jury is still out. JAAD 2006; 54:844. Centers for Disease Control (DCDC). Iron defi ciency-United States, 1999–2000. Morbidity Mortality Wkly Rep 2002; 51:897–899. Puolakka J, Pakarinin A, Jarvinen A, Vihko R. Serum ferritin as a measure o6f iron stores during and after normal pregnancy with and without iron supplements. Acta Obstetricia et Gynecologica Scandinavica-Supplement 1980; 95: 43–51. Kantor J, Kessler LJ, Brooks DG, Cotsarelis G. Decreased serum ferritin is associated with alopecia in women. J Invest Dermatol 2003; 121:985–988. Sinclair R. There is no clear association between low serum ferritin and chronic diffuse telogen hair loss. Br J Dermatol 2002; 147:982–984. Aydingoz I, Ferhanoglu B, Guney O. Does tissue iron status have a role in female alopecia? J Eur Acad Dermatol Venereol 1999; 13:65–67. Rushton DH. Nutritional factors and hair loss. Clin Exp Dermatol 2002; 27:396–404. Hard S. Non-anaemic iron defi ciency as an etiology factor in diffuse loss of hair of the scalp in women. Acta Derm Vernereol 1963; 43:562–569.

Zinc Arnaud J Beani FC, Favier AE, Embliard R. Zinc status in patients with telogen efﬂ uvium. Acta Derm Venereol 1995; 75:248–249. Willis MS, Monaghn Z, Miller ML, et al. Zinc induced copper deﬁ ciency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol 2005;123(1):12225–12231.

Fatty Acid Riella MC, Broviac J, Wells M, Scribner BH. Essential fatty acid deﬁ ciency in human adults during total parenteral nutrition. Ann Intern Med 1975; 83:786–789. Skolnik P, Eaglestein WH, Ziboh VA. Human essential fatty acid deﬁ ciency. Arch Dermatol 1977; 113: 939–941.

Vitamin D Sutton AL, McDonald PN. Vitamin D more than a “bone-a-ﬁ de” hormone (A review). Molecular Endocrinol 2003; 17(5):777–791. McMichael PTR 01/21/08 Chapter 09

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Vegesna V, O’Kellly J, Uskokovic M, et al. Vitamin D3 analogs stimulate hair growth in nude mice. Endocrinol 2002; 143(11): 4389–4396.

Minoxidil Arck PC, Hanjiski B, Peter EM, et al. Topical minoxidil counteracts stress-induced hair growth inhibition in mice. Exp Dermatol 2003; 12(5):580–590. Bamford JT. A falling out following minoxidil: telogen efﬂ uvium. J Am Acad Dermatol 1987; 16(1pt1):144–146. Berger RS, Fu JL, Smiles KA, et al. The effects of minoxidil, 1% pyrithione zinc and a combination of both on hair density: a randomized controlled trial. Br J Dermatol 2003; 149(2):354–356. Tosti A, Iorizzo M, Vincenzi C. Finasteride treatment may not prevent telogen efﬂ uvium after minoxidil withdrawal. Arch Dermatol 2003; 1139(9):1221–1222. Wang J, Lu Z, Au JL. Protection against chemotherapy-induced alopecia (Review). Pharmaceutical Research 2006; 23(11):2505–2514.

Scalp Dermatitis Tosti A. Piraccini BM, Van Neste DJ. Telogen effl uvium after allergic contact dermatitis of the scalp. Arch Dermatol 2001; 137(2):187–190. Berger RS, Fu JL, Smiles KA, et al. The effects of minoxidil, 1 zinc pyrithrione an a combination on both on hair density: a randomized controlled trial. Brit J Dermatol 2003; 149(2):353–362. Burkhart CG. Beau’s lines. An association with pustular psoriasis and telogen effl uvium. Arch Dermatol 1980; 116(10):1190–1191. Elewski B, Lking MR, Phillips TJ. Effi cacy and safety of a new once-daily topical ketoconazole 2% get in the treatment of seborrheic dermatitis: a phase III trial. J Drdrugs Dermatol 2006; 5(7):646–650. Firooz A, Solhpour A, Gorouhi F, et al. Pimecrolimus cream 1% vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial. Arch Dermatol 2006; 142(8):1066–1067. Inui S, Itami S. Reversal of Androgenetic alopecia by topical ketoconazole: relevance of anti-androgenic activity. J Dermatol Sci. 2007; 45(1):66–68. Jiang JM, Tsuboi R, Kojima Y, Ogawa H. Topical application of Ketoconazole stimulates hair growth in C2H/HeN mice. J Dermatol 2005; 32(4):343–347. Kuznetov AV, Erlenkeuser-Uebelhoer I, Thomas P. Contact dermatitis to propylene glycol and dodecyl gallate mimicking seborrheic dermatitis. Contact dermatitis 2006; 55(5):307–308 Pierard-Franchimont C, Xhaufl aire-Uhoda E. Loussouarn G, Saint Leger D, Pirard GE. Dandruff- associated smouldering alopecia: a chronobiological assessment over 5 years. Clin Ex Dermatol 2006; 31(1):23–26. Stanimirovic A, Skerlev M, Stipic T, et al. Has psoriasis it own characteristic trichogram? J Dermatol Sci 1998; 17(2):156–159. Schwartz RA, Janusz CA, Janniger CK. Seborrheic dermatitis: an overview. Am Fam Physician. 2006; 74(1):125–130. Vena GA, Micali G, Santoianni P, et al. Oral terbinafi ne in the treatment of multi-site seborrheic dermatitis: a multicenter, double-blind placebo-controlled study. Int J Immunopathol Pharmacol 2005; 18(4):745–753. Zisova LG. Fluconazole and its place in the treatment of seborrheic dermatitis—new therapeutic possibilities. Folia Med (Plovdiv) 2006; 48(1):39–45.

Psychological Stress Arck PC, Handjiski B, Peters EM, Hagen E, Klapp BF, Paus R. Topical minoxidil counteracts stress- induced hair growth inhibition in mice. Exp Dermatol 2003; 12(5):580–590. Arck PC, Handjiski B, Peters EM, et al. Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inﬂ ammatory events via neuropeptides substance P- dependent pathways. Am J Pathol 2003; 162(3):709–712. Hadsheiw IM, Foitzik K, Arck PC, Paus R. Burden of hair loss: stress and the underestimated psychosocial impact of telogen efﬂ uvium and Androgenetic alopecia J Invest Dermatol 2004; 123(3):455–457. Otomo S. Hair growth the effect of minoxidil (Review). Nippon Yakurigaku Zasshi-Folia Pharmacologica Japonica 2002; 119(3):167–174.

Surgery Desai SP, Roaf ER. Telogen efﬂ uvium after anesthesia and surgery. Anesth Analg 1984; 63(1):83–84. Knuttrel R, Torabian SZ, Fung M. Hair loss after rhytidectomy. Dermatol Surg 2004; 30(7):1041–1042. McMichael PTR 01/21/08 Chapter 09

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Treatment Buddie J, Tronnier H, Rahlfs VW, Frei-Kleiner S. Systemic therapy of diffuse efﬂ uvium and hair structure damage. Hautarzt 1993; 44(6):380–384. Mecklenburg L, Tobin DJ, Muller-Rover S, Paus R. Active hair growth(anagen) is associated with angiogenesis. J Investig Dermatol 2000; 114(5):909–916. Olsen EA, Hordinsky M, Whiting D, et al. The importance of dual 5 alpha reductase inhibition in the treatment of male pattern hair loss: Results of a randomized placebo-controlled study of dutasteride versus ﬁ nasteride. JAAD 2006; 55:1014–1023. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blinded-controlled trail to determine the effectiveness of Botanically Derived inhibitors of 5AR in the treatment of Androgenetic alopecia. Alternative and Complimentary Medicine 2002; 8(2):1–14. Vexiau P, Chaspoux C, Boudou P, et al. Effects of minoxidil 2% vs cyproterone acetate treatment on female Androgenetic alopecia: a controlled, 12 month randomized trial. Br J Dermatol 2002; 146(6):992–999.

Future Trueb RM. Dermocosmetic aspects of hair and scalp. J Investig Dermatol 2005; 10(3):289–292. Hoffman RM. Topical liposome targeting of dyes, melanins, genes, proteins selectively to hair follicles (Review). J Drug Targeting 1998; 5(2):67–74. Tabbakhian M, Tavakoli N, Jaafari MR, Daneshamouz S. Enhancement of follicular delivery of ﬁ nasteride by lipsomes and niosomes 1. In vitro permeation and in vivo depositon studies using hamster ﬂ ank and ear models. Int J Pharm 2006; 112(1–2):1–10. McMichael PTR 01/21/08 Chapter 09 McMichael PTR 01/21/08 Chapter 10

10 Cicatricial Alopecia

Paradi Mirmirani Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, and University of California, San Francisco, California, U.S.A.

INTRODUCTION Scarring or cicatricial alopecias (CAs) are a poorly understood group of disorders that destroy the hair follicle, replace it with scar tissue, and cause permanent hair loss. Despite astounding strides forward in our understanding of hair biology, the CAs have been, until recently, an “orphan” of the hair disorders, neglected in the clinical and research realm. Our challenge is to harness the knowledge we have gained in hair biology to improve our understanding of these incredibly devastating diseases that leave patients with permanent hair loss. Fortunately, progress is occurring, including efforts to clarify clinical and histologic classiﬁ cation of the diseases, and to identify major areas of interest in research.

BACKGROUND In 2001 the North American Hair Research Society (NAHRS) sponsored a workshop in which a preliminary working classifi cation of the primary CAs was developed. This classifi cation was based on the predominant histologic infl ammatory infi ltrate (Table 1) (1). It was hoped that the classifi - cation would serve to clarify and unify the often vague or divergent terminology and diagnostic categories found in the literature and to facilitate collaborative trials to determine pathogenic factors and effective therapeutic options (1). A prospective evaluation of this provisional classifi cation found that the lymphocytic and neutrophilic groups were readily distinguished histologically, however, within the two groups clinically distinct primary CAs could not be diagnosed with certainty refl ecting the limits of present understanding (2). The challenge facing hair researchers was to move “the study of this form of CA . . . from the twentieth century morphology to twenty-fi rst century cell biology” (2). This call to action was met with a fi rst-ever CA Research Colloquium in 2005. This meeting brought together hair biologists and researchers from other fi elds to share current research on CAs and to explore and defi ne important areas for future research (3).

MECHANISMS Animal Models and the Sebotrophic Hypothesis Mouse models with mutations of genes expressed in the mouse sebaceous gland, specifi cally the asebia mouse (stearyl-coenzyme A desaturase gene) and defolliculated (gasdermin 3-a transcription factor), have a clinical and histologic picture similar to CA seen in humans (3–8). This work suggests that the sebaceous gland may be central to the pathogenesis of CAs. The sebotrophic mechanism puts forth the notion that the desquamation of the inner root sheath is dependent on the normal function of the sebum and that the absence of the normal gland leads to obstructed outfl ow of the hair shaft. Subsequently there is infl ammation and eventual destruction of the follicle. Although the sebaceous gland plays a central role, the problem could be proximal or distal to this gland, leaving room for the possibility that environment, toxins, infection, etc. may play an initial role (3). Studies reviewing the histopathology of CAs have consistently found loss of sebaceous glands in the affected tissue (2,9,10). Furthermore, biopsies of clinically unaffected scalp in patients with lichen planopilaris have shown early sebaceous gland atrophy (2). Therefore it is possible that human CA also begins with sebaceous gland involvement or dysfunction and may even fall into a group of obstructive folliculopathies that would include acne vulgaris, and the overlap syndrome follicular occlusion triad in which sebaceous and terminal follicles are diseased (3). McMichael PTR 01/21/08 Chapter 10

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TABLE 1 Classifi cation of Cictricial Alopecias Primary scarring alopecias: pathology directed at the hair follicle Lymphocytic-mediated Chronic cutaneous lupus erythematosus Classic lichen planopilaris Frontal fi brosing alopecia Graham Little syndrome Pseudopelade (Brocq) Central centrifugal cicatrcial alopecia Keratosis follicularis spinulosa decalvans Neutrophilic-mediated Folliculitis decalvans Tufted folliculitis Dissecting cellulitis/folliculitis (perifolliculitis abscedens et suffodiens) Secondary scarring alopecias: pathology non-specifi cally affects the hair follicle Infl ammatory/autoimmune Follicular mucinosis (alopecia mucinosa) Scleroderma/morphea Infectious Viral Fungal Bacterial Neoplastic Primary and metastatic carcinoma Granulomas Physical agents X-ray Burns Source: From Ref. 1.

Stem Cells and Immunology The failure of affected follicles to regrow in primary CA is thought to be because of destructive infl ammatory changes at the level of the insertion of the arrector pili muscle into the region of the follicular bulge (11–14). This is where the slow-cycling hair follicle stem cells that are capable of initiating follicular renewal at the end of the resting phase of the hair cycle are located. Studies suggest that the hair follicle stem cells and not the epidermal stem cells are injured in these disorders, however, whether these cells are a primary target or destroyed as an innocent bystander is a question that remains to be resolved (3). The identifi cation of a distinct pattern of infl ammatory and tissue-altering interactions that occur in CA is both useful as a diagnostic strategy and as an initial step in unraveling the immunological basis for hair loss. Prior studies have found that the human hair follicle appears to have immune privilege with major histocompatibility complex (MHC) class I negativity, and an immunosuppressive cytokine milieu (15). In normal anagen hair, macrophages are virtually absent from the hair follicle epithelium. It has been proposed that deletion of hair follicles may be caused by a macrophage-driven attack on epithelial hair follicle stem cells in the bulge of the outer root sheath under pathologic circumstances (15). Immunostaining of biopsy specimens suggest increased CD8+ T cells compared to CD4+ cells and have also shown increased macrophages around the perifollicular sheath (11). Gene array studies have been supportive of this immunologic pattern, having found increased expression of genes involved in macrophage activation, apoptosis, and tissue remodeling in lichen planopilaris (LPP) patients compared to controls (16). In the patients with neutrophilic CAs, an abnormal host response to bacteria, perhaps similar to that seen for P. acnes has been postulated (17). Alternatively, the underlying pathophysiology may be similar to that seen with the lymphocytic scarring alopecias, however, bacteria may provide an ongoing nidus for infl ammation thus perpetuating the destruction of hair follicles.

Peroxisomes and Lipid Metabolism More recent work using microarray techniques suggests that CAs may be an acquired disorder of the peroxisomes (18). Peroxisomes are single, membrane-bound, ubiquitous, subcellular organ- elles catalyzing a number of indispensable functions in the cell, including lipid metabolism and McMichael PTR 01/21/08 Chapter 10

Cicatricial Alopecia 139 the decomposition of harmful hydrogen peroxide. Several cutaneous manifestations of peroxisome biogenesis disorders have been reported (19,20) and it is intriguing to note that patients with the peroxisomal disorder, X-linked dominant, or recessive CDP (XCDP2) display epidermal hyperkeratosis and follicular plugging with CA (20,21). One model of the pathogenesis of CA is that external or genetic triggers lead to localized peroxisomal dysfunction, leading to abnormal lipid homeostasis, lipid accumulation causing tissue damage (lipotoxicity) of the pilosebaceous unit. This tissue damage then triggers chemokine/cytokine expression, recruits lymphocytes and macrophages, and activates a lipid-mediated programmed cell death (lipoapoptosis) thereby contributing to permanent hair loss in LPP (18). Future studies and animal models elaborating this pathogenetic model and the evaluation of peroxisome proliferator-activated receptors (PPARs) as a potential therapeutic target in treating CA are warranted.

EPIDEMIOLOGY The epidemiology of primary CAs in the general population is unknown. The prevalence has been reported to range from 3.2–7.3% in two retrospective studies (22,23). The most common causes of CA include chronic cutaneous lupus erythematosus, LPP, and central centrifugal CA, but can vary depending on geographic location and referral pattern (24).

CLINICAL PRESENTATION Patients with CA may present with acute onset or ongoing hair loss and symptomatology. Symptoms include itching, burning, pain, redness and/or drainage from the scalp. A thorough history should be completed to evaluate for autoimmune disease, systemic illness, infections, neoplasms, associated infl ammatory skin disease, and radiation treatment or burns. On physical exam, the diagnostic hallmark of all forms of CA is visible loss of follicular ostia. Signs of scalp infl ammation including erythema, scaling, pustules, scalp bogginess; compound follicles and wiry hairs are also commonly seen. Another characteristic fi nding in active areas of CA is a positive pull test with anagen bulbs seen on hair mount (Fig. 1).

Lymphocytic CAs Chronic cutaneous lupus erythematosus (CCLE) also known as discoid lupus erythematosus (DLE) is a common cause of scarring alopecia. Women are more commonly affected than men with an age of onset typically between 20 and 40 years; it is uncommon in children (25,26). The prevalence of CCLE has been reported to be increased among African-American women (27,28). Scalp involvement with CCLE is seen in a majority of patients, and may often be the presenting symptom (27). Scalp tenderness and itching are frequently reported. Erythema, scale, and pigmentary changes are more pronounced than in the other forms of scarring alopecia and these fi nding may be seen at the center of the alopecic patch unlike other CAs in which the infl ammation is typically at the outer rim or edge. Typical scalp lesions are round or “discoid” in appearance; follicular plugging and adherent scale may be present (Fig. 2). The “carpet tack” sign may be elicited with retraction of the scale, revealing keratotic spikes that correspond to follicular openings on the undersurface (29). Presence of the disease in areas other than the scalp can make the diagnosis more certain. LPP is a scarring alopecia seen more commonly in middle-aged women. There is no known racial predilection. Patients are often quite symptomatic with itching, burning, and pain of the scalp. Examination reveals patchy alopecia or a more diffuse thinning of the scalp with characteristic perifollicular erythema and perifollicular scale at the margins of the areas of alopecia (Fig. 3) (30). Disease can be indolent or slowly progressive, but rarely involves the entire scalp. Fifty percent of patients with LPP lack evidence of lichen planus at sites other than the scalp (31). Two subtypes or variants of LPP are commonly recognized, frontal fi brosing alopecia and Graham Little syndrome. Frontal fi brosing alopecia is a more recently described variant of LPP that affects almost exclusively post-menopausal Caucasian women (32,33). The pathogenesis of the disease seems to be unrelated to hormone replacement status. This disease presents as a bandlike fronto-temporal alopecia that progresses to involve the temporal-parietal scalp (Fig. 4). The skin pallor in the band of alopecia anterior to the frontal hairline contrasts with the sun-damaged skin of the lower forehead and may also be a helpful feature in recognizing this variant of LPP. Loss of eyebrows is another variable clinical fi nding that if present can McMichael PTR 01/21/08 Chapter 10

140 Mirmirani

FIGURE 1 Anagen hair bulb. make the diagnosis more certain. The Graham Little-Piccardi variant of LPP is characterized by cicatricial scalp hair loss along with non-cicatricial loss of body hair, notably axillary and pubic hair; on biopsy, however, the latter regions show a cicatricial process (34). Pseudopelade as described by Brocq presents with irregularly defi ned, white-colored, coalesc- ing patches of alopecia with atrophy and loss of follicular markings (Fig. 5) (35,36). This type of presentation has been called “footprints in the snow.” Onset of disease is in adulthood, with no clear gender or ethnic predilection. Follicular hyperkeratosis and infl ammation is usually not seen and patients are usually without symptoms. The clinical presentation is frequently similar to alopecia areata (thus the term “pseudo” pelade, the French word for alopecia areata) however on close inspection the characteristic loss of follicular markings distinguishes the two types of hair loss. Central centrifugal CA (CCCA) is the term that encompasses hair loss previously termed “follicular degeneration syndrome” or “hot-comb alopecia” (1,37,38). The literature on hot-comb alopecia describes hair loss primarily in middle-aged black women, and suggests that specifi c haircare practices are associated with this disorder (37,39). However, this type of hair loss has been reported in men and in patients not using any suspect styling techniques and thus the alternative term follicular degeneration syndrome was suggested based on specifi c histologic fi nd-

FIGURE 2 (See color insert.) Discoid lupus. McMichael PTR 01/21/08 Chapter 10

Cicatricial Alopecia 141

(A)

(B)

FIGURE 3 (See color insert.) Lichen planopilaris (A) and lichen planopilaris perifollicular erythema and scaling (B). ings. Since this initial histologic description, it has been shown that premature desquamation of the inner root sheath is seen in other types of CA (10,38,40,41), therefore the consensus now is to use the more descriptive term central centrifugal CA. As the name suggests, this disorder typically starts at the crown and advances to the parietal scalp; the reason for the hair loss in this typical pattern remains unexplained (1). Patients may complain of itching or discomfort, or have no symptoms at all, but notice an enlarging area of alopecia over time (Fig. 6). Keratosis follicularis spinulosa decalvans (KFSD) is an x-linked or sporadic disorder characterized by widespread keratosis pilaris, scarring alopecia of the scalp and brows, and photo- phobia (42). Some classify this disorder along with a heterogeneous group of related disorders (keratosis pilaris atrophicans faciei/ulerythema opryogenes, atrophoderma vermiculata, and folliculitis spinulosa decalvans) under the umbrella of keratosis pilaris atrophicans (43). Symp- toms of KFSD typically begin in infancy or childhood with follicular hyperkeratosis preceding the scarring alopecia.

Neutrophilic CAs Folliculitis decalvans, tufted folliculitis, and dissecting cellulitis represent a group of scarring alopecias with a suppurative phase. Tufted folliculits is sometimes considered a localized variant of follicultitis. These diseases affect men and women from young adulthood to middle age. Dissecting cellulitis may present as part of the so-called follicular occlusion triad that includes acne conglobata and hidradenitis suppurativa and is seen primarily in black men. Clinically, any region of the scalp may be involved and is characterized by recurrent follicular pustules,

FIGURE 4 Frontal ﬁ brosing alopecia. McMichael PTR 01/21/08 Chapter 10

142 Mirmirani

FIGURE 5 (See color insert.) Pseudopelade. patchy scarring alopecia, tufted or compound follicles, or presence of boggy plaques with sinus tract formation (Figs. 7 and 8) (44).

Mixed CAs Folliculitis (acne) keloidalis is a disorder that occurs mostly in young black patients, although it has been reported in black women and Caucasian men. The lesions typically start as small papules or pustules on the back of the neck but can progress to larger hypertrophic scars or keloid-like plaques; occasionally there are coexisting sinus tracks and pus. It has been postulated that mechanical irritation, injury during short haircuts, and inﬂ ammation from impaction of short curved hair may trigger the problem. However it has recently been suggested that folliculitis keloidalis is a primary scarring alopecia based on the histopathologic appearance of early lesions (45). Erosive pustular dermatosis is a rare disorder in which patients are described as having a large, asymptomatic, boggy plaque on the scalp with superﬁ cial crusts and pustules. The lesions are seen most commonly in the elderly with extensive actinic or traumatic skin damage (46). Acne nectrotica is another rare, relapsing disorder seen in adults that is characterized by papulopustules in the frontal hair line and seborrheic areas that heal with hemorrhagic crusts and eventual punched-out varioliform scars (47).

FIGURE 6 Central centrifugal cicatricial alopecia. McMichael PTR 01/21/08 Chapter 10

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FIGURE 7 (See color insert.) Folliculitis decalvans. HISTOPATHOLOGY A biopsy is warranted in all scarring alopecias to determine the predominant infi ltrate, its location, and extent; this information can help confi rm the clinical diagnosis and also help guide the physician’s choice of treatment (2,48). The biopsy should be taken from the active border of hair loss where some hairs still remain. A 4-mm punch biopsy is adequate and must include subcutaneous fat to ensure sampling of the entire follicular unit and any anagen follicles. The biopsies may be sectioned horizontally and vertically (Fig. 8). Vertical sections are useful for giving information about the epidermis. However, horizontal sections are becoming the method of choice as they offer the advantage of evaluating large numbers of follicles simultaneously, determining hair density, telogen/vellus ratio, anagen-to-telogen ratio and location of infl ammatory infi ltrate (9,49,50). Routine staining with hematoxylin and eosin is recommended as a standard evaluation. Direct immunofl uorescence is of value in histopathologically inconclusive cases, with a high specifi city and sensitivity for chronic cutaneous lupus erythematosus and a high specifi city but low sensitivity for lichen planus (51). Verhoeff-Van Gieson (VVG) elastic stain may be of value in differentiating end-stage CAs (52). Despite numerous attempts to classify the various types of CA, no clear histopathologic categorization has emerged, as such. The North American Hair Research Society characteristic categorization is advocated as a provisional classifi cation method. Typical histopathologic features seen in biopsy specimens of patients with lymphocytic and neutrophilic are listed in Table 2. Given much of the histologic and clinical overlap among various forms of CA, it is recommended that a descriptive, standardized histopathologic “checklist” reporting of follicular architecture, type, location, and extent of the infl ammatory infi ltrate, presence or absence of sebaceous glands, and presence of fi brosis, is the clearest form of pathologic reporting (2,40). In the future, specifi c immunophenotyping and molecular markers may be found that could distinguish and clarify the various clinical types of CAs.

FIGURE 8 (See color insert.) Dissecting cellulitis. McMichael PTR 01/21/08 Chapter 10

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TABLE 2 Histopathologic Findings for Primary Cicatricial Alopecias Lymphocytic group Decreased follicular density Perifollicular high-level lymphocytic infi ltrates (around infundibulum and isthmus) Loss of sebaceous epithelium or sebaceous gland atrophy with glands present but smaller in size and number Perifollicular lamellar fi brosis Follicular fusion (compound follicles) Inner sheath degeneration Neutrophilic group Decreased follicular density Early: Peri-infundibular neurophilic infi ltrate Later: Peri-infundibular and perivascular infl ammation, with lymphocytes, neutrophils, plasma cells, and naked hair shafts with perifollcular granulomas Loss of sebaceous epithelium or sebaceous gland atrophy with glands present but smaller in size and number Perifollicular lamellar fi brosis Reticular dermal scarring Marked follicular fusion (compound follicles) Inner sheath degeneration Source: From Ref. 1.

TREATMENT Prior to counseling the patient on treatment options, it is crucial that the patient understand that the goal of treatment is to (i) alleviate the patient’s symptoms, and (ii) arrest the progression of disease, but regrowth of hair in bare areas is not possible. With these common goals, patient and clinician can work together to determine the best treatment regimen and to evaluate its effi cacy over time. The therapeutic strategy is generally based on (i) the degree of infl ammatory infi ltrate on biopsy (sparse, moderate, dense), and (ii) clinical assessment of disease. Components of the clinical assessment include the following:

1. Patient symptoms (itching, pain, burning) 2. Clinical signs (perifollicular scale, perifollicular erythema, pustules, crusting, pull test: anagen/total) 3. Extent of hair loss (determined by patient self-report, review of photographs, and clinical exam) (53)

Despite using specifi c outcome measures, the unclear natural course of the diseases can make it diffi cult to determine if the disease has responded to a specifi c treatment or if it is in “remission,” or has “burned out.” The vast array of treatments for CA described in the literature must be evaluated in this context. The treatment guidelines listed below are not meant to be exhaustive, but instead refl ect the practices of the author.

Medical Medical treatment options are broadly grouped into treatments for lymphocytic and neutrophilic CA (Tables 3 and 4). More than one treatment may be used concurrently (i.e., combination of topical and systemic) especially when the patient has evidence of moderate to dense inﬂ ammatory inﬁ ltrate, clinical signs of disease activity, and progression of hair loss.

Lymphocytic Topical/intralesional therapy Topical anti-inﬂ ammatory agents are considered the mainstay of treatment for lymphocytic scarring alopecia and can be used exclusively for limited disease, or for maintenance/remission. High-potency topical steroids are considered safe for long-term use on the scalp. The vehicle chosen for the scalp varies, depending on the needs and hairstyles of the patients with topical solution or foam preferred by many white patients and ointment or oil preferred by many blacks. Nonsteroid topical anti-inﬂ ammatory cream or ointment (tacrolimus, pimecrolimus) can be compounded in a lotion to provide an alternative treatment. Intralesional corticosteroid in McMichael PTR 01/21/08 Chapter 10

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TABLE 3 Treatment Algorithm for Lymphocytic CAs Tier 1 treatments Topical high-potency corticosteroids Topical nonsteroid anti-infl ammatory creams (tacrolimus, pimecrolimus) Intralesional corticosteroids Tier 2 treatments Hydroxychloroquine Low-dose antibiotics for anti-infl ammatory effect Acitretin Tier 3 treatments Cyclosporin Mycophenolate mofetil Prednisone Note: A combination of treatments from each tier can be combined for maximal effi cacy. Tier 3 treatments are typically reserved for patients that have active disease and have failed Tiers 1 and 2. the form of triamcinolone acetonide 10 mg/cc can provide dramatic relief of symptoms and is often used as a “bridge” treatment for a few months until the full effect of other treatments has taken effect. Injections are directed at the active border, where signs of infl ammation or a positive anagen hair pull is present. In active lesions of CCLE, the central area of the plaque should also be injected; if the lesion is treated early, hair regrowth can occur.

Systemic therapy Hydroxychloroquine. Hydroxychloroquine has been used worldwide as an anti-malarial, but is also an established steroid-sparing antilymphocytic medication. Given its safety and low side-effect proﬁ le, hydroxychloroquine is considered to be the ﬁ rst line systemic treatment for lymphocytic mediated alopecia. The usual starting dose is 200 mg twice daily, with the expectation that the medication will start to take effect after 8–10 weeks, and will be continued for 6–12 months (48). A baseline eye exam is recommended as well as complete blood count and liver function tests; checking G6PD levels is controversial.

Antibiotics: Low-dose antibiotics are known to have anti-inﬂ ammatory properties. As an alternative for patients who do not tolerate hydroxychloroquine, doxycycline or minocycline at doses of 50–100 mg daily can be used. Antibiotics are used for 6–12 months and then slowly tapered off as tolerated.

Acitretin: Acitretin is considered a ﬁ rst-line treatment for cutaneous lichen planus based on a blinded placebo-controlled study (54,55). Because of this, the use of acitritin at low doses (10 mg) has been advocated for patients with LPP. Cutaneous lichen planus may respond as quickly as 1–2 months, however, in LPP a longer treatment regimen of 6–12 months may be required.

Mycophenolate mofetil. Mycophenolate mofetil is an immunomodulating medication known to inhibit activated T cells. Given its effectiveness, tolerability, and safety proﬁ le, it has been advocated as the preferred second-line treatment for patients with persistent symptoms and hair loss after a 3–6 month trial of hydroxychloroquine (48). If patients tolerate the starting dose of .5 g twice daily for 1 month, the dose is escalated to 1 g twice daily and continued for 5–6 months. Baseline and monthly lab tests include liver function and complete blood count.

Cyclosprorine: Cyclosporine (CsA) is a calcineurin inhibitor that acts by suppressing T-cell activation and proliferation and also inhibits T-cell secretion of proinﬂ ammatory cytokines such

TABLE 4 Treatment Regimens for Neutrophilic CA Staphylococcal eradication with clindamycin and rifampin Alternative antibiotics: erythromycin, cepahlosporins, trimethoprim sulfamethoxozole, or a ﬂ uoroquinolone with or without concomitant rifampin are variably effective. Supplemental topical antibiotics: mupirocin, clindamycin, isotretinion McMichael PTR 01/21/08 Chapter 10

146 Mirmirani as interferon-gamma responsible for macrophage activation (56). CsA is also known to cause hypertrichosis, which is likely mediated by hair keratinocyte differentiation as well as retardation of catagen. Beneﬁ cial effects of short-term CsA therapy (2–5 months) in patients with LPP (53) have been reported in dosages of 3–5 mg/kg/day. Patient monitoring is done according to CsA concensus guidelines, which include baseline documentation of blood pressure x2, serum creatinine x2, complete blood count, liver function test, and blood urea nitrogen, urinalysis, and follow-up every 2 weeks for 1 month, then monthly.

Prednisone. Oral prednisone can be used to rapidly diminish the inﬂ ammatory signs and symptoms, however given the side-effect proﬁ le, it is not considered for long-term use and is used only as a temporary or bridge treatment. A prednisone taper of one to two months duration can be considered.

Neutrophilic Recognizing the central role of Staphylococcus aureus, treatment regimens aimed at eradication of bacterial carriage have provided a signifi cant improvement of outcome. It must be noted however, that repeat cultures may be needed to determine the offending bacteria, since the predominant bacteria may change over time. Culture material is obtained from intact pustules, or from extracted hair bulbs or biopsy specimens. A regimen of clindamycin 300 mg twice daily and rifampin 300 mg twice daily for 10 weeks has been shown to be effective in inducing a sustained remission, although further courses may be needed (17,57). The addition of topical mupirocin to the nares for staphylococcal eradication or for longer duration of remission may be advisable. Topical clindamycin solution can be prescribed for ongoing treatment/prevention of recurrence. Other antistaphylococcal antibiotics such as erythromycin, cepahlosporins, trimethoprim sulfamethoxozole, or a fl uoroquinolone with or without concomitant rifampin are variably effective. Dramatic improvements in dissecting cellulitis have been reported with use of isotretinoin, especially if the disease is found in tandem with other features of the so-called follicular occlusion triad. Small starting doses with slow escalation to avoid fl ares are recommended, but with a goal of treatment dose of 1 mg/kg/day for at least 5 months although a longer treatment course may be required (48). If dissecting cellulitis is seen unaccompanied, or if there is a strong suppurative component with growth of S. aureus, then a course of antibiotics for bacterial eradication is warranted prior to considering isotretinion.

Mixed Treatment of the mixed CAs depends on the predominant appearance of the disorder at the time of presentation. If the predominant morphology is that of pustules crusting and sinus tracts then topical and/or oral antibiotics should be emphasized in the treatment regimen. Commonly used antibiotics include topical clindamycin and oral quinolones. Antibiotics are often combined with intralesional corticosteroids for treatment of concomitant inﬂ ammatory papules or hypertrophic scars.

Surgical Surgical treatments for CA are less commonly described in the literature and may hold a limited role in the treatment algorithm. Current surgical treatments consist of scalp ﬂ aps, reduction procedures with or without prior tissue expansion, and autologous hair transplantation; these procedures are often combined or done serially (58). Patients with traumatic types of alopecia are generally seen to be the most appropriate candidates for surgery since there is little likelihood for progression of hair loss. Nevertheless, more physicians are advocating the option of surgical hair restoration in patients with treated, or burnt-out inﬂ ammatory CA that has been quiescent. There are no studies to determine the optimal period of quiescence before undertaking surgery; some have advocated 6–9 months, while others have waited 3 years (58,59). Other limitations to surgical hair restoration include the lack of appropriate donor sites and atrophy of the recipient area. Variations on hair transplantation have been advocated to address these hurdles, including “test graft session” and waiting three months, use of larger hair plugs to improve graft blood supply and survival as well as the use of Er:YAG laser to ablate holes for autologous hair transplantion to minimize trauma to the donor site (58,59). The future of McMichael PTR 01/21/08 Chapter 10

Cicatricial Alopecia 147 surgical hair restoration may lie in cloning hair follicles, thus providing an unlimited supply of donor grafts; technological advances will likely make this a reality in the next decade. Surgical treatment may also play a role in providing symptomatic relief for patients with suppurative, boggy, pus-ﬁ lled lesions, or sinus tracts. Incision and drainage of these types of lesions may relieve symptoms and hasten healing. Surgical removal of hypertrophic scars can be an option in folliculitis keloidalis for improved cosmesis.

CONCLUSION CAs represent a challenge to researchers, practitioners, and patients alike; understanding the causes of the disorder, making the diagnosis, and providing treatment is still often elusive. Study of these disorders on a molecular level will no doubt provide much needed insight into the pathophysiology and provide targeted treatment options as well.

REFERENCES 1. Olsen EA, Bergfeld WF, Cotsarelis G, et al. Summary of North American Hair Research Society (NAHRS)-sponsored Workshop on CA, Duke University Medical Center, February 10 and 11, 2001. J Am Acad Dermatol 2003; 48(1):103–110. 2. Mirmirani P, Willey A, Headington JT, Stenn K, McCalmont TH, Price VH. Primary CA: histopathologic fi ndings do not distinguish clinical variants. J Am Acad Dermatol 2005; 52(4): 637–643. 3. Stenn KS, Cotsarelis G, Price VH. Report from the CA colloquium. J Invest Dermatol 2006; 126(3):539–541. 4. Stenn KS, Sundberg JP, Sperling LC. Hair follicle biology, the sebaceous gland, and scarring alopecias. Arch Dermatol 1999; 135(8):973–974. 5. Stenn KS. Insights from the asebia mouse: a molecular sebaceous gland defect leading to CA. J Cutan Pathol 2001; 28(9):445–447. 6. Zheng Y, Eilertsen KJ, Ge L, et al. Scd1 is expressed in sebaceous glands and is disrupted in the asebia mouse. Nat Genet 1999; 23(3):268–270. 7. Sundberg JP, Boggess D, Sundberg BA, et al. Asebia-2J [Scd1(ab2J)]: a new allele and a model for scarring alopecia. Am J Pathol 2000; 156(6):2067–2075. 8. Lu Y, Bu L, Zhou S, et al. Scd1ab-Xyk: a new asebia allele characterized by a CCC trinucleotide insertion in exon 5 of the stearoyl-CoA desaturase 1 gene in mouse. Mol Genet Genomics 2004; 272(2):129–137. 9. Headington JT. CA. Dermatol Clin 1996; 14(4):773–782. 10. Sperling LC, Cowper SE. The histopathology of primary CA. Semin Cutan Med Surg 2006; 25(1):41–50. 11. Mobini N, Tam S, Kamino H. Possible role of the bulge region in the pathogenesis of infl ammatory scarring alopecia: lichen planopilaris as the prototype. J Cutan Pathol 2005; 32(10):675–679. 12. Wiedemeyer K, Schill WB, Loser C. Diseases on Hair Follicles Leading to Hair Loss Part II: Scarring Alopecias. Skinmed 2004; 3(5):266–269. 13. Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001; 81(1):449–494. 14. Cotsarelis G, Millar SE. Towards a molecular understanding of hair loss and its treatment. Trends Mol Med 2001; 7(7):293–301. 15. Christoph T, Muller-Rover S, Audring H, et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol 2000; 142(5):862–873. 16. Karnik P SM, McCormick TS, Mirmirani P. Microarray-based gene expression profi ling in primary CA implicates p53-dependent abnormal cytokine production, concurrent apoptosis and tissue remodeling in disease pathogenesis. Journal of Investigative Dermatology 2005; 124:470, 604. 17. Powell JJ, Dawber RP, Gatter K. Folliculitis decalvans including tufted folliculitis: clinical, histological and therapeutic fi ndings. Br J Dermatol 1999; 140(2):328–333. 18. Karnik PSM, McCormick TS, Cooper K, Mirmirani P. Peroxisomes and Lipid Metabolism in the Pathogenesis of Primary CA. Society of Investigative Dermatology 2006;617. 19. Smith KJ, Dipreta E, Skelton H. Peroxisomes in dermatology. Part II. J Cutan Med Surg 2001; 5(4):315–322. 20. Smith KJ, Dipreta E, Skelton H. Peroxisomes in dermatology. Part I. J Cutan Med Surg 2001; 5(3):231–243. 21. DiPreta EA, Smith KJ, Skelton H. Cholesterol metabolsim defect associated with Conradi- Hunerman-Happle syndrome. Int J Dermatol 2000; 39(11):846–850. 22. Tan E, Martinka M, Ball N, Shapiro J. Primary CAs: clinicopathology of 112 cases. J Am Acad Dermatol 2004; 50:25–32. 23. Whiting D. Cicatricial clopecia: clinico-pathological fi ndings and treatment. Clin Dermatol 2001; 19:211–225. McMichael PTR 01/21/08 Chapter 10

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24. Shapiro J. Cicatricial (scarring) alopecias. In: Shapiro J, ed. Hair Loss: Principles of Diagnosis and Treament of Alopecia. London: Martin Dunitz Ltd, 2002:155–174. 25. George PM, Tunnessen WW, Jr. Childhood discoid lupus erythematosus. Arch Dermatol 1993; 129(5):613–617. 26. Headington J. CA. Dermatol Clin 1996; 14:773–782. 27. Callen JP. Chronic cutaneous lupus erythematosus. Clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol 1982; 118(6):412–416. 28. McCarty DJ, Manzi S, Medsger TA, Jr., Ramsey-Goldman R, LaPorte RE, Kwoh CK. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum 1995; 38(9):1260–1270. 29. Ross E, Tan E, Shapiro J. Update on primary CAs. J Am Acad Dermatol 2005; 53:1–37. 30. Annessi G, Lombardo F, Gobello T, Puddu P. A clinicopathologic study of scarring alopecia due to lichen planus. Am J Dermatopathol 1999; 21:324–331. 31. Mehregan D, Van Hale H, Muller S. Lichen planopilaris: clinical and pathologic study of forty-fi ve patients. J Am Acad Dermatol 1992; 27:935–942. 32. Kossard S. Postmenopausal frontal fi brosing alopecia. Scarring alopecia in a pattern distribution. Arch Dermatol 1994; 130(6):770–774. 33. Kossard S, Lee M, Wilkinson B. Postmenopausalfrontal fi brosing alopecia: a frontal variant of lichen planopilaris. J Am Acad Dermatol 1997; 36:59–66. 34. Horn RT, Jr., Goette DK, Odom RB, Olson EG, Guill MA. Immunofl uorescent fi ndings and clinical overlap in two cases of follicular lichen planus. J Am Acad Dermatol 1982; 7(2):203–207. 35. Dawber R. What is pseudopelade. Clin Exp Dermatol 1992; 17:305–306. 36. Braun-Falco O, Imai S, Schmoeckel C, Steger O, Bergner T. Pseudopelade of Brocq. Dermatologica 1986; 172(1):18–23. 37. LoPresti P, Papa CM, Kligman AM. Hot comb alopecia. Arch Dermatol 1968; 98(3):234–238. 38. Sperling LC, Sau P. The follicular degeneration syndrome in black patients. ‘Hot comb alopecia’ revisited and revised. Arch Dermatol 1992; 128(1):68–74. 39. Mahe A. Scarring alopecia and ethnicity. Arch Dermatol 2001; 137(3):374–375. 40. Sperling LC. Scarring alopecia and the dermatopathologist. J Cutan Pathol 2001; 28(7):333–342. 41. Sperling LC, Skelton HG, 3rd, Smith KJ, Sau P, Friedman K. Follicular degeneration syndrome in men. Arch Dermatol 1994; 130(6):763–769. 42. Porteous ME, Strain L, Logie LJ, Herd RM, Benton EC. Keratosis follicularis spinulosa decalvans: confi rmation of linkage to Xp22.13-p22.2. J Med Genet 1998; 35(4):336–337. 43. Ross EK, Tan E, Shapiro J. Update on primary CAs. J Am Acad Dermatol 2005; 53(1):1–37; quiz 38–40. 44. Sullivan J, Kossard S. Acquired scalp alopecia. Part II: a review. Austral J Dermatol 1999; 40:61–72. 45. Sperling LC, Homoky C, Pratt L, Sau P. Acne keloidalis is a form of primary scarring alopecia. Arch Dermatol 2000; 136(4):479–484. 46. Pye RJ, Peachey RD, Burton JL. Erosive pustular dermatosis of the scalp. Br J Dermatol 1979; 100(5):559–566. 47. Fisher DA. Acne necroticans (varioliformis) and Staphylococcus aureus. J Am Acad Dermatol 1988; 18(5 Pt 1):1136–1138. 48. Price VH. The medical treatment of CA. Semin Cutan Med Surg 2006; 25(1):56–59. 49. Whiting D. The value of horizontal sections of scalp biopsies. J Cutan Aging Cosmetic Dermatol 1990; 1:165–173. 50. Templeton SF, Santa Cruz DJ, Solomon AR. Alopecia: histologic diagnosis by transverse sections. Semin Diagn Pathol 1996; 13(1):2–18. 51. Trachsler S, Trueb RM. Value of direct immunofl uorescence for differential diagnosis of CA. Dermatology 2005; 211(2):98–102. 52. Elston DM, McCollough ML, Warschaw KE, Bergfeld WF. Elastic tissue in scars and alopecia. J Cutan Pathol 2000; 27(3):147–152. 53. Mirmirani P, Willey A, Price VH. Short course of oral cyclosporine in lichen planopilaris. J Am Acad Dermatol 2003; 49(4):667–671. 54. Cribier B, Frances C, Chosidow O. Treatment of lichen planus. An evidence-based medicine analysis of effi cacy. Arch Dermatol 1998; 134(12):1521–1530. 55. Laurberg G, Geiger JM, Hjorth N, et al. Treatment of lichen planus with acitretin. A double-blind, placebo-controlled study in 65 patients. J Am Acad Dermatol 1991; 24(3):434–437. 56. Gafter-Gvili A, Sredni B, Gal R, Gafter U, Kalechman Y. Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes. Am J Physiol Cell Physiol 2003; 284(6):C1593–C1603. 57. Powell J, Dawber RP. Successful treatment regime for folliculitis decalvans despite uncertainty of all aetiological factors. Br J Dermatol 2001; 144(2):428–429. 58. Podda M, Spieth K, Kaufmann R. Er:YAG laser-assisted hair transplantation in CA. Dermatol Surg 2000; 26(11):1010–1014. 59. Callender VD, McMichael AJ, Cohen GF. Medical and surgical therapies for alopecias in black women. Dermatol Ther 2004; 17(2):164–176. McMichael PTR 01/21/08 Chapter 11

11 Structural Hair Abnormalities

Hope V. Dinh Department of Dermatology, St. Vincent’s Hospital, Melbourne, Victoria, Australia Rodney D. Sinclair Department of Dermatology, St. Vincent’s Hospital and Department of Medicine (Dermatology), The University of Melbourne, Melbourne, Victoria, Australia Jack Green Department of Dermatology, St. Vincent’s Hospital, Melbourne, Victoria, Australia

INTRODUCTION An understanding of the normal variations of the hair shaft is essential to be able to tell whether one is dealing with a hair-shaft disorder. The normal hair shaft has a consistent diameter throughout its length, with the most common shape in cross section being oval. Signiﬁ cant variations exist particularly in different racial groups from straight to woolly hair as well as in thickness of the hair shaft. The medulla is a normal feature of the hair shaft and is characterized by a central cavity, but is only present in some individuals. Its appearance can vary from a continuous cavity throughout the hair shaft to being only intermittently present. The medulla can be pigmented or remain clear on light microscopy analysis.

Weathering Hairs grow, on average, 1 cm per month, so the tip of a hair fi ber that is 35 cm long has been exposed to environmental insults for approximately 3 years. These include bleaching/coloring, dyeing, perms, and combing. Such activities result in features of weathering (Fig. 1) that are more pronounced at the distal end of the hair. These include damage to the hair cuticle leading to fraying or loss of cuticular cells from the distal hair shaft. The exposed cortex may then fray, leading to split ends. Other features of weathering include longitudinal splits and trichorrhexis nodes (Fig. 2). If weathering is seen in the proximal hair shaft (particularly within the fi rst 2 cm from the scalp) this is considered pathological and may either be present nonspecifi cally or be related to a characteristic hair-shaft anomaly.

Examination of the Hair Shaft Most disorders (perhaps apart from disorders leading to uncombable hair, which is better diagnosed with electron microscopy) can be diagnosed on light microscopy of hair samples. The hairs are mounted between two glass slides and examined. Polarization of the hairs also helps in making a diagnosis. It is important to take hair samples from multiple sites as pathology can be of intermittent severity and it is helpful in noting which is the proximal end of the hair to determine if weathering changes are pathological. Cutting hairs at the scalp surface is an appropriate way to collect hairs. It is only when considering a disorder such as loose anagen syndrome that hairs need to be obtained by hair pull.

Classifi cation of Hair-Shaft Disorders A major division of hair-shaft disorders is into those associated with hair fragility and those that do not affect the integrity of the hair shaft. Within each of these categories for each specifi c hair abnormality consideration should be given to whether the hair-shaft disorder is occurring as an isolated phenomenon, in association with other cutaneous or noncutaneous abnormalities, or as a syndrome. It is important to note that hair-shaft disorders can have signifi cant variations in severity from barely noticeable even subclinical anomalies to severe effects (particularly in the hair-shaft McMichael PTR 01/21/08 Chapter 11

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(A)

(B)

FIGURE 1 Scanning electron microscopy showing normal hair (A) compared to weathered hair (B). disorders associated with fragility). These variations can even occur between patients with the same genetic mutation in the same family. The condition may be present throughout the entire scalp or maybe patchy or even localized. With many hair-shaft disorders, e.g., monilethrix and pili annulati, an improvement can often occur as the patient gets older. Patients with fragility disorders usually present with short hair that breaks easily. The condition may vary in distribution and severity. For these patients, haircare advice is required to minimize the impact of grooming habits (Table 1).

PROXIMAL TRICHORRHEXIS NODOSA Trichorrhexis nodosa describes a localized thickening of the hair shaft due to fractures and fraying of the cortex to resemble a node (Fig. 2). It is considered pathological if found with the ﬁ rst few centimeters of the proximal hair shaft and is termed proximal trichorrhexis nodosa if no

FIGURE 2 Trichorrhexis nodosa. McMichael PTR 01/21/08 Chapter 11

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TABLE 1 Advice to Patients with Fragile or Excessively Weathered Hair Avoid wetting hair when showering or taking a bath. Do not wash the hair more than once a week. When shampooing, always use a conditioner, and leave it on the scalp for at least fi ve minutes before rinsing. Use a conditioner without shampoo if the hair is clean. After wetting the hair, only pat it lightly dry and do not rub it with a towel. Do not blow-dry the hair or use hot combs. Comb the hair with a wide-toothed comb no more than once a day. Do not brush the hair. Avoid all hairdressing procedures. In particular do not have hair bleached, dyed, straightened, permanent waved (permed), crimped, or pleated. The hair should only be cut with sharp scissors, and not a razor. Protect the hair from excessive exposure to sunlight, by wearing a loose-fi tting hat or scarf. Avoid tight hats and bathing caps. Do not tie the hair back tightly in a ponytail or in braids. Consider a satin pillowcase to reduce friction while sleeping. other specifi c hair anomaly is associated with it. If a fracture occurs transversely through the node, the end of the hair resembles a small paintbrush. This is known as trichoclasis and the clinical correlate is a split end. However an assessment of what is pathological needs to also consider the patient’s racial background. African hair often withstands trauma poorly and nodes are common in long hair. Vigorous attempts to straighten curly hair may cause nodes to occur sooner and closer to the root. When severe, this is described as acquired proximal trichorrhexis nodosa. In contrast, Caucasian and Asian hair is stronger than African hair and even the most vigorous abuse tends to produce distal rather than proximal acquired trichorrhexis nodosa. Trichorrhexis nodosa is the most common defect of the hair shaft leading to hair breakage (1). Treatment of trichorrhexis nodosa (congenital or acquired) involves the avoidance of mechanical or chemical injury to hair. Strict protection from exacerbating injury is required (Table 1).

MONILETHRIX Monilethrix is a rare autosomal dominant hair-shaft disorder characterized by beading of hairs and hair fragility, and is associated with keratosis pilaris (Fig. 3). Severity varies considerably from barely detectable effects to severe fragility. When severe, the entire scalp is affected and patients are totally bald or more often have a sparse covering of short, twisted, broken and lusterless hairs. This can, at times, lead to diagnostic confusion with congenital hypotrichosis. Perifollicular erythema is occasionally seen. Hairs of the eyebrows, eyelashes, face, pubis, and legs may be involved but only rarely in the absence of scalp signs. There may be an association with fragility and splitting of the nails. Follicular keratosis and abnormal hairs are found most frequently on the nape and occiput but may affect the entire scalp. Occasionally there is no keratosis pilaris, suggesting that the follicular hyperkeratosis is not important in the genesis of the beaded hairs. Beaded hairs may sometimes be seen on dermatoscopy.

FIGURE 3 Monilethrix. McMichael PTR 01/21/08 Chapter 11

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Monilethrix can be caused by mutations on chromosome 12q13 in the type II hair cortex keratins genes hHb1, hHb3 and hHb6. The most pathogenic mutations in hHb6 affect either the start of the rod domain at the helix initiation motif or the end of the rod domain at the helix termination motif (2). Both these sites in the rod domain contain a sequence that is very susceptible to point mutation. However, not all patients harbor these type II hair keratin mutations and an autosomal recessive clinical form overlapping with localized autosomal recessive hypotrichosis has been associated with mutations in desmoglein 4 (DSG4) (3), which belongs to the desmosomal cadherin superfamily. In fact, patients with autosomal recessive monilethrix appear to have more severe disease than those with an autosomal dominant aetiology with more extensive alopecia and papular rash. Retinoids (4) have been used with variable success and improvement in the condition may be related to resolution of the keratosis. Minoxidil has also been used but the condition may also spontaneously improve over time. Hair microscopy is diagnostic. Intermittently placed nodes form and the internodes tend to be the site of transverse hair fracture. Typically, the elliptical nodes are 0.7–1.0 mm apart but there may be variation in internodal distance and nodal thickness. Excessive weathering of the hairs with ﬂ uting and disruption of the cuticle is most marked at the internodes. There are case reports of rare associations with mental and physical retardation, abnormal dentition, cataract, syndactyly and koilonychia.

PSEUDOMONILETHRIX Some patients with features suggestive of a hair-shaft disorder have been found on light microscopy to have an irregular beading of hair resembling nodes seen in monilethrix and so are called pseudomonilethrix. The beading is produced as an artifact of mounting hairs on glass slides and is of no signiﬁ cance. On scanning electron microscopy, the widened beads can be seen to be an optical illusion. They merely represent art factual indentations of the shaft viewed in cross section.

PILI TORTI Flattened and twisted hairs may occur in a number of hair dystrophies. In the twisting hair dystrophy known as pilitori, or “corkscrew hair,” there is irregular thickening of the outer root sheath and fl attened hairs rotate completely through 180 degrees at irregular intervals. The twists can resemble beads on light microscopy and may be confused with monilethrix. Occa- sional twists of less than 180 degrees do not qualify as true pili torti. These incomplete twists may occasionally occur in normal hair (seen in African hair and in the pubic/axillary hairs of other races). In pili torti, hair is often normal at birth, but is gradually replaced by abnormal twisted hairs that may be detected as early as the third month. Affected hairs are brittle, fracture easily, and do not grow to any considerable length. Pili multigemini may occur. Patients present with a sparse and short coarse stubble over the entire scalp and may have a few circumscribed bald patches. Longer hairs may be seen in areas subject to less trauma. Minimizing trauma is the key aim. Patients may complain that they have never required a haircut before. Scattered hairs have a spangled appearance due to light refl ecting off the twists. Occasionally the hairs are unruly, resembling uncombable hair syndrome. A late-onset variant of isolated pili torti that fi rst presents after puberty with patchy alopecia has also been described. Menke’s kinky-hair syndrome is an X-linked recessive syndrome. The defective gene, MKN or ATP7A, encodes for a copper-translocating membrane protein ATPase that prevents copper transport and leads to the accumulation of intracellular copper in some tissues. The affected child typically has pale, lax skin and intellectual or neurological impairment secondary to degeneration of cerebral, cerebellar, and connective tissue. Affected males have pili torti, growth retardation and progressive psychomotor retardation. Female carriers may have more limited features due to random X inactivation. Affected females demonstrate patchy areas of short, broken, and twisted hairs, along Blaschko’s lines on their scalp. It is unknown why the abnormality in copper metabolism makes the hair twist and defects in copper metabolism have not been demonstrated in other forms of pili torti. As copper is a cofactor for tyrosinase, affected hairs are lighter in color. McMichael PTR 01/21/08 Chapter 11

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TABLE 2 Syndromes Associated with Pili Torti Syndrome Description Menke’s kinky hair syndrome Pale skin, light-colored hair, and progressive psychomotor retardation due to an X-linked recessive inborn error of intestinal copper transportation Bjornstad’s syndrome Autosomal dominant or recessive condition with sensorineural deafness Basex syndrome Basal-cell carcinoma and follicular atrophoderma Conradi-Hunermann syndrome Chondrodysplasia punctata, limb asymmetry, characteristic facies, spontaneously resolving congenital ichthyosiform erythroderma, hypotrichosis, cicatricial alopecia, follicular atrophoderma, limb asymmetry, abnormal nails, and cataracts Crandall’s syndrome Sex-linked, with sensorineural deafness and hypogonadism Citrullinemia Hereditary arginosuccinic acid synthetase deﬁ ciency Trichothiodystrophy Ichthyosis, photosensitivity, brittle sulfur-deﬁ cient hair, mental and growth retardation, neutropenia, and decreased fertility Salti-Salem syndrome Hypogonadotrophic hypogonadism Some ectodermal dysplasias Characteristic facies, nail, sweating, and dental defects

Other ectodermal abnormalities that may occur in association with pili torti include keratosis pilaris, nail dystrophy, dental defects, corneal opacities, and mental retardation. Speciﬁ c syndromes of which pili torti is a component are listed in Table 2. The twisting hair dystrophies are a diverse group and prognosis is variable. Patients with true pili torti can be reassured that most will improve at puberty. Without treatment Menke’s patients slowly deteriorate and die within the ﬁ rst few years of life. Partially treated males may develop long unruly hair that resembles uncombable hair.

NETHERTON’S SYNDROME (TRICHORRHEXIS INVAGINATA) Netherton’s syndrome is a rare autosomal recessive syndrome characterized by a specifi c ichthyosiform erythroderma; ichthyosis linearis circumfl exa (ILC) combined with a specifi c hair-shaft defect known as trichorrhexis invaginata and, frequently, an atopic state, which may be associated with multiple allergies. The disease is caused by mutations in the SPINK5 gene resulting in a lack of the serine protease inhibitor LEKTI and dysregulation of epidermal proteolysis (5,6). Trichorrhexis invaginata (also called “bamboo hair”) occurs due to intussusception of the distal portion of the hair shaft (which is fully keratinized and hard) into the proximal portion (which is incompletely keratinized) (7). Netherton’s syndrome is usually diagnosed in the fi rst few days after birth with widespread erythema and scaling. The face is often affected. In the following months or years, there are migratory, serpiginous, erythematous, scaling lesions (ILC) gradually appearing on the trunk and extremities, with advancing borders having a characteristic double-edged scale. These characteristic lesions are seen in three-quarters of reported cases but their extent and persistence is variable. Lesions may coalesce and progress to erythroderma. The patient may present primarily with either cutaneous changes or with sparse and fragile hair. The neonatal skin changes in infancy vary in severity. Erythroderma and exfoliation may lead to complications of secondary infection, dehydration, or failure to thrive during the fi rst year. Often the ichthyosiform erythroderma improves in late childhood. Pruritus aggravated by heat is a prominent symptom. The hair defect may be very obvious on hair microscopic examination or so infrequent that examination of hundreds of hairs is needed to make a diagnosis. If hair-shaft examination is negative but clinical suspicion remains, further hair-shaft examinations at a later date are appropriate. Apart from trichorrhexis invaginata, “golf-tee” hairs where the distal portion of the bamboo hair fractures, leaving a cupped proximal ragged end is also a feature of Nether- ton’s syndrome. The scalp hair is dry, lusterless, and fragile. It cannot grow to normal lengths, especially in areas most susceptible to friction. In adults, the scalp hair may improve slowly and the bamboo defects may only appear in the eyebrows or limb hair. An atopic tendency is frequently but not always present. Flexural eczema, asthma, allergic rhinitis, angioneurotic oedema, urticaria, or anaphylactoid reactions may occur in patients and their relatives. Due to this atopic diathesis, cases may be confused with atopic dermatitis. McMichael PTR 01/21/08 Chapter 11

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TABLE 3 Ectodermal Dysplasias Associated with Pili Torti Salamon’s syndrome Arthrogryphosis and ectodermal dysplasia Ectodermal dysplasia with syndactyly Tricho-odonto-onycho-dysplasia with syndactyly Pili torti and enamel hypoplasia Pili torti and onychodysplasia Rapp-Hodgkin’s syndrome Ankyloblepharon-ectodermal dysplasia cleft lip and palate syndrome

Other variable features observed in this disease are failure to thrive, aminoaciduria, mental retardation, recurrent infections, and non-speciﬁ c immune defects. Recently, the potential of a polyclonal antibody against LEKTI has been investigated for immunohistochemical diagnosis of this disease (8). Such a test may prove helpful in the early diagnosis of this disease when infants may not have enough hairs for adequate microscopic analysis.

TRICHOTHIODYSTROPHY Trichothiodystrophy (TTD) is a heterogeneous group of autosomal recessive disorders characterized by brittle sulphur-defi cient hairs. The characteristic fi nding is alternating light and dark (tiger tail) bands. Trichoschisis (a clean transverse fracture through the hair shaft including the cuticle) is also seen in this disorder, but it can also be seen in normal hairs. Hair fragility results from the failure of high sulphur protein migration to the exocuticular part of the cuticle cells and hair cysteine content is usually half of normal. Other associated neuroectodermal abnormalities include short stature, ichthyosis, mental retardation, nail dystrophy, cataracts, photosensitivity, and neurological defi cits. Syndromes associated with TTD are listed in Table 4. Features are varied and include photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature (PIBIDS). Some patients only exhibit hair changes. Sparse, brittle hair of different lengths may be seen and non-scalp hairs can also be affected. The nails are brittle and dystrophic. A diffuse follicular keratosis with or without an ichthyosiform erythroderma sometimes develops. Hair microscopy reveals brittle, weathered hair with characteristic trichoschisis. Flattened and twisted ribbon-like hairs can also be seen. Polarized light microscopy demonstrates the characteristic “tiger-tail” pattern of alternating dark and light diagonal bands. It is unknown what causes the abnormal banding pattern but alternating sulphur content along hair shafts is thought to contribute (9,10). For a diagnosis of true TTD, all hairs must be affected by the banding in contrast to “pseudo-TTD” where not all hairs are affl icted. However, the banding

TABLE 4 Syndromes Associated with Trichothiodystrophy P I B ICH D S N Other abnormalities Trichoschisis + Sabinas syndrome + + + Ocular BID syndrome + + + + Quadriplegia, ﬁ ts IBID or Tay’s syndrome + + + + + Dental, ocular, cardiac, colloidian skin at birth, progeria-like facies, neurological manifestations PIBID syndrome + + + + + + + XP SIBID syndrome + + + + + + Osteosclerosis, cataracts ONMR syndrome + + + + Recurrent infections Marinesco-Sjogren’s + + + Neurological and dental syndrome Abbreviations: B, brittle, sulphur-deﬁ cient hair often associated with brittle nails; D, decreased fertility; I, intellectual impairment; Ic, ichthyosis; N, neutropenia; ONMR, onychotrichodysplasia neutropenia mental retardation; P, photosensitivity; S, short stature; XP, xeroderma pigmentosa. McMichael PTR 01/21/08 Chapter 11

Structural Hair Abnormalities 155 pattern is not exclusive to TTD and has been described in older patients with methionine defi - ciency, pseudopili annulati (11), argininosuccinic aciduria, and acrodermatitis enteropathica (12). As such, the diagnosis of TTD is confi rmed by low cysteine content, which parallels total sulphur content. Prenatal diagnosis of this condition has been achieved (13) and investigators have recently discovered that the disease gene for non-photosensitive TTD maps to chromosome 7 (14). There is no specifi c treatment for TTD and there is no trend towards spontaneous resolution. Associated abnormalities require attention, particularly minimizing sun-related skin damage.

PILI ANNULATI Pili annulati or ringed hair is a rare autosomal dominant hair-shaft disorder characterized by banded hairs (Fig. 4). It is not associated with fragility and so does not cause a cosmetic defi - cit, as the hairs are able to grow to normal length. The hairs are often spangled and this can impart an attractive appearance. The banding is not present at birth but is often apparent after the neonatal hair is shed. Usually the condition becomes clinically apparent by age two years. Thereafter the phenotype is strongest in the fi rst two decades of life and often becomes less obvious in adulthood. However this is not invariably the case. The extent of banding can also be affected by other hair disorders, for example there are reports of pili annulati banding lessening in regrown hairs after episodes of alopecia areata (15). There is a wide spectrum of expressivity between individuals, even in the same family and many individuals may only be detected on light microscopic examination of hairs. Light microscopic examination reveals that the banding is caused by air-fi lled cavities within the cortex that are between 0.1 and 2 mm wide. In examination of unfi xed hairs the pathological bands are lighter than the normal sections. However on examination of fi xed hairs, the pathological bands are darker than the normal sections of cortex. Polarization of hairs can sometimes allow the bands to be seen more clearly (Fig. 5). The genetic locus for pili annulati has been linked to an area on chromosome 12 (16,17). Interestingly, this is not an area that contains hair keratin genes. Pseudo pili annulati, sometimes seen in normal hair, is an apparent banding that resembles pili annulati. It is when twisted hair is examined by light microscopy and appears to have alternating light and dark bands. Clinically the hair is normal and electron microscopy of the hair is also normal.

WOOLLY HAIR AND WOOLLY HAIR NAEVUS Woolly hair is the occurrence of tightly coiled scalp hair in an individual not of African origin. The name derives from a resemblance to sheep’s wool. The condition may be localized or generalized and congenital or acquired.

FIGURE 4 Pili annulati. Source: Courtesy of Rebecca Davies, Melbourne. McMichael PTR 01/21/08 Chapter 11

156 Dinh et al.

FIGURE 5 Polarized light microscopy showing pili annulati.

The congenital diffuse form is usually inherited as an autosomal dominant trait, although recessive inheritance has been described. Congenital localized woolly hair naevus occurs sporadically. Acquired woolly hair or acquired progressive kinking may occur either as a pro- drome to androgenetic alopecia or as a drug side effect. In diffuse woolly hair, excessively curly hair is present at birth or within the two years of life. Though tightly coiled it is not strictly African hair and perhaps better approximates pubic hair. The hairs in woolly patches are not fragile and often are hypopigmented. A variant called diffuse partial woolly hair has been recently described as an autosomal dominant condition (18). This presents in young adulthood with two distinct populations of scalp hair; one straight and the other very curly. The curly hairs are thinner than normal hairs, which may contribute to the clinical appearance of a reduction in hair density. In this condition the hair is brittle and may develop proximal trichorrhexis nodes and fractures. Frequently, the hair never grows to more than 2 or 3 cm. Woolly hair naevus displays the same phenotype as described above but occurs as one or more circumscribed patches of tightly curled scalp hair that are often slightly lighter in color than the rest of the hair. It is also present at birth or appears within the ﬁ rst 2 years of life. Acquired woolly hair has been variously described under the names of acquired progressive kinking, whisker hair or symmetrical circumscribed allotrichia. All three appear to be variants of the same condition. It ﬁ rst presents at adolescence with an irregular band around the edge of the scalp that runs from above the ears to the occipital region. This hair becomes coarse, unruly, kinky, dry, lustreless and like the whiskers of the beard. Patients may notice the area rarely requires cutting. Hair microscopy shows a general waviness and half-twists. There may be some clinical confusion with curly hair. However microscopic examination of normal curly hair of the scalp McMichael PTR 01/21/08 Chapter 11

Structural Hair Abnormalities 157 reveals an oval cross section without twisting or other features. Due to the, at times, unruly appearance of the hairs, there may be confusion with pili torti, uncombable hair syndrome or loose anagen syndrome. In some cases there have been reports of an association with verrucous or linear epidermal naevus, usually on the neck or arm. An epidermal naevus directly beneath the woolly hair naevus has also been reported and has been associated with a variety of ectodermal defects and called the woolly hair naevus syndrome. In over half of reported cases, a pigmented or epidermal naevus is present but not at the same site (19). Other occasional associations include keratosis pilaris atrophicans, pili torti, pili annulati and a variety of ocular, skeletal and developmental defects. Naxos disease is the association of woolly hair, keratoderma and cardiomyopathy and has been linked to impaired desmoplakin function leading to a decline in keratinocyte adhesion (20). As such, an eye examination is recommended for woolly haired patients. There have been some reports of drug-induced woolly hair for example from treatment with oral retinoids.

UNCOMBABLE HAIR SYNDROME This syndrome is characterized by unruly hair due to a distinctive hair-shaft defect, which leads to the production of hair with a triangular or kidney-shaped cross section and longitudinal groove. It is also known as spun-glass hair, cheveux incoiffables, or pili trianguli et canaliculi. Cases occur sporadically and have also been inherited, both an autosomal dominant and autosomal recessive trait. Apart from a variation of hair-shaft cross section from round or oval (which is normal) to kidney-shaped or triangular, the hairs may also display a well-defi ned longitudinal depression (but this fi nding is not specifi c for this disorder). The hairs may twist, but tend to be resistant to weathering. It has been suggested that the cross-sectional shape of the hair renders it more rigid, and combined with the minimal cuticular weathering, encourages the hair to stand on end. The abnormal hairs are not noticed at birth but usually with the fi rst three to four years of life, but it may not be noticed until the child is 12 years. Examination reveals hair that stands up away from the scalp and is diffi cult to style or comb fl at. Sometimes these efforts may lead to hair breaking but there is no inherent fragility of the hairs, which is often silvery-blond, wiry, and frizzy. The distinctive silvery blond hair color is due to refl ection of light from the fl at surface of the differently angulated hair shafts, although the hair may occasionally be red. The hair has been likened to synthetic doll’s hair. The eyebrows and eyelashes are normal. In most cases, the entire scalp is involved but in some patients pathology may be limited to localized areas. Light microscopy may appear normal or show twists and homogenous longitudinal shadowing to one side suggestive of a groove. This is one of the few hair-shaft disorders in which a signifi cant improvement in diagnostic yield is obtained by electron microscopy. With this modality not only are the longitudinal depressions seen but also the triangular or kidney- shaped cross section is clearly evident, which may be missed on light microscopic examination. The defect may be secondary to an abnormal confi guration of the inner root sheath, which keratinizes before the hair shaft and thus determines its shape (21). Spiral indentations, trichorrhexis nodes and trichoptilosis may also be present. Horizontal scalp histology shows the irregular shape of some of the hair follicles and can be used to confi rm the diagnosis in diffi cult cases or if an electron microscope is not available. Occasional triangular hairs may occur in the normal population as well as in a variety of ectodermal dysplasias and Marie Unna hypotrichosis may shows grooved hairs. Microscopy is only diagnostic if the groove is seen in more than half of plucked hairs and the diagnosis often requires clinicopathological correlation. It may be confused with acquired progressive kinking of hair. Biotin has been reported to be helpful (22) but this has not been a universal experience. Patients who grow their hair long report better manageability.

STRAIGHT HAIR NEVUS A straight hair nevus is where a localized area of African scalp hairs are straight. It is the opposite of a woolly hair nevus and is an uncommon ﬁ nding. The straight hairs are round in cross section with the cross-sectional shape thought to determine whether the hair is straight or curly. McMichael PTR 01/21/08 Chapter 11

158 Dinh et al.

A straight hair nevus is usually but not invariably present at birth. In at least one case it developed from a patch of apparently normal hair at the age of 6 months. Both light and scanning electron microscopy aid diagnosis. Apart from the round cross section of the hair, the cuticular scales are often small and their pattern disorganized. It has been suggested that straight hair nevus may represent a localized form of uncombable hair syndrome, however the hairs do not show a longitudinal groove or triangular cross-section on electron microscopy. Recently local or diffuse straight hair nevus has been described in patients with acquired immunodefi ciency syndrome (AIDS) and scalp biopsy in these patients has shown a lympho- histiocytic infi ltrate and fi brosis around the upper and mid-follicle. There have also been reports of diffuse straight hair nevus occurring in two adult patients receiving treatment with interferon-alpha and ribavirin for hepatitis C virus (23). The straight hair remitted once treatment was ceased but in one patient, the straight hair recurred upon treatment re-initiation. Rarely the abnormal hair may be associated with an underlying epidermal nevus, but more commonly the scalp is normal.

LOOSE ANAGEN SYNDROME Loose anagen syndrome (LAS) is a disorder of abnormal anagen hair anchorage, characterized by the easy ability to painlessly pluck a large numbers of scalp anagen hairs. Its incidence is estimated at 2 to 2.25 occurrences per million per year (24). The condition is frequently familial, with an autosomal dominant mode of inheritance with variable expressivity but sporadic cases have also been reported. Anagen hairs can often be easily plucked from one or both apparently normal parents. Gene mutations encoding for the specifi c companion-layer keratin (K6HF) have been observed in some family members with LAS (25). This suggests the genetic basis of LAS may involve more than one gene encoding for keratins expressed in the inner root sheath. There is generalized disturbance of cellular adhesion, with poor anchorage between the inner root sheath and hair cuticle. Premature inner root sheath keratinization has been implicated in this. Traction on the hair then causes separation of the hair from the inner root sheath, which remains attached to the rest of the follicle. Females are more often affected than males but this trend may be due to underreporting in males, who tend to keep their hair short. The condition does not present until the age of 2 to 9 years when parents complain the child has easily pluckable hair that infrequently requires cutting. There may be diffuse hair thinning, which is vellus in character, uneven hair lengths or focal areas of alopecia. Hair is unruly and may have a tacky feel to it. The typical patient is a fair-haired girl with dry and lusterless hair. LAS has been identifi ed in patients with darker hair but the darker hair pigmentation may obscure light miscroscopy diagnosis. The condition is usually restricted to scalp hair but eyebrows and body hair can also be affected. The child is usually otherwise healthy. However, LAS has been associated with hereditary or developmental disorders. These include colobomas (26), Noonan syndrome, hypohidrotic ectodermal dysplasia, EEC syndrome, trichorhinophalangeal syndrome, nail-patella syndrome, and FG syndrome (27). Patients with LAS and alopecia areata have also been reported. Increased hair shedding of about 300 hairs per day is reported. It is important to note that loose anagen hairs can be found in the normal population and are not pathognomonic of LAS. Three phenotypes of LAS have been described (28). Patients with type A LAS have sparse hair that does not grow long and patches of dull, unruly hair. Patients with type B LAS have diffuse or localized patches of unruly hair; and patients with type C LAS have increased hair shedding. Types A and B appear in children and the condition may evolve into type C around the age of 8 years (29). The trichogram shows 98–100% anagen hairs and is related to the fact that plucking normal hairs precipitates the onset of the next anagen. Scalp histology demonstrates a cleft between the inner and outer root sheaths. The inner root sheath appears homogenized due to premature keratinization of the layers of Huxley and Henle. Perifollicular infl ammation is absent, and some hairs are uninvolved. Light microscopy of the hair bulb is usually suffi cient for diagnosis and reveals an anagen root with no outer root sheath and distinctive misshapen hairs. There are ruffl ed cuticle cells McMichael PTR 01/21/08 Chapter 11

Structural Hair Abnormalities 159 near the root and mild hair-shaft distortions with grooving or twisting. Additionally, the external root sheath is absent from the plucked anagen hair, while the internal root sheath and the cuticle are absent distal to the bulb. Examination of the distal hair shafts may show kinking similar to that seen in woolly hair. Trichorrhexis nodes and longitudinal grooves are occasionally seen. Electron microscopy demonstrates abnormally shaped hairs with longitudinal grooves and slight twisting about their axis resembling uncombable hair syndrome, pili torti or woolly hair. Distal to the bulb the cuticular scales are rolled backward creating a rippled appearance. LAS should be distinguished from alopecia areata, in which exclamation mark hairs may be found, and from telogen efﬂ uvium where the plucked hairs are club hairs. Cases of loose anagen syndrome have been described in adults but generally, the condition improves spontaneously during the mid to late teen years with improvement in the length, density and pigmentation of hairs. There is no speciﬁ c treatment for the condition. The ability to easily extract hairs often persists.

POHL-PINKUS LINES Pohl-Pinkus lines are relatively common narrowings in hair-shaft diameter, which are frequently unrecognized and may appear following serious illness, major surgery or antimitotic chemotherapy. The narrowing is due to early anagen hairs being sensitive to events that may produce a temporary disturbance of protein synthesis in the hair matrix and are usually noticed with the naked eye some months after an insult. Longer narrowings or anagen efﬂ uvium may appear with ongoing injury or larger doses of chemotherapy and the proportion of affected hairs is variable. Hair microscopy and electron microscopy show a transition in hair diameter and may demonstrate a lighter hair shaft. Longitudinal twists and grooves may also occur during the course of the illness. Pohl Pinkus lines are the hair equivalent of Beau’s lines in nails. Frequently, these two conditions co-exist.

PERIPILAR CASTS Hair casts (also known as peripilar keratin casts or pseudonits) are relatively common sleeve- like keratinous tubular structures of variable size that encircle the hair shaft and may be seen in children and adults. Disorders of keratinisation and inﬂ ammation of the follicular ostium produces the casts. Peripilar casts are more commonly seen in scaly scalp disorders such as psoriasis and seborrhoeic dermatitis, and may also accompany lichen planopilaris or traction alopecia.The casts are predominantly composed of retained internal root sheath adhering to the emerging hair shaft and bulging from the follicular openings. When the casts bulge out of follicular openings they resemble comedones. The casts can also be of a non-keratin type; derived from chemicals (e.g., haircare products) or microorganisms (bacteria or fungi) attaching to the hair (30). There may be diagnostic confusion with pediculosis, but the ability to slide these whitish- yellow scales easily up and down the hair shaft is the distinguishing factor. Hair casts may also be mistaken for trichorrhexis nodes and trichonodosis. The casts can be removed manually with a ﬁ ne-toothed comb or treatment of the underlying hyperkeratotic scalp disorder may lead to resolution.

PILI MULTIGEMINI Pili multigemini is often a developmental defect where bundles of large, thick terminal hairs emerge from a single dilated pilosebaceous canal. It mainly occur in the beard area in adults and on the scalp of children. They have been recently reported on the back (31). It has been suggested that pili mutigemini in a linear distribution may follow Blaschko’s lines (32). Multiple matrices and hair papillae (2–8) give rise to numerous terminal hairs that all con- verge on a single infundibulum. The abnormal follicle is lined by a common outer root sheath but each hair also has its own individual inner root sheath. Individual hairs are distorted, being ﬂ attened, ovoid or triangular in shape. Neighboring hairs may adhere to one another or bifur- cate and later re-adhere. This is referred to as pili bifurcati. It can also occur as an isolated defect McMichael PTR 01/21/08 Chapter 11

160 Dinh et al. in otherwise normal follicles. Open comedos and trichostasis spinulosa frequently contain multiple trapped vellus hair, and their distinction from multigeminate follicles depends on the size of the hairs that emerge from the follicle. Within a patch of cicatricial alopecia it is common to see pili multigemini. Pili multigemini has been rarely reported in association with cleidocranial dysostosis.

TRICHONODOSIS Trichonodosis is a relatively common acquired condition where a single or double knot occurs in the hair shaft, either spontaneously or in response to rubbing or scratching. It is commonly found in African patients with short hair and in people of other ethnicities with short, curly hair. Mechanical knotting of the short and curly hairs is caused by rubbing or scratching the skin. Trichonodosis is usually an incidental ﬁ nding of little signiﬁ cance. Some patients may present thinking they have nits, especially when the knots occur in pubic or auxiliary hair. The knots can be seen on close inspection with the naked eye, and are easily demonstrated with hand-held epiluminescence microscopy or with light microscopy. Only the part of the hair shaft containing the knot is abnormal; the rest of the hair shaft is unaffected. Brushing or combing often tightens the knots, pulls the hair out at the root or fractures the hair at the site of the knot. The condition is often temporary but may be recurrent.

BUBBLE HAIR Bubble hair is an acquired, localized, reversible, hair-shaft defect characterized by air bubbles within the hairs related to repeated cosmetic trauma from heated tongs or curling devices. It is thought that water seeps into the hair cortex and boils when heated with the curling tongs. Curling tongs may generate temperatures in excess of 180ºC. The steam thus generated produces focal or diffuse bubbles and the hair is weakened at these sites. Patients present with a focal area of brittle hair on the scalp with hair breakage or loss. There is also a change in the texture of the involved hairs that become straight and stiff. Bubble hair may clinically resemble acquired trichorrhexix nodosa, however the two conditions are easily distinguished by light microscopy, where the air bubbles within the cortex are easily identiﬁ ed. Other coincidental features of weathering due to excessive treatment of the hair may be evident. The condition is self-limiting and patients should avoid further precipitating factors. Avoiding the use of curling/straightening tongs, especially on wet hair, may be sufﬁ cient. Hair dryers should not be used on the hottest setting in predisposed individuals.

TRICHOSTASIS SPINULOSA Trichostasis spinulosa is a common condition and is a variant of a comedo that contains numerous vellus hairs entrapped in a keratinous cheesy plug. It is a normal age-related process. It is due to follicular hyperkeratosis retarding the expulsion of telogen hairs in large sebaceous follicles. Propionibacterium acne and Pityrosporum spp. have been implicated but this has not been conﬁ rmed (33). It is classically seen as large non-pruritic pilosebaceous follicles on the nose and face, which resemble comedomes. A second variant has been described in young adults with numerous itchy, keratotic pinhead-sized follicular papules located predominantly on the trunk and upper arm. Often hairs are visible in the follicular papule. It occurs from adolescence onwards with great variation in lesion number. Between 5 to 50 hairs may be present in a single follicle, which looks like a horny plug. These hairs are thought to have accumulated through retention by the thick keratinous material. There may be a mild perifolliculitis and numerous follicles may be involved. Histologi- cally, hair follicles with numerous pigmented vellus hairs and keratin-ﬁ lled sebaceous glands are seen. Distinction from a comedo may be academic. This condition should be differentiated from pili multigemini where multiple hairs emerge from the same pilosebaceous gland with McMichael PTR 01/21/08 Chapter 11

Structural Hair Abnormalities 161 a common outer root sheath. It may resemble keratosis pilaris, especially if located on the trunk. The lesions can often be extruded but, new lesions often appear with time. Topical retinoids have been shown to be helpful as both a keratolytic and to reduce sebaceous gland size. Depilatory wax can be used however patients may consider the waxing a greater inconvenience than the disorder. Recently, treatment with the pulsed-diode laser has been trialled with promising results (34).

BIRD’S-NEST HAIR AND DREADLOCKS This is a condition where there is usually irreversible matting or tangling of the scalp hair that occurs when shampooing. The tangling is due to an interaction between the heightened electrostatic forces produced from wet hair and the rotary action of washing on weathered, high friction hairs. Matting is an extreme form of tangled hair and more commonly occurs in long, wavy hair. Predisposing factors include long hair that has not been cut for a number of years, badly weathered hair, and poor scalp hygiene The process is akin to felting, as utilized in the textile industry where there is compacting of fi bers with friction and compression in a liquid medium. The individual fi bers become fused together and can only be teased apart with considerable force. This scenario is recognized in the home when wool clothing shrinks after incautious washing. Bird’s-nest hair is not uncommon, but most cases are localized and dealt with by hairdressers. Dreadlocks can represent religious affi liations or, more commonly, are a desired style sym- bolizing African heritage. They can also be the preferred natural style for coarse, curly hair. On microscopy, deposits of shampoo can be seen with the electron microscope bound to the hairs and matting individual fi bers together. The hairs are not knotted, but actually fused together and thrown into intertwining loops. A random weave or tangling of hair is seen. Other evidence of weathering is usually seen. The term plica neuropathica has been used to describe an extremely rare condition in which the hair becomes compacted into numerous, irregularly twisted, irreversibly entangled plaits. Focal matting of the hair is probably a common occurrence and is easily remedied by cutting or untangling the hair.

REFERENCES 1. Whiting DA. Hair shaft defects. In: Olsen ED, ed. Disorders of Hair Growth: Diagnosis and Treatment. New York: McGraw-Hill, 2003. 2. Djabali K, Panteleyev AA, Lalin T et al. Recurrent missense mutations in the hair keratin gene hHb6 in monilethrix. Clin Exp Dermatol 2003; 28:206–210. 3. Zlotogorski A, Marek D, Horev L et al. An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. J Invest Dermatol 2006; 126:1292–1296. 4. de Berker D, Dawber RP. Monilethrix treated with oral retinoids. Clin Exp Dermatol 1991; 16:226–228. 5. Komatsu N, Takata M, Otsuki N et al. Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J Invest Dermatol 2002; 118:436–443. 6. Chavanas S, Bodemer C, Rochat A et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 2000; 25:141–142. 7. Ito M, Ito K, Hashimoto K. Pathogenesis in trichorrhexis invaginata (bamboo hair). J Invest Dermatol 1984; 83:1–6. 8. Ong C, O’Toole EA, Ghali L et al. LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome. Br J Dermatol 2004; 151:1253–1257. 9. Calvieri S, Zampetti M, Corbo A et al. Preliminary results of the use of a microanalysis system of the hair in patients with trichothiodystrophy. G Ital Dermatol Venereol. 1988; 123:583–585. 10. Rossi A, Daniele L, Bonaccorsi P et al. Microanalysis: applications in hair study. In: Van Neste D, Randall VA, eds. Hair Research for the Next Millenium. Amsterdam: Elsevier, 1996:87–89. 11. Lee SS, Lee YS, Giam YC. Pseudopili annulati in a dark-haired individual: a light and electron microscopic study. Pediatr Dermatol 2001; 18:27–30. 12. Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update on the sulfur-deﬁ cient brittle hair syndromes. J Am Acad Dermatol 2001; 44:891–920. McMichael PTR 01/21/08 Chapter 11

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13. Quintero RA, Morales WJ, Gilbert-Barness E et al. In utero diagnosis of trichothiodystrophy by endoscopically-guided fetal eyebrow biopsy. Fetal Diagn Ther 2000; 15:152–155. 14. Nakabayashi K, Amann D, Ren Y et al. Identifi cation of C7orf11 (TTDN1) gene mutations and genetic heterogeneity in nonphotosensitive trichothiodystrophy. Am J Hum Genet 2005; 76:510–516. 15. Green J, Sinclair RD, de Berker D et al. Disappearance of pili annulati following an episode of alopecia areata. Clin Exp Dermatol 2002; 27:458–460. 16. Green J, Fitzpatrick E, de Berker D et al. A gene for pili annulati maps to the telomeric region of chromosome 12q. J Invest Dermatol 2004; 123:1070–1072. 17. Giehl KA, Eckstein GN, Benet-Pages A et al. A gene locus responsible for the familial hair shaft abnormality pili annulati maps to chromosome 12q24.32-24.33. J Invest Dermatol 2004; 123:1073–1077. 18. Guidetti MS, Fanti PA, Piraccini BM et al. Diffuse partial woolly hair. Acta Derm Venereol 1995; 75:141–142. 19. Stieler W, Otte HG, Stadler R. Multiple woolly hair nevi with linear epidermal nevus and persistent pupillary membrane. Hautarzt 1992; 43:441–445. 20. Norgett EE, Hatsell SJ, Carvajal-Huerta L et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate fi lament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000; 9:2761–2766. 21. Mallon E, Dawber RP, De Berker D et al. Cheveux incoiffables—diagnostic, clinical and hair microscopic fi ndings, and pathogenic studies. Br J Dermatol 1994; 131:608–614. 22. Shelley WB, Shelley ED. Uncombable hair syndrome: observations on response to biotin and occurrence in siblings with ectodermal dysplasia. J Am Acad Dermatol 1985; 13:97–102. 23. Bessis D, Luong MS, Blanc P et al. Straight hair associated with interferon-alfa plus ribavirin in hepatitis C infection. Br J Dermatol 2002; 147:392–393. 24. Sinclair R, Cargnello J, Chow CW. Loose anagen syndrome. Exp Dermatol 1999; 8:297–298. 25. Chapalain V, Winter H, Langbein L et al. Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study. Arch Dermatol 2002; 138:501–506. 26. Hansen LK, Brandrup F, Clemmensen O. Loose anagen hair syndrome associated with colobomas and dysmorphic features. Clin Dysmorphol 2004; 13:31–32. 27. Tosti A, Piraccini BM. Loose anagen hair syndrome and loose anagen hair. Arch Dermatol 2002; 138:521–522. 28. Olsen EA, Bettencourt MS, Cote NL. The presence of loose anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc 1999; 4:258–260. 29. Shieh X, Yi X. Hair casts: a clinical and morphologic control study. Arch Dermatol 1992; 128:1553– 1554. 30. Lee JS, Kim YC, Kang HY. The nevoid pili multigemini over the back. Eur J Dermatol 2005; 15:99–101. 31. Schoenlaub P, Hacquin P, Roguedas A et al. Pili multigemini: a pilar dysplasia with linear disposition. Ann Dermatol Venereol 2000; 127:205–207. 32. Chung TA, Lee JB, Jang HS et al. A clinical, microbiological, and histopathologic study of trichostasis spinulosa. J Dermatol 1998; 25:697–702. 33. Manuskiatti W, Tantikun N. Treatment of trichostasis spinulosa in skin phototypes III, IV, and V with an 800-nm pulsed diode laser. Dermatol Surg 2003; 29:85–88. McMichael PTR 01/21/08 Chapter 12

12 Scalp Prostheses: Wigs, Hairpieces, Extensions, and Scalp-Covering Cosmetics

Ingrid E. Roseborough Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, U.S.A.

INTRODUCTION Wigs and hairpieces have been worn for centuries, and have evolved with prevailing social mores and fashion trends. Ancient Egyptians wore wigs to protect their shaved heads from the sun, while seventeenth-century British aristocrats wore them to defi ne social rank. In modern times, wigs, hairpieces, extensions, and scalp-covering cosmetics are used to either change the appearance of a hairstyle or to camoufl age hair loss. In the setting of hair loss due to a medical condition, custom-made wigs are also known as scalp prostheses. Theses devices enable patients to maintain the normal appearance of hair while undergoing treatment for an underlying condition. Alternatively, many patients choose to wear a wig or hairpiece in lieu of medical or surgical treatment. The choice depends on factors including the type, duration, and extent of hair loss and individual economic and lifestyle factors. Health professionals play an important role in introducing hair prostheses to patients. A discussion of wigs and hairpieces at the appropriate time can be very useful in helping patients cope with various forms of alopecia. The tone and timing of this discussion must be considered carefully. Ideally, the option of a hair prosthesis should be presented in the course of an in-depth patient interview. After a thorough history and physical examination, the diagnosis should be discussed in detail. Patients will have questions about the extent, potential chronic- ity, and possibility of remission of their condition, so the professional should be prepared to answer these questions with as much evidence-based information as possible. When discussing treatment, hair prostheses can be introduced while outlining medical and surgical options for therapy. The option of a hair prosthesis should not be presented as a “last resort.” It should be considered a reasonable, practical, and effective means of coping with hair loss. The goal of this chapter is to acquaint medical professionals with the most common devices used for hair replacement. The practitioner will be able to identify the types of wigs, hairpieces, and extensions that are worn by patients and recognize the potential benefi ts and problems associated with their use. Although a detailed study of specifi c hairstyles is beyond the scope of the chapter, basic wig and hairpiece construction will be discussed. Equipped with this information, the medical practitioner will be able to partner with the patient to make an informed choice about hair replacement.

HAIR TYPES The type of hair used in wigs and hair extensions falls into two broad categories: human and synthetic. The choice of hair type generally depends on the speciﬁ c hair style and intended duration of wear.

Human Hair Human hair is the most expensive, but also the most durable and versatile material for good construction. With proper care, human hair can withstand heat styling, color application, and chemical treatment for permanent waving and straightening. Human hair strands come from sources all over the world. China, India, Indonesia, and European countries are major manufacturers. Hair harvested from each region has its own characteristics. In developing countries, the sale of hair is a signiﬁ cant source of income. Factories McMichael PTR 01/21/08 Chapter 12

164 Roseborough hold contracts with communities and villages for hair grown under controlled conditions. The hair must be covered to protect it from environmental stress and the hair donors are encouraged to eat nutritious diets to produce healthy locks. When the hair is ready for collecting, it is divided into two groups: remi and non-remi hair. Remi is the fi nest and costliest grade of hair available. It is shaved directly from the scalp and bundled so that the roots of the hair are at one end and the tips are at the other. This method of collection ensures that the cuticles of the hair shafts point in the same direction and will subsequently resist tangling. In non-remi hair, the roots and tips of the hair are bundled irrespective of direction. Non-remi hair may be cut or fallen hair collected from the fl oor. Once the hair is collected and bundled, it is sanitized, decuticlized, and blended for color. The fi nest virgin remi hair does not undergo decuticlization and care is taken to retain the fi ber’s natural characteristics. Further processing of the hair may include bleaching to lighten and change color, chemical straightening to achieve a more silky texture, or permanent waving to introduce a soft wave or tight curl pattern. Hair of Chinese origin is popular for its strength, abundance, and low cost. The shafts are very straight and coarse and can withstand multiple chemical treatments. Indian hair is fi ner and slightly more expensive than Chinese hair, but comes in variety of textures that can mimic the curl pattern of many ethnicities. Hair of European origin is considered the fi nest available for wigs. The fi ber is fi ne and soft and comes in a variety of natural colors, but it is of limited supply. In general, African hair is not used to make hair goods. Due to its moisture content and tensile properties, African hair cannot withstand the heavy chemical processing required to make stands suitable for wigs and hairpieces. In order to create textures suitable for ethnic hair, Asian and Indian hair fi bers are permanent waved to produce tighter curl patterns. Terms used for ethnic hair textures include kinky, yaki, and silky.

Synthetic Hair Man-made hair fi bers offer the advantage of limitless supply, low cost, and great texture and color diversity. Hair goods made with synthetics are signifi cantly less expensive than those made with human hair. After gentle washing, synthetic hair strands generally retain their shape and color and require less maintenance than human hair. The science of synthetic hair has made signifi cant advances in recent years. The newest man-made fi bers are lightweight, durable, color fade-resistant, and have excellent curl retention properties. However, most synthetic strands are generally not as durable as human hair. They loose luster and become frayed and tangled after repeated use. Synthetic hair is made from a variety of materials including nylon, polyester, and plastic. The fi bers come in an endless array of colors and textures that realistically mimic human strands. Once the synthetic strand is manufactured, it will not accept color or chemical treatments. Synthetic hair cannot be styled with high heat because the fi bers will quickly denature and melt. Most wigs and hairpieces that are gray in color are synthetic because it is diffi cult to achieve suffi cient color lifting in human hair to produce subtle gray tones. In order to achieve a desired look, different materials may be weaved into the same hairpiece. Human-synthetic blended pieces offer the versatility and durability of human hair combined with the low cost and abundance of synthetics. In some hair goods, wool and other animal hair fi bers are blended to create specifi c textures.

WIGS Wigs are worn for many purposes. For some, a wig is an accessory that can be changed and rotated to match current fashion trends, regardless of the presence or absence of natural scalp hair underneath. For others, especially people with hair loss due to a medical condition, a high quality wig is an essential component of everyday grooming. No matter what the reason for wearing a wig, a general knowledge of wig construction will assist the buyer in making a choice that is appropriate for his or her needs. Full human-hair wigs are the most like natural scalp hair and with proper care can last for years. However, realism and durability come at signiﬁ cant expense. The least costly human McMichael PTR 01/21/08 Chapter 12

Scalp Prostheses: Wigs, Hairpieces, Extensions, and Scalp-Covering Cosmetics 165 hair wigs generally cost about $300, while custom-designed and color-matched pieces can range from $1000 to $5000. The cost of care and maintenance must also be included in the price of the human hair wig. Once wet, human hair loses its shape and needs to be restyled in order to maintain its original appearance. Given these factors, human-hair wigs may be the best option for people who have signifi cant and sustained hair loss, wear the same wig on a daily basis, and want to achieve the most natural appearance possible. Synthetic wigs are a good option for people who only wear wigs occasionally or for those who like to change hairstyles often. They are also an excellent choice for patients with waxing and waning or patchy hair loss from alopecia areata or for those who expect full hair regrowth after chemotherapy. Synthetics are light and provide a very realistic appearance without incur- ring the signifi cant expense of human-hair wig. Colors can range from basic black to blond to more unusual hues like pink and green. The downside of synthetic wigs is that they do not last as long as human hair. Although synthetics usually revert back to their manufactured state after wetting, with repeated wash and wear over time, they become irreversibly tangled and matted. Most synthetic wigs that cost under $100 will last a few months to a year. Newer, more expensive, premium synthetics may last a longer period of time. In addition to the fi ber material choice, the amount of scalp coverage must be considered when buying a wig. For people with sustained or permanent scalp-hair loss, as seen in patients with alopecia areata totalis or universalis, a full custom-designed scalp prosthesis may be required. Full wigs may be heavy, hot and irritating, so the purchaser must be informed about cap materials, base construction, and methods of attachment. For people with thinning hair due to androgenetic alopecia, stable patches of hair loss due to scarring alopecia, or for those who just need “a little extra” hair to fi ll out a desired style, a hairpiece, partial wig, or wiglet may be appropriate. Professional wig designers, stylists, and retailers are the best resource for choosing an appropriate wig. In addition to giving expert advice on wig selection, style, and fi tting, they can teach customers how to properly maintain the piece to achieve its full potential. Wig retailers range from ultra premium hair salons to inexpensive and convenient wig shops. Wig buyers should be encouraged to peruse a variety of shops and services before choosing the wig that suits their needs. A list of wig and hairpiece resources is listed at the end of the chapter.

Wig Construction Wigs can be made from individual or small groups of hair strands that are hand-tied into a base. Hand-tied wigs are labor-intensive and pricey, but offer the most natural appearance because the hair can be parted or blown in different directions. Wefts are multiple hairs that are machine-sewed together at one end to make a long curtain of hair. Machine-sewed wigs and hairpieces are less expensive than hand-tied, but have a less natural appearance. Caps are the base to which strands or wefts of hair are attached to make a wig. Caps come in standard sizes for pre-made wigs and professionally designed sizes for custom wigs (Figs. 1 and 2). A standard cap, the most widely available model, is made of an elastic mesh frame-

FIGURE 1 Semi-custom soft mesh cap. McMichael PTR 01/21/08 Chapter 12

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FIGURE 2 Interior of custom soft mesh cap. work. The elastic is covered with stretch lace netting to give the wig its shape. Wefts of hair machine-sewn onto the elastic can only face one, pre-styled direction. They cannot be parted in another way without revealing the lace base. Capless wigs are similar to standard caps except that the construction is more open. The closed lace covering is placed only over strategic parts of the base to give it support. This results in a lighter, cooler, more comfortable fi t. Top-of-the line wigs bases are made of a thin, cool monofi lament material that is designed to mold to the shape of the head. Hair is then strategically or completely hand-tied to the base to provide maximum style versatility (Fig. 3). In some models, a skin-colored latex coating is applied over the monofi liment to give the appearance of natural scalp showing through the part (Fig. 4). Monofi lament wigs are an ideal choice for people with broad areas of bare scalp who may be irritated by standard caps. A properly sized wig should fi t securely on the head and be able withstand normal head movement and reasonable amounts of wind. The choice of wig attachment depends on comfort, style, and the amount of hair underneath the wig. Removable wigs may be attached with clips and combs to underlying natural scalp hair. Other attachment options include adhesives, double-sided tape, silicone strips, snaps and Velcro (Fig. 5). Wigs may be designed for daily at-home removal or semi-permanent adhesion with special bonding agents. Adhe- sive agents should be used with extreme care because with improper use they may cause damage to underlying skin and scalp hair. Professional consultation is recommended for attachments with scalp-bonding agents. Ideally, professional stylists should safely attach and remove glued-on wigs and hairpieces, identify problems related to wigs including hair breakage and contact allergies, and if necessary, advise clients to seek dermatological evaluation for scalp problems.

FIGURE 3 Soft-base vacuum custom wig. McMichael PTR 01/21/08 Chapter 12

Scalp Prostheses: Wigs, Hairpieces, Extensions, and Scalp-Covering Cosmetics 167

FIGURE 4 Human hair custom soft-mesh wig while wet.

For patients with total scalp-hair loss, a vacuum-attached wig may be a consideration. This type of wig can only be attached to the scalp if it is completely bare, as in alopecia totalis or universalis. First a mold is made of the patient’s head (Fig. 6). Then a silicone base is fashioned from the head mold (Fig. 7). Fine-quality human hair that is specifi cally selected to match the patient’s natural hair color is carefully inserted into the silicone base (Figs. 8–10). When placed on the head, the silicone base fi ts snugly without the need for additional attachments. Vacuum wig manufacturers state that patients can lead very active lifestyles with silicone wigs, including swimming and riding roller coasters. The prostheses take many months to make and are very costly. Patients that suffer from medical hair-loss conditions may qualify for fi nancial assistance for the purchase of hair prostheses. The amount of coverage is broad and ranges from tax exemption to coverage for the entire cost of the wig. Physicians may be asked by insurance companies for a detailed description of the specifi c hair-loss diagnosis. For alopecia areata, submission of the American Academy of Dermatology’s White Paper on the condition may be helpful to obtain coverage. When issuing a prescription for a wig, the physician should write for “a full cranial prosthesis.”

HAIRPIECES Hairpieces differ from wigs in that they are not designed to cover the entire scalp. Hairpieces have a broad deﬁ nition, and the term may be subject to individual interpretation. Wiglets, partial wigs, half wigs, top pieces, falls, and ponytails may all fall under the rubric of a hairpiece. Like wigs, they may be made out of human or synthetic hair, although man-made pieces are by far the most common. They can be bought from upscale wig salons, beauty supply shops, shopping mall hair accessory carts and Web sites. Many hairpieces have similar construction to

FIGURE 5 Double-sided tape for wig attachment. McMichael PTR 01/21/08 Chapter 12

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FIGURE 6 Cast of patient scalp.

FIGURE 7 Mold of scalp and trial vacuum base.

FIGURE 8 Inside of hard-based vacuum.

FIGURE 9 Hair side of hard-based vacuum custom wig. McMichael PTR 01/21/08 Chapter 12

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FIGURE 10 Custom hard-based human hair wig while wet. wigs, with individual strands or wefts of hair attached to a variably sized woven bases (Fig. 11). The base is then clipped, pinned, taped or glued to the scalp and the natural scalp hair is styled under or around the piece. Hair integration caps have broadly spaced wefts so that scalp tresses can be teased through the openings and blended with the artifi cial locks. The result gives the appearance of a thicker, fuller head of hair. Hairpieces may also be attached to banana clips, decorative barrettes, headbands, or even baseball and swimming caps. These pieces give the appearance of long full hair without permanent attachment or great time and expense. A hairpiece is a good choice for people with androgenetic alopecia. Full wigs can be hot and irritating and may not be necessary to address a focal area of thinning hair. Depending on the specifi c pattern, patients with androgenetic alopecia may be diffusely thin at the bitemporal, frontal, or vertex scalp. However, they may have adequate to excellent hair density over the parietal and occipital scalp. A small hairpiece that covers a specifi c area of thinning can be color-matched and integrated with the natural growth hair for a seamless result. Similarly, a hairpiece may be a savvy solution for patients with irreversible hair loss due to scarring alopecia. If there is little to no active hair loss around a stable scarred patch of scalp, a hairpiece can be designed to fi t just over the scarred area. Professional designers may be helpful in creating a hairpiece for this purpose.

OPTIONS FOR MEN Modern hairpieces and toupees offer a natural-appearing option for men who want to camoufl age hair loss. Toupees are constructed in the same way as hairpieces designed for women. Wefts or strands or hair are hand-tied or machine sewn onto a fi ne mesh or lace base. Many pieces feature polyurothane borders to achieve a more snug fi t around the scalp. Toupees are typically color-matched and cut so that the frontal and vertex scalp are covered, and the natural occipital hair is left free. Full wigs are also available for men with total scalp-hair loss.

FIGURE 11 Small human hairpiece cut to ﬁ t areas of alopecia. McMichael PTR 01/21/08 Chapter 12

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Toupees can be attached to the scalp with clips, combs, bonding agents, or double-sided tape. Many adhesives can last for days to weeks without being removed. The wearer can shampoo and style the hairpiece as he would his own hair. However, bonding agents must be used with caution, as they may cause irritation, pruritus, or a contact allergy. Most adhesive manufacturers suggest a 24–48-hour “patch test” of the product behind the ear to evaluate for potential reactions. Double-sided tape comes in various strengths and widths, depending on the intended duration of wear and style of the toupee. For fi rst-time toupee wearers, professional consultation is recommended for cut, style, and method of attachment. Hair replacement companies also offer hair systems for men, often referred to as “nonsur- gical hair transplants.” Although techniques may vary, hair systems involve precision placement of synthetic or human strands directly onto growing scalp hairs in a thinning area. The hairs are attached with adhesive agents and cut to match the surrounding natural strand pattern. The bonded strands may also be attached to a fi ne mesh framework that is custom-cut to fi t the area of bare scalp. Hair systems may cost thousands of dollars for initial placement, care products, and routine maintenance and styling.

OPTIONS FOR CHILDREN As the old adage dictates, “children are not small adults.” Wigs and hairpieces designed for adult heads will not fi t a small child. In addition, hairstyles designed for adults may not be age-appropriate for kids. To address this issue, many hair-good manufacturers now make kid- friendly wigs in designs that are lighter and smaller with softer base construction. For children with hair loss due to a medical condition such as alopecia areata, cancer, loose anagen syndrome, and burn injury, fi nancial assistance for the purchase of hair prostheses may be available. Nonprofi t organizations such as Locks of Love provide hairpieces to fi nancially disadvantaged children under the age of 18.

HAIR EXTENSIONS Hair extensions, also called weaves, add length and volume to an existing style or create a completely new hair look. The difference between wigs and hair extensions is that, while wefts and strands of hair on a wig are attached to a base, hair extensions are attached to natural scalp locks. This means that in order to wear a hair weave, there must be a sufﬁ cient and stable amount of natural growth hair to attach the extensions to. Consequently, due to the unpredictable course of the disease, hair weaves may not be the best option for patients with alopecia areata. As in wigs, strands used in manufacturing hair extensions can be either human or synthetic. Weave hair is sold as individual, separate strands, or elongated wefts of hair, commonly referred to as tracks. Human-hair extensions have the advantage of durability and ﬂ exibility. Depending on the method of attachment, human-hair extensions can be washed and styled along with the natural scalp hair. Synthetic-hair weaves are less expensive and come in a variety of colors, but cannot withstand heat styling and frequent shampoos. Synthetic weaves may also not look as natural as human hair. The cost of hair extensions is highly variable. It is determined by the method of attachment and the time required to achieve the desired look. Clip-on, temporary hair extensions can cost as little $10, while elaborate, strand-to-strand professional hair weaves can cost thousands. With the increased prevalence of hair weaves in popular media, manufacturers are constantly developing new and less expensive ways to add length to hair.

Methods of Attachment The simplest hair extensions have plastic or metal clips that attach close to the scalp-hair root. These extensions are inexpensive, easy to use, and have little potential for long-term damage to hair. In a traditional “weave,” the natural scalp hair is parted into neat rows and tightly braided close to the scalp in concentric circles or corn rows. Typically, some scalp hair is left in unbraided rows to blend in with the hair extensions and camouﬂ age the tracks. The tracks are attached to the braided cornrows with a needle and thread. The thread color matches the hair and the tracks are sewn on tightly and secured. This method of attachment can last for several McMichael PTR 01/21/08 Chapter 12

Scalp Prostheses: Wigs, Hairpieces, Extensions, and Scalp-Covering Cosmetics 171 months, but when the natural scalp hair grows past a few millimeters, the weaved-in hair tracks need to be tightened or replaced. Alternatively, tracks of hair can be glued in close approxima- tion to the corn-rowed scalp hair (Fig. 12). Special weave adhesives are sold for this purpose and often require a solvent for removal. Glued-on tracks are generally not as stable as those that are sewn on, and do not last as long. A newer method of attaching hair extensions involves strand-to-strand hair bonding. Most techniques involve attaching a few strands of extension hair to an equal amount of scalp hair with a synthetic polymer, wax, glue, or plastic tube. A heated instrument, similar to a glue gun, melts and fuses the extension strands onto the scalp hair. A few keratin-based polymers on the market do not require melting and reportedly cause less damage to the natural hair. Bonded hair strands can last for several months and can be washed and styled regularly. The extensions are removed with either heated instruments or solvents. This method of attachment requires professional consultation and is often very expensive.

Braids Although not traditionally viewed as a hair weave, many braided hairstyles involve adding human or synthetic hair strands to natural scalp locks. Braided hair extensions ensure that all braids are of a uniform width and length. A variety of braided styles are available and different materials are used to achieve specifi c looks. Thick “box-style” braids are typically created with synthetic hair and are braided to the tip of the extension hair shaft. To lock the braid in place and prevent unraveling, the ends of the braid are melted together with a fl ame or boiling water. “Micro” braids that are small, fi ne, and loose on the ends are usually created with human hair or human–synthetic hair blends. (See Figure 13 for synthetic braid extensions.) In some braided styles, materials such as cotton or wool yarn are woven in to achieve a desired texture.

Potential Benefi ts and Problems Associated with Hair Extensions Hair extensions are worn by people of every ethnicity and socio-economic level. In recent years, celebrities have popularized hair extensions to keep up with current fashion trends. In the past, a full wig was required to drastically change a hairstyle, but with extensions, a long-lasting, natural-appearing look can be created within hours. If done correctly, weaved or braided-in hair can be washed, cut, dyed, and heated-styled without signifi cant damage to the underlying scalp hair. Many women of African decent choose to wear hair extensions to temporarily spare their natural hair from the damaging effects of chemical styling and heated appliances. Exten- sions can provide a healthy break from processing without sacrifi cing style. However, the maintenance of hair weaves can be challenging. Patients with latex allergies may be allergic to the glue and boding agents required to attach extensions (1,2). Patch testing of these agents is recommended before applying them to the scalp, and they should be removed at the fi rst sign of irritation. Traction alopecia has been associated with extensions attached to relaxed hair (3). Direct strand to strand extensions can damage the hair shaft if applied and removed incorrectly. A professional who is familiar with the application of extensions should be consulted for proper care. Braiding the hair too tightly can cause breakage (4), irreversible traction alopecia (5,6), and traction folliculitis (7). Hairstyles should be neat and

FIGURE 12 Hair weave glued onto existing hair. McMichael PTR 01/21/08 Chapter 12

172 Roseborough

FIGURE 13 Braided hair extensions. secure, but never braided so tightly that the scalp is tender afterwards. The direction of braiding should be changed or released frequently to avoid prolonged unidirectional tension. In order to maintain the integrity of the style, many people decrease the frequency of shampoos. If the scalp is prone to seborrheic dermatitis, inadequate cleansing of the scalp underneath the hair weave can exacerbate the condition. Patients should shampoo gently and regularly, utilizing cotton tipped applicators or soft bristled toothbrushes to make contact with scalp, if necessary. A dermatologist should be consulted if there is a new or prolonged scalp abnormality as the result of hair-extension use.

HAIR COSMETICS For many patients with thinning hair due to androgenetic or senescent alopecia, the most noticeable areas of loss are over the frontal and vertex scalp. As the hair density decreases, spaces between individual hairs increase and the scalp becomes more apparent. Commercially available hair cosmetics may be an option to camoufl age the areas of thinning. Hair cosmetics reduce the contrast between scalp color and hair color, making thinning areas appear less noticeable. Hair cosmetics are best worn by individuals with mildly decreased hair density. Several products are available, depending on the extent of the area that needs coverage. Toppik™ Hair Building Fibers (Spencer Forrest, Inc., Westport, Connecticut, U.S.A.) are made of hair-colored keratin fi bers that sprinkle out of a can and cover the thin areas. Other products such as Good Looking Hair (GLH) Thickener Spray® (Ronco, Inc., Simi Valley, California, U.S.A.) feature a spray-on application method to camoufl age thinning areas. Some clinicians recommend using camoufl age makeup, such as Dermablend® (L’Oreal USA, New York, New York, U.S.A.). There are also products similar to wide eyeliner pencils that fi ll in bare scalp and tinted lotion-based cosmetics that rub on. Hair cosmetics are relatively easy to apply, but require some practice for a natural appearance. The products wash out after wetting the scalp and need to be reapplied or touched-up daily. Most products are safe to use and rarely cause irritation.

Options for Eyebrow and Eyelash Loss For patients with alopecia areata, the loss of eyebrows and eyelashes can be both uncomfortable and cosmetically undesirable. Both hair-bearing regions function in protecting the eyes form airborne particles, sweat, and bright ambient light. Medical treatments are available for eyebrow loss, but unfortunately, there are no reliable treatments that can regrow eyelashes. To camouﬂ age brow and lash loss, the options are mostly cosmetic. Pencils, tattoos, and stencils can be used to create realistic eyebrows. “Eyebrow wigs” with net adhesive backing can be custom-made. For lashes, human and synthetic eyelashes are available. The lashes are attached with skin adhesive. Eyelids can also be tattooed, but should be done with care by an experienced professional. McMichael PTR 01/21/08 Chapter 12

Scalp Prostheses: Wigs, Hairpieces, Extensions, and Scalp-Covering Cosmetics 173

TABLE 1 Selected Online Resources for Hair Replacement Products and Services National Alopecia Areata Foundation Marketplace www.naaf.org/marketplace/marketplace.asp Locks of Love® Helps disadvantaged children suffering from medical hair loss www.locksoﬂ ove.org Eyebrowz® Eyebrow styling kits www.eyebrowz.com/ Toppik®Hair Building Fibers www.toppik.com/ Great Looking Hair (GLH)® System www.ronco.com Dermablend® (L’Oreal, USA) www.dermablend.com

CONCLUSION Wigs, hairpieces, and scalp-covering cosmetics are important and often underutilized tools in helping patients manage hair loss. Medical professionals should be familiar with options for hair replacement and should feel comfortable introducing appropriate resources to patients. A reference guide for hair replacement products and services is listed in Table 1.

REFERENCES 1. Wakelin SH. Contact anaphylaxis from natural rubber latex used as an adhesive for hair extensions. Br J Dermatol 2002;146(2):340–1. 2. Cogen FC, Beezhold DH. Hair glue anaphylaxis: a hidden latex allergy. Ann Allergy Asthma Immunol 2002;88(1):61–3. 3. Khumalo NP, Jessop S, Gumedze F, et al. Hairdressing is associated with scalp disease in African schoolchildren. Br J Dermatol 2007;157(1):106–10. 4. Grimes PE. Skin and hair cosmetic issues in women of color. Dermatol Clin 2000;18(4):659–65. 5. Rudolph RI, Klein AW, Decherd JW. Corn-row alopecia. Arch Dermatol 1973;108(1):134. 6. Halder RM. Hair and scalp disorders in blacks. Cutis 1983;32(4):378–80. 7. Fox GN, Stausmire JM, Mehregan DR. Traction folliculitis: an underreported entity. Cutis 2007;79(1):26–30. McMichael PTR 01/21/08 Chapter 12 McMichael PTR 01/21/08 Chapter 13

13 Hair Transplantation

Ron Shapiro Shapiro Medical Group, Bloomington, Minnesota, U.S.A. Valerie D. Callender Department of Dermatology, Howard University College of Medicine, Washington, D.C. and Callender Skin and Laser Center, Mitchellville, Maryland, U.S.A.

SOCIAL IMPACT OF HAIR LOSS Although there are those who accept hair loss gracefully, for many it is the cause of signiﬁ - cant social and psychological stress. Concern over hair loss has been documented throughout history. Recently, a 5000-year-old body from the Neolithic Age was found frozen outside of Austria. The frozen body had a neatly trimmed beard and closely cropped hair, which could be evidence that the appearance of hair was important as far back as 5000 years ago. One of the oldest known medical texts is an ancient Egyptian papyrus scroll. Among its remedies is an ointment for restoring hair loss consisting of equal parts crocodile and hippopotamus fat. The ancient Greek physician Hippocrates took an interest in hair loss that was stimulated by his own baldness (indeed, the name for the permanent fringe of hair that encircles the back and sides of the head has sometimes been referred to as Hippocratic wreath). And the biblical story of Samson and Delilah is perhaps the most famous “hair equals virility” story of all time (1). In modern times over 50% of men and 25% of women suffer from some degree of hair loss (2–4). Over 2 billion dollars a year are spent on various treatments for hair loss. No other facial feature will change one’s appearance as much as hair loss. Dermatologists and other physicians are often asked to evaluate patients for hair loss. Apart from establishing the etiology of hair loss, patients want to know how the hair can be restored. Hair transplantation has become a signiﬁ cant treatment tool in the armamentarium for hair loss. A survey by the International Society of Hair Restoration Surgery (ISHRS) estimated that over 80,000 hair transplant procedures are performed yearly in the United States alone. It is ranked as the second highest cosmetic procedure performed on men. This chapter reviews the advances that have occurred in hair restoration procedures and examines procedures for areas not commonly thought of as being treatable, such as eyebrows and eyelashes. Various concerns that dermatologists and other physicians may have in deciding whether patients should be referred for possible hair replacement, particularly as it relates to cicatricial and non-cicatricial forms of alopecia, are discussed as are special considerations involved in treating Asian and African-American patients.

HISTORY AND EVOLUTION OF HAIR TRANSPLANTATION Historically, male-pattern baldness (MPB) is the most common indication for hair transplantation. It is caused by exposure of hair to the androgen dihydrotestosterone (DHT) which is a metabolite of testosterone created when testosterone reacts with the enzyme 5-α-reductase (5). When susceptible scalp hairs are exposed to DHT they become ﬁ ner and shorter with each recurring growth cycle, eventually leading to baldness. The severity of MPB varies dramatically and can be as mild as minor recession of the hairline or as severe as complete loss of the hair on the superior aspect of the scalp. Genetically determined differences in the sensitivity to DHT explain these variations between people. However, even in the most severe case of MPB, hair loss does not occur in the horseshoe-shaped ring of hair in the occipital and lateral fringe areas of the scalp because this hair is not sensitive to the effects of DHT. The ﬁ rst description of hair transplantation was actually written by Okuda in Japan in the 1930s. He used hair transplantation to treat burn victims during World War II. However, records of Okuda’s work were lost after the war. In 1950 Norman Orientreich rediscovered the McMichael PTR 01/21/08 Chapter 13

176 Shapiro and Callender process and successfully performed the fi rst hair transplant in the United States for patients with MPB (6,7). He proved when “donor” hair from the permanent horseshoe-shaped fringe area on the back and sides of the head was moved to the balding “recipient” area on the top of the scalp that it continued to grow and did not fall out. Donor hair from the fringe area remains insensitive to DHT and this property of donor hair and not local properties in the recipient area that enables transplanted hair to grow. Orientreich called this property “donor dominance” and it is the property that makes hair transplantation possible. It is important to point out that this fringe of donor hair is a fi nite and limited area that can only produce a fi nite and limited amount of donor hair. The concept of a limited donor supply is important as it places a limit on what can be accomplished. Although Orientreich demonstrated that hair could be moved and it would indeed grow, the original procedure often created an unnatural look and therefore had limited application. The desire to improve naturalness has led to many improvements in the technique, more natural results, and a broader range of applications.

Standard Punch Grafting From 1950 to the early 1980s the only procedure available to the public was the technique made popular by Orientreich, called standard punch grafting (Fig. 1A) (6). This procedure used large circular grafts (often called “plugs”) that were harvested by round punches. Each graft was about the size of a pencil eraser and contained as much as 15 to 30 hairs per graft. Only 50–100 of these grafts were used at a time and they were placed into round recipient sites also created by punches. There were intrinsic problems with this technique that led to unnatural results. First, the large plugs had to be spaced rather far apart due to the constraints of blood supply and this led to the “doll’s-head” look commonly associated with transplants of the past.

FIGURE 1 History of change. (A) Standard punch-graft technique used large grafts (14–24 hairs) with small sessions (50–100 grafts). It created an unnatural look in both donor and recipient area. (B) Mini-micro grafting used moderate to small size grafts (4–12 hairs) and moderate size sessions (400–1000 grafts). Donor hair was taken as a linear strip. (C) Follicular unit grafting uses tiny 1–4 hair grafts cut under a microscope in larger sessions of 1500–2500 grafts. Results are more natural. McMichael PTR 01/21/08 ColorInsert

FIGURE 2.6 Typical light microscope picture of the hair surface. Although the cuticle is visible, little information is gained from the inside of the ﬁ ber.

FIGURE 2.8 Polarized light micrograph of trichothiodystrophy showing a typical “tiger tail” appearance.

FIGURE 2.9 Unpolarized and polarized images of a telogen root. The polarized image reveals more information of the keratinization pattern within the telogen club root.

FIGURE 4.2 Horizontal scalp biopsy, upper sections. (See page 42 for full legend.) McMichael PTR 01/21/08 ColorInsert

FIGURE 4.21 Horizontal section, isthmus level: Terminal hair shaft follicle from innermost to the outermost: the medulla, cortex containing melanin pigment, and cuticle.

FIGURE 4.27 Telogen germinal unit, vertical section. (See page 57 for full legend.)

FIGURE 6.2 Moderately severe dandruff scale in the scalp. McMichael PTR 01/21/08 ColorInsert

FIGURE 7.7 Higher magniﬁ cation of a follicular unit emphasizing the small, dystrophic hair ﬁ bers commonly seen in long-standing disease.

Acute versus chronic telogen effluvium (shedding)

Triggers Genes Inflammation Stromal Metabolic Endocrine Hormones Androgens Drugs Systemic disease Stress Acute

Repetitive Chronic

FIGURE 9.4 Shedding patterns and triggers.

FIGURE 10.2 Discoid lupus. FIGURE 10.3 Lichen planopilaris. McMichael PTR 01/21/08 ColorInsert

FIGURE 10.5 Pseudopelade.

FIGURE 10.7 Folliculitis decalvans.

FIGURE 10.8 Dissecting cellulites. McMichael PTR 01/21/08 ColorInsert

FIGURE 13.2 Under magniﬁ cation, hair is seen to grow in natural groupings of 1–4 hairs called follicular units.

FIGURE 13.4 Recipient incisions. (See page 183 for full legend.)

(A) (B)

FIGURE 13.15 Central centrifugal cicatricial (C) alopecia (CCCA). (See page 193 for full legend.) McMichael PTR 01/21/08 ColorInsert

Figure 14.1 Saw palmetto (Serenoa repens). Figure 14.5 He Shou Wu (Polygonum mulﬂ orum, aka FoTi).

Figure 14.6 Rosemary (Rosemarinus ofﬁ cinalis). Figure 14.9 Elderberry (Sambucus nigra canadensis). McMichael PTR 01/21/08 ColorInsert

Figure 14.11 Thyme (Thymus vulgaris). Figure 14.10 Soy (Glycine max).

FIGURE 15.1 Hirsutism: A female with increased terminal hair growth in a male distribution on the face. McMichael PTR 01/21/08 ColorInsert

FIGURE 18.1 Friar Tuck sign of trichotillomania.

FIGURE 19.2 Kerion formation in tinea capitis.

FIGURE 19.3 Clinical appearance of louse scalp infestation. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 177

The only way to at least partially resolve this doll’s-head appearance was to do multiple procedures in an attempt to fi ll in the gaps between the plugs. Many patients frustrated and disappointed with the initial results simply did not fi nish the process. Even if patients did fi n- ish the process other problems with naturalness occurred over time due to the ineffi cient use of the limited donor supply. To fi ll in the gaps, physicians were forced to use up the entire donor supply in a very small area. Very unnatural islands of grafted hair became noticeable over time as hair loss progressed and receded away from these heavily grafted areas. It was during this time that physicians learned to appreciate and take into account the progressive nature of hair loss when planning hair transplantation in patients with MPB. Another problem with this technique was that it wreaked havoc with the donor area. The punches used to harvest these “plugs” from the donor area often left a scarred checkerboard pattern in the back of the head. The technique of Standard Punch Grafting is obsolete and no longer used. Unfortunately there are still many patients who used this old technique in the past and others mistakenly think that they represent hair transplantation methods today.

Combination Mini-Micro Grafting The desire to improve naturalness led to the use of smaller grafts. By the late 1980s and early 1990s a technique called mini-micro grafting became the standard (Fig. 1B). Graft size had been reduced to 4–12 hairs per graft. Small slit incisions were now used for the recipient area instead of round punches. The decreased vascular trauma associated with these smaller slit incisions enabled a larger number of grafts to be placed closer together in a single session. Procedure size increased to an average of 400 to 800 grafts per session. Donor harvesting and graft preparation techniques improved also. Donor tissue was no longer harvested with individual round punches but rather from a single strip of donor tissue (a process called strip harvesting). The harvested strip was subsequently divided into individual grafts. This produced less scarring, leaving behind a single linear scar rather than a checkerboard pattern. Strip harvesting also increased the total amount of hair that could be harvested from the donor area. Mini-micro grafting was a vast improvement over standard punch grafting, but the results were still not totally natural under all conditions, and room for improvement still existed

Follicuar Unit Transplantation By the mid 1990s follicular unit transplantation (FUT) (Fig. 1C) became the state-of-the-art procedure used in hair transplantation. This revolutionary advance occurred when physicians observed that hair grows and exits the scalp in tiny, naturally occurring groupings of 1–4 hairs called follicular units (Figure 2). With this observation physicians began using microscopic magniﬁ cation to create grafts that keep these natural groupings intact (8,9). These 1–4 hair grafts, called follicular unit (FU) grafts are so tiny they can be placed in micro-incision about the size of a needle. The reduction in graft and recipient site size allowed for larger numbers of

FIGURE 2 (See color insert.) Under magniﬁ cation, hair is seen to grow in natural groupings of 1–4 hairs called follicular units (FU). McMichael PTR 01/21/08 Chapter 13

178 Shapiro and Callender grafts to be placed closer together with less danger of vascular trauma. Procedures consisting exclusively of FU grafts could range from 1500–2500 depending on the size of the area being treated. FU grafts can be placed at densities of about 20–30 grafts/cm, which is signiﬁ cantly closer than with mini grafts. These tiny grafts replaced hair with the same size groupings found in nature. By placing large numbers of these grafts in patterns that mimic nature, an undetect- able result could be produced. The degree of naturalness produced with FUT enabled physicians to treat situations that could not be treated before and expanded the application and use of hair transplantation. FUT enabled more delicate work such as eyebrows, eyelashes, beards, and mustaches to be done. FU grafts have also been found to be successful in some cases of trauma- and disease-induced scarring alopecias. Most physicians now use FU grafts exclusively when performing hair transplantation procedures. However, for the sake of completeness, is should be mentioned that some physicians still use a combination of mini-grafts and FU grafts in selected situations. They feel that in certain situations combining FU grafts with slightly larger mini-grafts can achieve better density; and can do so without noticeably sacriﬁ cing naturalness. This is a controversy in hair transplantation that has yet to be resolved.

Scalp Reductions, Flaps, Tissue Expanders Scalp reductions, ﬂ aps, and tissue expanders are other tools that can be used to treat areas of alopecia on the scalp. These are much more aggressive procedures and have a greater degree of morbidity than hair transplantation. The results are often not natural. With the advent of FUT these procedures have fallen out of favor for purely cosmetic procedures as the results are not worth the morbidity. However they still have a place in the reconstruction and treatment of the more severe traumatic alopecia and should not be forgotten. The morbidity is warranted when severe traumatic alopecia’s (from burns, accidents, congenital abnormalities, etc.) have created severe aesthetic deformities that limit social interaction and quality of life. There are two ﬂ ap procedures that are still used in hair restoration with good results:

1. The Frechet triple fl ap is a procedure used to treat the balding crown. The procedure gets its name from Dr. Patrick Frechet in Paris, France, who performs this procedure. It is a method of using a combination of serial scalp reductions in the crown followed by an elegant rotating fl ap procedure to cover a balding crown (10). 2. The second procedure is the female hairline advancement fl ap performed by Dr. Shelly Kabak- er in San Francisco, California. It is a procedure where females with an unusually high hairline may have the hairline surgically pulled down rather than grafting a new hairline (11).

In properly selected patients these two ﬂ ap procedures are still useful. However, over 90% of the procedures done today to treat alopecic scalps are done with FUT.

BASIC PRINCIPLES OF HAIR TRANSPLANTATION Meeting a patient’s expectation of naturalness and density, both now and in the future if hair loss progresses, is the most important goal in hair transplantation. Achieving this takes skill with the procedure, but also requires setting proper expectations with patients. Understanding the following basic principles are helpful in understanding how to achieve success.

The Issue of Naturalness Creating naturalness is probably the most important goal in hair transplantation. However, it is important to note that simply using FU grafts does not guarantee natural results. Knowledge of natural patterns and the ability to reproduce these patterns are also necessary. An analogy would be similar to using a small paint brush as a tool to paint delicate art. Having the small paint brush is not enough . . . one also needs to know how to paint. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 179

The Issue of Density Meeting a patient’s expectation of density is the second most important goal in hair transplantation. Expectation of density refers to the area of baldness that can be covered and the degree of fullness that can be achieved in these areas. Achieving this goal can be difﬁ cult for a number of reasons.

Poor Survival FU grafts are very delicate and therefore susceptible to trauma and decreased survival. Cutting and placing large numbers of these very tiny grafts close together without trauma is technically difﬁ cult. There are many steps throughout the procedure (donor harvesting, graft preparation, recipient site creation, and placing) where the grafts are vulnerable. Many innovative techniques have been developed over the years to improve survival. With the use of these innovations a skilled and experienced physician can minimize trauma and the survival rate can increase to 90–100%.

Limited Supply of Donor Hair Even with good survival rates there is another reason that creating the appearance of fullness can be a challenge. There is only a ﬁ nite and limited amount of donor hair available to move from the donor area to the balding recipient area. The amount of donor hair available for transplantation can often be less than the amount of hair that originally existed in a balding area before hair loss started, especially in patients with extensive hair loss. Therefore, to some extent our hands our tied and we simply cannot reproduce—at least hair for hair—the same mathematical density that existed before hair loss started. Consequently, a major goal in hair restoration surgery is to be able to create the “appearance” of fullness at lower-than-normal “mathematical” densities. Fortunately, this goal is achievable.

Creating the “Illusion” of Density A normal “illusion” of density or “appearance” of fullness can be maintained until approximately 50% of original hair is lost. This longheld and widely accepted dermatologic concept was veriﬁ ed in a study by Marritt, who demonstrated that “parted” hair in a 1-cm area did not begin to appear “thin” or to “widen” until approximately 50% of the original hair was lost. This same principle applies in reverse when replacing hair. In other words hair only needs to be replaced to approximately 50% of its original volume to create an appearance of fullness. Another principle that allows us to create the illusion or appearance of fullness at lower- than-normal mathematical densities is that the appearance of fullness is not only determined by the quantity of hair in a given area, but also by the effectiveness of hair at creating this illusion. Stated another way, equivalent amounts of hair can appear thicker or thinner depending on how effective this hair is in creating the illusion of fullness. The following factors and characteristics have an inﬂ uence on the ability of hair to appear full.

Low color contrast between the scalp and hair: When there is a low-color contrast between the hair and scalp (such as with blond hair on light skin and black or brown hair on dark skin) the wavelength of light reﬂ ected from the scalp is similar to that of the hair shaft. This makes it more difﬁ cult to notice thinning and increases the illusion of density Products used to color the scalp exert their effect in the same manner. Hair curl and caliber: Curly hair and higher caliber hair is more effective at creating the appearance of fullness because these characteristics increase the amount of hair surface area in a given volume of space, that is interposed between the scalp and eye. Angle of hair leaving the scalp: The shingling effect that occurs when hair is placed at a more acute angle positions the hair in a manner such that more of the surface area of the hair lies between scalp and the eye. It also causes the hair to overlap creating a greater illusion of density. Orientation of hair: It has been proposed that orientating grafts in what is called a “coronal” incision may create a greater illusion of density because this causes the hairs in the grafts McMichael PTR 01/21/08 Chapter 13

180 Shapiro and Callender

to line up side by side instead of one on top of each other, thereby creating more of a wall between the scalp and the eye.

An understanding of the above principles helps us deal with our patients in two very important ways. First it allows us to better predict and consequently educate patients about the degree of fullness they may achieve with a given amount of hair depending on differences in the curl, color, and caliber of the hair. It also gives us tools such as angling, shingling, and different ori- entations that may help us to create a greater appearance of density.

Hair-Loss Progression One of the main difﬁ culties facing physicians treating male- and female-pattern alopecia is that hair loss can progress at an unpredictable rate. Patients with mild hair loss today may have severe hair loss in the future. Physicians need to be careful to transplant hair in a pattern that will look natural not only today but also if the hair loss progresses and recedes away from the transplanted area. Areas of thinning that improved when transplanted hair was added to native hair may become thin again in the future as native hair is lost. Patients need to be educated about the possibility of needing more work in the event of progression. Physicians also have to leave enough donor hair in reserve to treat any possible progression.

Adjunctive Medical Treatment There are currently two FDA-approved medical treatments for hair loss: minoxidil (Rogaine®) and fi nasteride (Propecia®). In order to obtain maximum density now and in the future it is important use adjunctive medical therapy to preserve existing native hair. Medical therapy may bring back some lost native hair but slowing down or stopping future loss is equally important. The use of medical therapy can affect surgical planning in a number of ways. On occasion the response is so good that patients decide they do not require surgery. On other occasions it improves the situation, so a smaller, less aggressive procedure is needed. Even if medical therapy is only minimally effective, a small amount of regrowth can signifi cantly improve the appearance of density in transplanted areas. Minoxidil is a topical application approved for both men and women. It is available in two strengths, 2% and 5%. It has been shown to either reduce hair loss or promote hair growth in about 80% of patients. Approximately 50% of men have their hair loss slowed, 35% continue to lose hair (i.e., no effect), and approximately 15% show some signs of regrowth. In men, 5% minoxidil has been shown to be more effective than 2%, demonstrating a dose-dependent response (12,13). It appears that minoxidil acts as a direct anagen-prolonging agent. A big problem with the use of minoxidil is compliance. The original product was oily and messy and the propylene glycol additive could cause irritation in patients. Recently, a new 5% foam-delivery system has been released without any propylene glycol. It is much easier to use and is therefore better accepted by patients. Finasteride is a 1-mg oral tablet taken daily that acts as a potent 5α-reductase type-2 inhibitor. It blocks the conversion of testosterone to dihydrotestosterone and decreases levels of DHT by about 65%. It has shown impressive effects in both blocking further hair loss and producing re-growth. The effects are greatest on the crown; however, it has some benefi cial affect in the frontal area also. Five-year results showed that by hair count, 65% of men were stable or improved (14,15). There is concern that the effi cacy of fi nasteride may wear off with time. However, there are patients that have taken fi nasteride for over 10 years with continued affects. Finasteride is not approved for use in women and a study by Merck & Co. on post-menopausal women over the age of 50 did not show any benefi t. There are a few small independent studies and anecdotal reports that suggest fnasteride may have some benefi cial effects in younger women. However, the use of fi nasteride is contraindicated in women of childbearing potential because of possible birth abnormalities in the fetus. In men, fi nasteride has a very low side-effect profi le. The most common concerns are sexual side effects, gynecomastia, and decreased sperm count. Even though the incidence of sexual side effects was low (1.8% with fi nasteride compared to 1.6% in placebo) and reversible when stopped, it is still unsettling to a few men. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 181

Dutesteride (Avodart®, GlaxoSmithKline, Philadelphia, Pennsylvania, U.S.A.) is a new 5α- reductase inhibitor that blocks both type 1 and 2 versions of the enzyme. It decreases levels of DHT greater than 90% and is felt to be more effective than Propecia. However it has a very long half-life and the side-effect proﬁ le is thought to be worse than that of ﬁ nasteride. It has not been released for the treatment of male-pattern baldness, yet some hair transplant clinics use it off label, with a warning about the potential side effect, on patients that are not responsive to Propecia.

Education to Set Expectations Even if work is done perfectly, a patient will not be happy if the results he receives are not what he expected. In order to insure expectations are realistic the following steps should be taken:

Evaluate available donor supply both in terms of total amount and the characteristics of the hair that may inﬂ uence its effectiveness at creating the appearance of density (color, curl, caliber, etc.). Every patient is different, with donor supply ranging from 4000 to 8000 FUs. Evaluate the size of the area of alopecia that needs to be treated. Predict as well as possible how much progression may occur in the future. Every patient is different based on their age, current severity of loss, family history, etc. Evaluate the patient’s expectations and desire for coverage. Evaluate whether the patient’s expectations of density and coverage are possible with the donor supply. Educate the patient about what is realistically possible now and in the future based on the donor supply.

If the patient’s expectations are not realistic or achievable, then surgery should not be performed at this time! It is important for hair transplant surgeons to be familiar with and be able to identify patients with body dysmorphic disorder (BDD). This is a psychiatric condition in which a patient obsesses about minor or imagined defects in their appearance. This obsession may markedly interfere with the patient’s ability to form personal relationships or to hold a job. If the perceived defect is corrected by aesthetic surgery, another defect will quickly be discovered. It is not uncommon for cosmetic surgeons, including hair restoration surgeons, to be approached by patients with BDD. Therefore, surgeons must be familiar with the proﬁ le of these patients, as they are not good candidates for surgery

THE PROCEDURE Follicular unit transplantation can be divided into 4 major steps: donor harvesting, graft preparation, recipient site creation, and placing of grafts.

Step 1: Donor Harvesting The goal of donor harvesting is to remove scalp tissue from the permanent donor area in a way that limits transaction or waste of the hair (Fig. 3A) and as small a scar as possible in the donor area. It is important to remain within the permanent fringe area when removing the donor strip. If we stray outside this area the grafts prepared may be lost as time progresses. The length and width of the strip harvested is based on the number of grafts needed and the donor density. It is important to measure the skin laxity of the donor area before taking out the donor strip. Some patients have very tight scalps and this limits the width that can be taken safely. Patients with poor donor density and tight scalps are in general poorer candidates for surgery. The donor is taken as a single strip using either a single scalpel or a two-bladed scalpel. Great care is taken to angle the blades to be parallel with the hair shaft in order to prevent transaction and damage to the FU. A new technique has been developed to help minimize the scar associated in the donor area with this incision. This is called a trichophytic closure. With this closure, one edge of the wound has the epithelium trimmed away, exposing the tips of the hair shafts. It is hoped that, after suturing, these hair shafts will grow through and camouﬂ age any scar. If multiple procedures are performed over time an attempt is made to include the previous scar in each incision in order to create a single scar. McMichael PTR 01/21/08 Chapter 13

182 Shapiro and Callender

FIGURE 3 Donor harvest and graft preparation. (A) Harvesting donor hair with single blade as single strip. (B) “Slivering” donor strip under the microscope. (C) Creating ﬁ nal 1–3 hair FU grafts. Abbreviation: FU, follicular unit.

An alternative form of donor harvesting called follicular unit extraction (FUE) has been advocated by some physicians. This technique involves utilizing a 1-mm punch to harvest individual FUs. The rationale for this technique is the avoidance of a linear scar, possibly allowing patients to cut their hair very short without any evidence of surgery. It has been promoted as the “scarless” surgery. However, a number of patients develop hypo-pigmented dots at the site of punches and this advantage is lost. Other drawbacks include an increased risk of transection with each blind punch (especially in patients with curly hair) and a limit to the number of grafts that can be done in a single session. Also, it is more time-consuming and considerably more expensive than strip harvesting, and it has therefore found limited popularity. However, in patients that only need a small amount of grafts or who are extremely worried about the donor scar, it is valid. The indications may expand as the technique is improved and made more efﬁ cient.

Step 2: Graft Preparation The harvested donor tissue is converted into grafts in two steps. The ﬁ rst and most critical step is called slivering, during which the donor strip is cut into thin slices or “slivers,” each about the width of one FU (Fig. 3B). It can be visualized as similar to slicing a loaf of bread. It is important to use a dissecting microscope during this step to avoid transection. These slivers are then further dissected into individual 1–4-hair FU grafts (Fig. 3C). The different-sized grafts are then separated and placed in different piles so they can be selectively distributed in the recipient area later. They are placed in cooled saline until they are ready to be placed.

Step 3: Creating Recipient Sites While the grafts are being cut, usually by highly trained assistants, the physician is making the recipient site incisions (Figure 4A). Recipient site incisions vary in size from .7–1.2 mm wide, with the smaller incisions used for the 1–2 hair grafts and the larger incisions used for the larger 3–4 hair grafts or hair that is tightly curled. A number of different instruments can be used to make these incisions. The author used a specialized blade-cutter that can be adjusted to create blades that vary in size. It is important for the physician to test the recipient sites to make sure the grafts ﬁ t properly and adjust the size of the blade if necessary. While making the recipient site the physician needs to create a pattern that imitates nature. The incisions also have to enter the scalp at the same angle and direction as normal hair. They need to be made at the proper depth in order limit damage to deep vessels. If a patient is only thinning in an area and has McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 183

FIGURE 4 (See color insert.) Recipient incisions (A) are made with a tiny needle in a natural pattern that selectively distributes the 1-hair grafts peripherally and the larger grafts more centrally. (B) Placing is done using jewelers’ forceps.

preexisting native hair, the physician needs to take care to avoid transecting these native hairs. True surgical loops for magniﬁ cation aids in this.

Step 4: Placing The ability to place grafts successfully is a critical step in the hair transplant procedure. The potential for graft trauma or dehydration occurring at this step is high. Placing a large number of tiny grafts into small incisions without trauma is technically diffi cult. The standard procedure is to use fi ne tipped micro-jewelers forceps to grab the graft at their base and then gently slide it into the incision (Figure 4B). The use of surgical loops for magnifi cation helps with this step. There is a tendency for grafts to get dehydrated if the process takes too long. Keeping grafts moist is critical as dehydration is probably one of the most common reasons for poor survival during placing.

Postoperative Course Patients should be educated about the postoperative course that follows this procedure. In general there are very few immediate postoperative problems, though a few patients may develop minor bleeding or infection in the donor area. There is some forehead swelling that occurs in about 20% of patients, which usually lasts only 3 days. The transplanted hair usually sheds by about 2–3 weeks at which time the patient looks like he did before surgery. It begins to grow at about 3 months and between 3–6 months a signifi cant change occurs and it is estimated that most patients have achieved about 60% of the affect by this time. Improvement continues for up to one year but by the end of a year usually what you see is what you get. Occasionally some patients may get a folliculitis around the 3-month mark when the hair starts to grow. This is easily treatable with topical compresses and antibiotics, if needed. In about 20% of patients a complication called shock loss or telogen effl uvium occurs. This describes when a percentage of the native hair that was still present in the recipient area before surgery temporarily is traumatized and goes into a telogen effl uvium. Usually this is temporary loss and the shocked hair will regrow. However, sometimes a percentage of the shocked hair will not regrow. There is more risk of this shock loss in patients that have only early thinning and a signifi cant amount of preexisting native hair. Shock loss is also more common in women. Patients with preexisting hair should be warned about this potential complication. McMichael PTR 01/21/08 Chapter 13

184 Shapiro and Callender

PRACTICAL APPLICATIONS OF HAIR TRANSPLANTATION Male-pattern baldness is the most common indication for hair transplantation. However, with the advances made in FUT, the indications have broadened. Women and ethnic groups such as individuals of African and Asian descent often seek out hair transplantation and have unique properties that need to be considered. Transplantation can now treat delicate areas of hair loss on the face such as eyebrows, eyelashes, beards, and mustaches. Other indications now include scarring on the scalp from accidents, burns, and surgery, although controversial transplantation can even be used to treat some forms of cicatricial and inﬂ ammatory alopecias.

Male-Pattern Baldness Male-pattern baldness (MPB) (Fig. 5) is the most common cause of hair loss in men and the common indication for hair transplantation. As stated earlier, in order to have a successful hair transplant, we need to meet the patient’s goals of both naturalness and density. Creating naturalness is achieved by using 1–4 hair FU grafts to mimic patterns and distributions of hair found in nature. Creating a natural hairline is most important. A hairline should initially appear irregular, soft, and ill defi ned but gradually take on more defi nition and substance as it moves posteriorly. Creating a hairline that is too abrupt or straight does not look natural and is a common mistake made by beginning transplant surgeons. To accomplish this goal only one hair FU graft is in the anterior portion of the hairline with a shift toward 2 hair FU grafts as we move toward its posterior portion. Behind the hairline, density is more important, and a shift toward larger 3–4 hair FU grafts is made. This is called selective distribution of grafts and is an important technique used in hair transplantation. It is also important to make incisions at the angle and direction that follows the natural fl ow of hair. The amount of density that we can ultimately create will depend on the severity of hair loss and the supply of donor hair. The severity of MPB varies dramatically and can be as mild as minor hairline recession of the hairline or as severe as complete loss of the hair on the superior aspect of the scalp. Hair loss is progressive at an unpredictable rate. It is very hard to predict how severe a pattern will develop in a patient when they are young. Family history helps a little but is not very reliable. Probably the best predictor is the age and severity at which hair loss begins. A patient that develops signifi cant hair loss at a very early age will most likely end up

FIGURE 5 Typical male-pattern baldness, before (A) and after (B). McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 185 with severe hair loss, while patient that only begins to recede in his 40s or 50s will most likely have less severe pattern. Predicting and communicating the degree of density and the area of coverage that can be provided to a patient is one of the most diffi cult skills to learn in hair transplantation. Since most patients have enough donor hair to cover the front half of their head, we usually suggest that patients treat the front half fi rst. When they are satisfi ed with the front we can move to the crown if there is donor hair left. The general dogma is to plan for the worst-case scenario and maximum hair loss. A more aggressive approach can be taken if a patient is older with minimal hair loss. The most diffi cult patients to treat and the ones who need to be educated the most about realistic expectations are:

patients that want their hairline too low, patients that are just beginning to thin and do not want to “see scalp,” patients with severe hair loss in both the front and crown who want full coverage every- where, young patients with early hair loss in whom it cannot be predicted how severely they will progress.

Female-Pattern Alopecia Hair transplantation can be successful for female-pattern alopecia (Fig. 6) and the number of females seeking hair restoration surgery is on the rise. In our society it is socially acceptable for a man to lose his hair. He may not like it, but at least male-pattern hair loss is considered “normal.” After all, a majority of men have some degree of noticeable hair loss by the time they reach midlife. Hair loss in females is not as socially acceptable. With female-pattern baldness, women feel “abnormal” and ﬁ nd themselves in a position that makes them extraordinarily uncomfortable. The incidence of female-pattern alopecia (FPA) is greater than most people realize. Nor- wood recently reported that female-pattern alopecia is as high as 30% in females over 30 years of age. Others have reported even higher incidents when females are carefully examined (16,17). One reason that this is not generally appreciated is that females are very good at hiding hair- thinning with hairstyles, products, and hairpieces. The pattern of hair loss in FPA is different than MPA in that the hairline is usually not affected but there is diffuse thinning in the central scalp behind the hairline. Ludwig and Olsen

FIGURE 6 Typical female-pattern baldness, before (A) and after (B). McMichael PTR 01/21/08 Chapter 13

186 Shapiro and Callender described the pattern slightly differently. Ludwig described FPA as occurring in a caudal and centrifugal pattern in which hair in the hairline is maintained, though it may thin to varying degrees. Ludwig created a scale in which she divided FPA into Ludwig type 1, type 2, and type 3, with the highest level of severity at type 3. Olsen described a “Christmas-tree” pattern of loss, which begins as a “widened part” but evolves into a zone of hair loss that is widest anteriorly at the hairline and gradually narrows, with ragged borders, more posteriorly. Females have some special issues that need to be addressed before deciding if they are good candidates for surgery. Females are prone to other causes of hair loss. If there are any signs or symptoms suggestive of an endocrine, metabolic, or dermatologic cause, they should be investigated and treated appropriately. It is also important to rule out temporary hair loss caused by severe emotional or physical stress leading to telogen effl uvium. However the majority of females seeking transplantation for hair loss have no apparent medical cause for FPB. Females are much more susceptible to the postoperative complication of “shock loss” or “telogen effl uvium” of existing native hair still present in the recipient area. Postoperative shock loss occurs when preexisting native hair is triggered to go into a telogen (resting) phase by the local stressors of surgery. In men this can occur from 10–20% of the time, while in females it occurs more frequently, almost 30–50% of the time. In general this shock loss is temporary, occurring about 2–3 months after surgery and resolving in about 4–6 months. However, in some situations it does not totally resolve, which leads to a less dense result. Women need to be warned about this before surgery. As with MPB, females must have appropriate expectations and enough donor hair to meet those expectations to be considered a good candidate for surgery. Females who are Lud- wig type 3 with severe hair loss may not be good candidates because they often have signifi cant thinning that extends over the entire scalp, including the parietal and occipital donor areas. They simply do not have enough donor hairs to perform a procedure. At the other extreme, females with very mild hair loss may also not be good candidates. Females with early thinning often want the full head of hair they had when younger and want to get to the point of “not seeing scalp.” They need to understand that this is clearly an unrealistic goal. Transplantation in these situations may actually make matters worse as the surgery may cause the loss of more preexisting hair in the recipient area than it adds. The best candidate is a female with moderate hair loss that is easily noticeable when she exposes the area. These females are usually very realistic about their goals. Obviously, all of them would like their hair to be as thick as possible, but most appreciate a moderate degree of increased thickness in the affected area that allows for better styling. In addition to FPB, other common indications for hair transplantation in females are the lowering of abnormally high hairlines either from heredity or after a brow lift, the creation of eyebrows and eyelashes, and for the treatment of scars secondary to trauma or cosmetic surgery. For females who have had little success with medical treatment, the possibility of hair transplanting should not be overlooked. Many females today can expect excellent results.

Females with High Hairlines Another abnormality quite commonly found in females is genetically high hairlines that give the appearance of a large forehead (Fig. 7). This may be the result of heredity or secondary to a brow lift. Women with this situation feel uncomfortable wearing their hair up or back and often wear bangs. Hair transplants are an excellent tool with which to lower the hairline. An alternative method of lowering the hairline is with the hairline advancement ﬂ ap discussed earlier in this chapter.

Eyebrows Eyebrows play an essential role in facial aesthetics (Fig. 8). Many women and some men seek help for thinning or absent eyebrows. With the reﬁ nement in FUT, normal appearing eyebrows can often be restored (18). Loss of eyebrow hair may be due to trauma such as burns and avul- sions, medical conditions such as hypothyroidism, or genetics. It may also be self-inﬂ icted due to long-term eyebrow plucking, or trichotillomania, which is an obsessive-compulsive hair pull- McMichael PTR 01/21/08 Chapter 13

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FIGURE 7 Lowering a high female hairline. Many women wish to lower an abnormally high hairline. This can be done with transplants or hairline advancement surgery. (A) Before, (B) postoperative appearance, and (C) resulting appearance. ing disorder. Approximately one-third of patients attribute their thin eyebrows to inheritance. It is important to treat and stabilize any underlying condition before transplantation. Enough time needs to pass after treatment to allow any potential regrowth of native hair to occur. Prior permanent makeup or tattooing is not a contraindication to eyebrow transplantation as the hairs will cover the tattoo. If the tattoo is to be removed it should be done so before transplantation. If the eyebrow tattoo was placed in an unaesthetic location that extends outside the normal boundaries of the eyebrow, it can be surgically removed leaving a ﬁ ne line that can then be easily concealed with the transplanted hair. It is important to understand the normal shape and patterns of eyebrows in order to recre- ate these shapes. The eyebrow can be divided into three parts: the medial portion is the head,

FIGURE 8 Eyebrow repair. Hair loss as result of chronic plucking: (A) before surgery and (B) after surgery. McMichael PTR 01/21/08 Chapter 13

188 Shapiro and Callender the central portion is the body, and the lateral portion is the tail. An arch occurs along the eyebrow in women. The direction and density of hair is different in each of these parts. The hair is less dense and directed upward in the medial head. The hair is most dense and is directed more horizontally in the central body. However, in the body, the cephalic-most hairs tend to grow at a slightly caudal angle, while the caudal-most hairs tend to grow at a slightly cephalic angle. This results in a cross-hatching affect and a greater illusion of density. In the tail, hairs are less dense and are directed horizontally. Only 1 and 2 hair grafts are used in the eyebrow with the 2 hair grafts designated for the thicker body of the eyebrow. Typically 200–250 grafts are transplanted into each eyebrow. These hairs are harvested from the occipital donor area as with any FUT procedure. The recipient incisions have to be angled very acutely to ensure the hairs lay ﬂ at against the skin and do not stick out. Patients have to be told that the hair will grow long like normal scalp hair and that they will need to trim the hair to the desired length on a regular basis. If after surgery the shape of the eyebrow is not exactly what the patient wanted it can be sculpted with electrolysis. Most patients get excellent results and are extremely grateful.

Eyelashes Eyelashes have important an anatomical function (Fig. 9). They shield the eye from injury from dust and grit. Eyelash transplants are usually reserved to treat functional total absence of the eyelash from disease or trauma. Eyelash loss can have a number of causes, including:

facial injury and scarring from traumatic events or surgery; self-inﬂ icted due to eyelid tattoos, long-term use of false eyelashes, or trichotillomania; or medical disorders such as thyroid disease, lichen planus, and alopecia areata.

The documented history of eyelash transplantation begins about 90 years ago with Dr. Franz Krusius, a German physician who published his technique for reconstruction of lost eyelashes. In 1980 Emmanuel Marritt published his technique for transplantation of single donor hairs from the scalp into the eyelid for eyelash reconstruction. In the same year, Robert Flowers reported a “pluck and sew” technique of eyelash reconstruction. Marcelo Gandelman has been demonstrating a modiﬁ ed version of this technique at hair transplantation workshops for the past 15 years. The potential for serious complications exist when performing eyelash transplantation. These include lid infections, distortion of the lid, injury to the tarsal plate, and misdirected hair damaging the cornea.

FIGURE 9 Eyelash transplant. Currently, eyelash transplantation is reserved for traumatic or medical eyelash loss that causes functional deﬁ cit. There is potential for cosmetic use in future. (A) Before surgery, (B) insertion, (C) after surgery. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 189

Recently, eyelash transplantation has been promoted for cosmetic enhancement of thinning eyelashes not due to trauma or disease. It needs to be said that there is controversy over the appropriateness of doing this due to the potential complications. Many recognized authorities in eyelash transplantation believe it should continue to be reserved for medically necessary eyelash replacement. However, very delicate innovations have been made in the technique that allow better control of hair direction as well as more gentle insertion into the lid margins. The particulars of the technique are as follows. A small amount of scalp tissue is removed from the back of the head and used as a donor source for the eyelashes. About 30 hairs are used for each eyelid. Only very fi ne single hair grafts are used. In contrast to other hair transplant procedures, the hair shaft is left long, like a piece of thread. This hair shaft is threaded through an opening at the back end of a very fi ne specialized curved surgical needle. The needle is then threaded through the top of the eyelid exiting through the tarsal plate at the point where normal eyelashes emerge. An attempt is made to follow the natural upward curve of the eyelash. As physicians gain more experience with this technique it may become more acceptable to use it for cosmetic indications alone (19). A class of drugs known as prostaglandin analogues have engaged interest for their potential use as a medical approach to eyelash enhancement. The best-known of these drugs is latanoprost, currently administered in eye drops to treat glaucoma. Ophthalmologists noted that latanoprost stimulated growth of existing eyelashes and darkened the eyelashes of treated patients. The effect has been studied as a possible medical approach to increasing the appearance of greater eyelash density. Side effects include blurred vision, eyelid infl ammation, and a temporary burning sensation. The use of prostaglandin analogues for reasons other than glaucoma treatment has not been thoroughly investigated. Their use for eyelash enhancement should be approached with great caution.

Beards and Mustaches Many men have bald spots or weak patches of hair in their beard or mustache (Fig 10). FUT is ideal for ﬁ lling in these areas. Normal facial hair usually consists of very thick and coarse 1-hair units. It is hard to ﬁ nd this degree of coarseness in the occipital donor area. Therefore, 2-hair grafts are usually used instead of 1-hair grafts in an attempt to match the thinness of the coarse beard hair. A common use for this procedure is to cover the defect resulting on the lip from a cleft palate repair.

Transplanting into Scar Tissue Caused by Physical Trauma Hair transplantation can be used to treat areas of scarring on the scalp caused by different types of physical trauma. These could include scars caused by burns, explosions, and accidents. Sometimes the scarring is iatrogenic and produced by surgical procedures such as face lifts, brow lifts, radiation treatment, or removal of a scalp tumor such as a hemangioma (Figs. 11–13). Special considerations are needed when transplanting into areas of scarring (20). The issue of the adequacy of blood supply to the scar tissue often arises. In addition to leading to poor graft survival, this limited blood supply can potentially leave the recipient area

FIGURE 10 Mustache and beard transplant. Many patients are born with patchy or complete areas of facial alopecia that can be treated with transplants. This patient used a mustache transplant to cover cleft-lip repair: (A) before surgery, and (B) after surgery. McMichael PTR 01/21/08 Chapter 13

190 Shapiro and Callender

FIGURE 11 Brow-lift scar. Many patient use transplants to cover scars caused by facial plastic surgery such as brow lifts or face lifts. (A) Before, (B) after. more vulnerable to infection, further ischemia, and necrosis. Although these are legitimate concerns, experience has shown that the blood supply in scar tissue is often suffi cient to accommo- date the appropriate placement of FU grafts. However, certain precautions and modifi cations should be taken. Some physicians have recommended assessing the blood supply by sticking the tissue with an 18-gauge needle and waiting for the appearance of blood. If none appears after a few minutes, one should be extremely cautious and consider test grafts in the area before committing to a larger procedure. Smaller grafts and in particular FU grafts should be used when transplanting into scar tissue. FU grafts, with their associated small recipient sites, have the greatest chance of survival and the least chance of causing ischemic injury in scar tissue. In general, one should always perform the fi rst transplant with a smaller number of grafts placed farther apart so as not to stress the blood supply. It is also prudent to wait longer in between sessions. With scar tissue it is better to plan on doing multiple, smaller sessions that succeed rather than one large session that fails. Although not proven, some physicians suggest that the use of a 2% to 5% solution of Rogaine for one week preoperatively and fi ve weeks postopera- tively may improve the blood supply and the odds of a successful transplant. Theoretically, the use of pentoxyphylline (Trental®, Aventis Pharmaceuticals, Bridgewater, New Jersey, U.S.A.) 400 mg, three times daily with meals for at least two weeks prior to surgery may also provide greater oxygenation to the tissue. Not all scars are the same and scar thickness can have an affect on transplantation. Some scar tissue is thick and tough, while other scar tissue is thin and friable. With thick hypertrophic scars, there is concern that the incisions will not gain access to the blood supply. In these

FIGURE 12 Third-degree burn scars. Transplants are used to reestablish hair in areas of burns. One has to be careful not to overwhelm the potentially reduced blood supply and cause necrosis. (A) Before surgery, (B) postoperative, with arrow pointing to small area of necrosis that resulted, and (C) result. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 191

FIGURE 13 Radiation-induced hair loss: sometimes radiation therapy for head and neck tumors results in areas of permanent hair loss. This patient had an area of permanent hair loss 7 years after resection and radiation therapy of a scalp tumor. (A) Before, (B) postoperative, (C) after.

situations, one should err on the side of making the incisions slightly deeper. Transplanting into thin atrophic scar tissue, such as that created by post-radiation injury, creates a different, and in our opinion, more diffi cult problem. The recipient area in this thin, poorly vascularized tissue is more prone to ischemia. In addition, the shallow skin makes it diffi cult to create incisions deep enough to house even tiny FU grafts. Making the incisions at a more acute angle can increase the length of the incisions and create a posterior “pockets” to house the graft. Carefully using a small amount of tumescent solution (without epinephrine) can temporarily distend the skin, making it easier to create these more acutely angled incisions. On several occasions, after the fi rst conservative transplant into an area of atrophic scarring, the tissue characteristics improve and become more favorable for a second transplant procedure. The tissue becomes thicker and more supple. It may be that the FU grafts act like multiple tiny skin grafts, and also may stimulate angiogenesis. One should always consider surgical excision as an alternative or adjunct to transplantation for areas of alopecia in the scalp. If the area of scarring is relatively small, and the surgeon is confi dent that the scar can be removed by an excision alone, then this should be considered. If an area of scarring is very large, sometimes it is better to fi rst excise a portion of the scarred area, leaving a smaller area to be transplanted.

Transplanting into Cicatricial Alopeicia The term cicatricial contains the Latin root cicatrix, which means a scar resulting from the formation and contraction of fi brous tissue. Historically, dermatologists have used the term cicatricial alopecia to refer to scarring alopecia caused by infl ammatory disease processes such as central centrifugal cictricial alopecia (CCCA), pseudopalade, lichen planopilaris, frontal fi brosing alopecia, discoid lupus erythematosus, etc. Transplanting into infl ammatory cicitricial alopecia is controversial (Fig. 14) (20). The current philosophy among hair transplant physicians for patients whose scarring is the result of infl ammatory disease processes is to be certain that the disease process has “burned out” before undertaking the procedure. A general rule of thumb has been to wait until there are no signs of active disease for approximately one to two years. It may be appropriate McMichael PTR 01/21/08 Chapter 13

192 Shapiro and Callender

FIGURE 14 Lichen planopilaris. Though controversial, hair transplantation is being used to treat areas of alopecia in “burned-out” cicatricial alopecia. This patient had one session of transplants for lichen planopilaris that had not changed in 4 years. (A) Before, (B) 2-year follow-up. to consult with a dermatologist or obtain a biopsy from the area to be transplanted to ascertain if the inﬂ ammatory or infectious process has subsided. The concern amongst transplant physicians is three-fold; that the disease process will reac- tivate and destroy the newly transplanted hair, that the transplant procedure may possibly reacti- vate the disease process, and that the survival rate may be somewhat decreased compared to grafts placed in normal tissue. There are no scientiﬁ c studies that address these issues. There is, however, a large body of empirical evidence in the transplant community demonstrating that grafts will grow successfully in burned-out areas of cicitricial alopecia (Figure 15). Patients are grateful for the cosmetic improvement. They often accept the risk that the growth may be poor or that they may lose grafts if the disease process reactivates. It may be that these patients sometimes accept these risks because we are improving on an unnatural deformity, rather than trying to reverse the natural balding process. However, it is important to educate these patients before the procedure and warn them about the possibility of disease recurrence and a decreased hair survival rate. In examining the patient, it is also important to be certain that the apparent scar is indeed a scar. For example, in rare instances, a basal cell carcinoma of the sclerosing type can mimic a scar. If there is any question about the diagnosis, the area should be biopsied.

Patients of African Descent Patients of African descent often request hair transplantation to treat areas of alopecia. Hair characteristics of patients of African descent present both advantages and disadvantages for the hair-restoration surgeon (21–23). If the surgeon understands these characteristics and works skillfully with them, then excellent results can be produced. A major challenge in patients of African decent is that they have an unparalleled degree of curl to their hair. A signiﬁ cant disadvantage of this curl is that it is much more difﬁ cult to harvest donor tissue and prepare grafts without transecting and damaging the follicles. This can lead to waste of the limited donor supply. The advantage of such an acute curl is that, compared to straight hair, each hair covers a greater amount of surface area in a given volume of space. This curve combined with another favorable hair characteristic, low contrast between dark hair and dark skin, make the hairs of patients of African decent much more effective at creating the illusion of density as compared with other ethnic groups. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 193

(A) (B)

(C)

FIGURE 15 (See color insert.) Central centrifugal cicatricial alopecia (CCCA). Graft survival after a test session in a patient with CCCA who was treated with anti-inﬂ ammatory agents for 9 months. (A) Before, (B) immediate postoperative appearance, (C) 6-month follow-up.

Modifi cations in strip-harvesting have been developed in an attempt to minimize the problem of transection. One modifi cation is infi ltrating the donor area with a large amount of saline tumescence. The pronounced turgor that is created in the tissue may help straighten these follicles as well as increase the distance between them, thereby decreasing the probability of transection. Another modifi cation is to bend the surgical blade used for harvesting in order for it to better follow the curve of the hair below the skin. A fi nal and more recent advancement is to harvest donor hair by using a scoring technique followed by blunt dissection. With this technique the skin is fi rst scored with a scalpel to only a few millimeters below the surface. Then a spreading device is inserted and the two edges are spread apart. Another challenge in patients of African descent is that the density of hair in the donor area is signifi cantly less than in Caucasians (60 FU/cm vs. 100 FU/cm) (24,25). If one were to only take into consideration the number of hairs/cm2, virtually all patients of African decent would be considered poor candidates for hair restoration surgery. However the density in the recipient area is also naturally lower. Therefore, when restoring an alopecic area in a patient of African descent, one does not have to achieve as high a mathematical density as in Caucasians in order to have a successful result. Post-traumatic keloid formation is more common in individuals of African descent than in Caucasians. A high index of suspicion is therefore necessary when transplanting in these individuals. One should check for the presence of keloids in areas of high fl exibility (elbow, wrist, shoulder, knee, etc.) as well as on the scapula area and the sternum. Performance of a “keloid test procedure” should be considered in patients that are likely to form keloids. This is done by transplanting a single 2-mm round graft to an area at the border of the recipient area in hair- bearing skin. A period of three months should then pass after which observation of the healing is made. If no keloid is seen, surgery can proceed. Although keloids can occur and are a concern in practicality they are very rarely reported (26). Other postoperative concerns that can occur more frequently in these patients are cobblestoning, hypopigmentation, and hyperpigmentation. McMichael PTR 01/21/08 Chapter 13

194 Shapiro and Callender

Making the incisions and placing the grafts is also slightly more diffi cult in these patients for the following technical reasons: the grafts have to be kept slightly larger due to the curl; the skin is tougher, which leads to more diffi culty in placing; the incisions are harder to visualize due to the dark skin; and there tends to be more bleeding, making it diffi cult to see. Therefore, the surgical instrumentation used in recipient site creation should be customized to accom- modate the extent of the hair curl. Typically, the selected instrument should produce incision sites greater than 1.2–1.5 mm in size. All of these challenges can be overcome with skill and experience. In addition to typical MPB and FPB there are a few other causes of hair loss that are more common to this group. Traction alopecia is a common form of hair loss in black women and develops from the chronic use of specifi c hairstyles, such as tight braiding, ponytails, and hair extensions. This form of alopecia is also common in Muslim Sikhs who pull their hair back to fi t in tight turbans. When this is done over a long period of time the hair loss can become permanent. It is amenable to hair transplantation as long as the underlying traumatic hairstyle and traction can be removed (Fig. 16). Chronic chemical injury due to straightening products is another cause of alopecia that may become permanent over a long period of time. This is amenable to hair transplantation as long as the inciting cause is removed. Central centrifugal cicatricial alopecia is a type of scarring alopecia seen in all ethnic groups and either gender, but is seen mostly in black women. Although controversial, the current feeling among hair-restoration surgeons is that once this disease is no longer active it may be amenable to hair transplantation.

Asians Hair transplantation in the Asian population is increasing in demand. A recent study by Pathomvanich found that the incidence of MPB in Asians is similar to that of Caucasians. This differs from previous studies that estimated the incidence of MPB to be approximately one- quarter that of Caucasians. The Asian patient has unique characteristics and demands that need to be considered when planning a hair transplant (27). The forehead of Asians tends to have less frontal projection than Caucasians and therefore appears wider and rounder. Asians prefer a rounder hairline than Caucasians and this has

(A)(B)

FIGURE 16 Traction alopecia. Surgical correction via hair transplantation offers a successful treatment option for patients with permanent forms of hair loss. (A) Before, (B) after. McMichael PTR 01/21/08 Chapter 13

Hair Transplantation 195 to be taken into considerations during the consultation when evaluating the realistic expectation of the patient. Donor density in Asians is usually lower than that of Caucasians with a higher percentage of smaller 1–2 hair FUs as apposed to 3–4 hair FUs. In addition, there is typically a high color contrast between black hair and light skin in Asians. Both these factors make it more diffi cult to create an illusion of density in Asians. On the other hand, the hair-shaft diameter in Asians men is usually signifi cantly greater than in Caucasians, helping to create a greater illusion of density with each hair. This counter-balances the problem of low donor density and high color contrast in Asians to some extent but not to the same degree that the extreme curl and minimal color contrast counter-balances low density in patients of African decent. The combination of thick, coarse, black hair on the white skin found in Asians makes the creation of naturalness more diffi cult. It was particularly diffi cult in the past when larger mini- grafts were used. However, with the exclusive use of FU grafts in these patients, naturalness can be created. Meticulous placement of only single-hair FU grafts at the hairline is particularly important in Asians as their hair is less forgiving with respect to naturalness than fi ner, lighter, curlier hair. With Asian patients it is often necessary to go an extra step and search for and select out a special population of the fi nest single-hair grafts for use at the hairline. Another area of concern with Asians is that any scarring that occurs in the donor area will be more visible than scars in Caucasians due to the high contrast between black hair and white skin. In addition Asians are more susceptible to keloid formation and hyperpigmentation than Caucasians but to a lesser degree than patients of African descent. In spite of all these issues, hair transplantation can produce good results in properly selected Asian patients. Low density and high color contrast is compensated for by the larger caliber follicles and the use of single-unit grafts at the hairline.

REFERENCES 1. Rassman W. A Brief History of Hair. A Comprehensive Guide to Hair Restoration. New Hair Institute, 1997:11–13 2. Norwood OT. Male pattern baldness: Classifi cation and incidence. South Med J 68:1359–1365, 1975. 3. Hamilton JB. Patterned loss of hair in man: types and incidence. Ann NY Acad Sci, 53:708–28, 1951. 4. Venning VA., Dawber, RPR. Patterned androgenetic alopecia in women. J Am Acad Dermatol, 18:1- 73-7, 1988. 5. Sawaya M, Price VH. Different levels of 5α-reductase Types 1 and 2, aromatase and androgen receptor in hair follicles in women and men with androgenetic alopecia. J Invest Dermatol 1997; 109: 269–300. 6. Orentreich N. Autografts in alopecias and other selected dermatological conditions. Ann NY Acad Sci 83:463–479, 1959. 7. Orentreich N. Pathogenesis of alopecia. J Soc Cosmet Chem 11:479–499, 1960. 8. Bernstein RM, Rassman WR, Szaniawski W, Halperin A: Follicular Transplantation. International Journal of Aesthetic and Restorative Surgery 3:119–132, 1995 9. Limmer BL: Elliptical donor stereoscopically assisted micrografting as an approach to further refi nement in hair transplantation. Dermatologic Surgery 20:789–793, 1994. 10. Frechet P. Scalp Extension. In: Unger W, Shapiro R (eds) Hair Transplantation. 4th Edition. Marcel Decker, New York 2004:765–785 11. Kabaker S. Female Hairline Advancement Flap . International Society of Hair Restoration Surgery Annual Meeting Sept 2006 San Diego 12. Whiting DA, Jacobson C. Treatment of female androgenetic alopecia with monoxide 2%. Int. J Dermatol 31:800–804, 1992. 13. Olsen E, et al, A randomized clinical trial of 5% topical minoxidil vs. 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men, Am Acad Dermatol, Sept. 14. Whiting DA. Advances in the treatment of male androgenetic alopecia. A brief review of fi nasteride studies. Eur J Dermatol 2001; 11:332–334. 15. Whiting DA, Waldstreicher J, Sanchez M, Kaufman KD, Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: Results of fi nasteride 1 mg treatment of men and post menopausal women. J Invest Dermatol Symposium Proceedings 1999;4:282–283. 16. Ludwig E. Classifi cation of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 97:247–54, 1977. 17. Unger R, Transplanting in women. Unger W, Shapiro R (eds) Hair Transplantation. 4th Edition. Marcel Decker, New York 2004:516–524. 18. Epstein J. Eyebrow Transplantation Hair Transplant Forum 2006; Volume 16, Number 4:121–123. McMichael PTR 01/21/08 Chapter 13

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19. ISHRS Website reference for eyelash at ISHRS.ORG. 20. Shapiro R, Rose P. Transplanting into scar tissue and other areas of cictircial alopecia. Unger W, Shapiro R (ed) Hair Transplantation 4th edition. Marcel Decker, NY 2004:606–609. 21. Meyer M. Hair restoration in patients of African descent. Unger W. Shapiro R (ed) Hair Transplantation 4th edition. Marcel Decker, NY 2004:595–602. 22. Cooley J. Hair Transplantation in Blacks, Haber B, Stough D, (ed), Priocedures in cosmetic surgery series, Hair Transplantation, Elsevier Saunders, 143–147. 23. Callender VD. Hair transplantation for pigmented skins. In: Halder RM. Dermatology and Dermatological Therapy of Pigmented Skins. Boca Raton, FL: Taylor & Francis 2006:245–257. 24. Bernstein RM, Rassman WR. The aesthetics of follicular transplantation. Dermatol Surg 1997;23(9):785–799. 25. Sperling LC. Hair density in African-Americans. Arch Dermatol 1999;135:656–658. 26. Brown MD, Johnson T, Swanson NA. Extensive keloids following hair transplantation. J Dermatol Surg Oncol 1990;16:867–869. 27. Demkerng Pathomavanich, Hair Transplantation in Asians, Haber B, Stough D, (ed), Procedures in Cosmetic Surgery Series, Hair Transplantation, Elsevier Saunders, 149–152. McMichael PTR 01/21/08 Chapter 14

14 Alternative Treatments for Hair Loss

Christine Jaworsky Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, U.S.A.

INTRODUCTION Alopecia is the clinical manifestation of many diverse causes. This chapter does not address the various etiologies of alopecia nor its varied clinical morphologies. It addresses alternative treatments for alopecia since many patients become frustrated with usual therapeutic regimens. This is particularly the case in patients with chronic and scarring alopecia. In patients with alopecia, in whom scarring is evident clinically or histologically, improvement becomes progressively unattainable. Even treatment of non-scarring alopecia can be problematic. Frustration often leads patients to search for therapeutic alternatives. The lay literature and Internet are replete with suggestions, advertisements, and promises that encourage and often eventually disappoint patients. It is important to be aware of possible alternative treatments and pitfalls in discussing treatments with our patients affected by alopecia. This chapter discusses herbal remedies, dietary supplements and other modalities used for alopecia. Data is scarce and does not frequently emanate from well-controlled studies. To add to the uncertainties, herbal remedies are regarded as dietary supplements. To this extent, their manufacture is not rigorously controlled as that of over-the-counter and prescription medicines. Therefore, even if an herbal remedy is useful in alopecia or other disorder, it is difﬁ cult to ascertain the potency, bioavailability and effectiveness of a given preparation on the market. Table 1 lists the agents and their methods of delivery.

HERBAL REMEDIES Saw Palmetto (Serenoa repens) The berries of Serenoa repens (Fig. 1), a dwarf palm tree that grows in the United States, contain 5α reductase inhibitors (5ARI) beta-sitosterol and liposterolic extract. The enzyme 5α reductase converts testosterone to dihydrotestosterone, which in turn can act on hair receptors to induce miniaturization in androgen-sensitive hair follicles in susceptible patients. Finasteride and its analogs, 5ARI, block this pathway and are used by prescription in the treatment of benign prostatic hypertrophy as well as androgenetic alopecia. When used in benign prostatic hypertrophy, saw palmetto only relieves the symptoms associated with prostatic enlargement without reducing the hypertrophy (1). One study of saw palmetto use is available in the literature. A placebo-controlled, double-blind pilot study using beta sitosterol and liposterol extracts of Serenoa repens showed a positive response to treatment in 10 males between the ages of 23 and 64 for androgenic alopecia (2). Although this is promising, larger similar series with standardized active agents are necessary to ascertain the degree of efﬁ cacy of saw palmetto and dosing in androgenic alopecia. In the presence of hirsuitism, one source recommends an oral dose of 200 mg two to three times per day (3). Other sources recommend 160 mg of saw palmetto berry extract twice daily (4). Standardization of the active ingredients is not available, thus the recommended doses vary signiﬁ cantly between preparations.

Pygeum (Prunus africana) Pygeum africanum (Fig. 2), an evergreen tree found in higher elevations of Africa, contains fatty acids that seem to have effects similar to those found in saw palmetto. Pygeum contains substances, which are not well elucidated, but have been reported to work synergistically to reduce and/or compete with testosterone (5). A 4% extract of Pygeum africanum at 250 mg a McMichael PTR 01/21/08 Chapter 14

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TABLE 1 Alternative Treatments for Alopecia Oral Topical Herbal remedies Saw palmetto X Pygeum X Nettle root X Ginkgo biloba X He Shou Wu X Rosemary X Prickly ash bark X Horsetail X Elderberry X Shea butter X Dietary supplements Iron, zinc, l-lysine, biotin X Pantothenic acid, B6, copper, zinc X Soy X Shampoos X Devices X Laser hair care X day is recommended by one source, although standardization of the active compounds is not universal.

Stinging Nettle Root Nettle root (Urtica dioica) (Fig. 3) (6) has been frequently combined with saw palmetto in preparations for benign hypertrophy. Although sources ascribe prevention of hair loss to this preparation, there is no evidence in the literature to substantiate this claim for nettle root alone. Its extract has been used in quantities of 200 mg orally per day and is cited as a source of phytos- terols. Any putative effect on alopecia of this herb has yet to be proven.

Figure 1 (See color insert.) Saw palmetto (Serenoa repens). McMichael PTR 01/21/08 Chapter 14

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Figure 2 Pygeum (Prunus africana).

Ginkgo Biloba Ginkgo biloba is named for its bi-lobed leaves (Fig. 4). Its leaf extract is a popular herbal remedy that is believed to improve blood ﬂ ow, particularly the microcirculation. It is used for memory deﬁ cits, problems with concentration, intermittent claudication, vertigo, and tin- nitus (7). Ginkgo may act as an antioxidant that scavenges for free radicals, similar to green tea. Some think that by improving circulation to various tissues, including that of the skin

Figure 3 Nettle root (Urtica dioica). McMichael PTR 01/21/08 Chapter 14

200 Jaworsky

Figure 4 Ginkgo biloba. and the hair follicle, will promote hair growth. The recommended dose is 120 to 160 or 240 mg of dry extract orally daily in two or three doses. It has not been documented to improve hair growth (8).

He Shou Wu (Polygonum multiﬂ orum) This herb is also known as fo-ti or Chinese knotweed (Fig. 5). It contains anthraquinones, particularly emodin (9). Taken orally, this herb acts as a laxative by irritating the lower gastrointestinal tract. Applied topically, this herb has been used traditionally to reduce hair loss and may be found in commercial preparations. There are no controlled studies evaluating this herbal remedy in alopecia.

Rosemary (Rosemarinus ofﬁ cinalis) The essential oil of rosemary leaves (Fig. 6) is an irritant and stimulates circulation to the skin. As a topical agent is has been used in the treatment of alopecia areata in one randomized double blind, controlled trial along with cedarwood, lavender, and thyme oils (see Aromatherapy below) (42). It has not been used orally in the treatment of alopecia.

Prickly Ash Bark (Zanthoxylum clava-herculis) The primary chemical constituents of prickly ash bark (Fig. 7) include essential oils, fat, sugar, gum, alkaloids, tannin, lignan, coumarins, and phenol. It has been used in the form of a lotion to stimulate the circulation, but has not been tested formally in the treatment of alopecia.

Horsetail (Equisetum arvense) A lotion made of this herb (Fig. 8) is said to be useful in the treatment of dandruff when used once daily (10). It has not been proven to be of use in alopecia. McMichael PTR 01/21/08 Chapter 14

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Figure 5 (See color insert.) He shou wu, also known as fo-ti (Polygonum multiﬂ orum).

Figure 6 (See color insert.) Rosemary (Rosemarinus ofﬁ cinalis). McMichael PTR 01/21/08 Chapter 14

202 Jaworsky

Figure 7 Prickly ash bark (Zanthoxylum clava-herculis).

Figure 8 Horsetail (Equisetum arvense). McMichael PTR 01/21/08 Chapter 14

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Figure 9 (See color insert.) Elderberry (Sambucus nigra canadensis).

Elderberry (Sambucus nigra) Elderberry (Fig. 9), a fruit-bearing deciduous shrub, has been used for various medicinal, cosmetic and culinary purposes for centuries. In Roman times it was used to dye hair. Its berries, ﬂ owers, inner bark, leaves, and roots contain a variety of substances including anthrocyanins, B vitamins, calcium, tannic acid, and vitamins A and D. The roots, stem, and leaves should be used with caution since they contain cyanogenic compounds that release cyanide and are poi- sonous. Topical poultices have been used to reduce swellings, while salves have been applied to “remove spots and freckles, and to preserve and soften the skin” (7). It has not been proven to improve hairgrowth.

Shea Butter Shea butter is a solid fatty oil made from the nut of the Karite nut trees , known as Mangifolia, that grow in the semi-arid savannah regions of Central and West Africa. It has been used in cooking, soaps, and various beauty products. It is thought to have beneﬁ cial vegetable fats that promote cell regeneration and circulation, and perhaps natural sun protectants. It has more emollient than anti-alopecic value (11).

DIETARY SUPPLEMENTS Iron There is much discussion in the literature about the relationship of serum ferritin levels and the occurrence of alopecia. Serum iron levels appear to be an inadequate refl ection of iron stores in the body. Multiple studies of patients with various alopecias examining ferritin levels are available in the literature. They indicate that mean serum ferritin levels do not differ from those of controls in alopecia totalis or alopecia universalis. One study showed that, in female patients with alopecia areata, mean serum ferritin levels were signifi cantly lower than those of controls (12). Other studies, however, have shown no signifi cant difference in the prevalence McMichael PTR 01/21/08 Chapter 14

204 Jaworsky of depleted iron stores in patients with alopecia areata in both men and women (13,14). In patients with telogen effl uvium, several authors have found improvement in patients who had low serum ferritin levels and were treated with oral iron and/or l-lysine daily (11,15,16). This improvement was noted as a reduction in the amount of hair shed as compared with controls objects. The overlap of chronic telogen effl uvium, diffuse alopecia in women, and androgenetic hairloss in women makes interpretation of data in these patients diffi cult. One prospective study of such patients showed 6% (12) of 194 patients to have serum ferritin levels lower than or equal to 20 ng/mL with normal hemoglobin levels (17). The patients with non-androgenetic alopecia showed no improvement with iron supplements, while 4 of 7 patients with androgenetic alopecia responded with reduction of shedding and increased hair volume with iron and spironolactone treatment. There is no uniform approach for screening of alopecia patients for serum iron and ferritin levels and iron supplementation. Screening seems to have less utility in male patients and in those with scarring alopecia. It may be more applicable in females with non-scarring alopecia. Studies of well defi ned types of hair loss accounting for variable factors with control groups and objective documentation will, in time, clarify this issue (18,19).

L-lysine Some lysine molecules are hydroxylated and others oxidized to aldehyde compounds in collagen. Menkes kinky hair syndrome is expressed partly because of deﬁ cits in this metabolic pathway (20). There is no literature, however, to substantiate l-lysine supplementation in alopecia.

Biotin Biotin defi ciency does not occur naturally in normal adults. It has been reported in children between the age of 10 and 21 months, who presented with alopecia, blepharitis, neurological symptoms, acidosis, and depressed immune reactions to various antigens. These infants responded rapidly to oral supplementation with biotin, which corrected multiple carboxylase defi ciencies (21,22). Biotin defi ciency may also be encountered in infants fed odd diets, such as an amino acid formula (23). Three children with uncombable hair were treated with biotin (24). One patient treated with 0.3 mg of biotin three times a day showed increased growth, strength, and combability of hair, although the triangular shape remained. The other two siblings also had ectodermal dysplasia. Their hair combability improved slowly without biotin therapy. Supplementation in adults, however, has not been documented to improve alopecia.

Pantothenic Acid Pantothenic acid, vitamin B5, is a naturally occurring vitamin found in beans, peas, meat, poultry, fi sh, and whole-grain cereal. Although pantothenic acid is necessary for normal metabolism, it has no recommended daily allowance (RDA), and no problems have been found that are caused by pantothenic acid defi ciency. Lack of pantothenic acid is exceedingly rare, and may be associated with a lack of other B vitamins, intestinal malabsorption, and severe life-threatening malnutrition. Its utility for hair growth has not been reported in the literature. Topical compounds may include panthenol (a synonym of pantothenic acid) but have not shown effi cacy. There have been reports, however, of contact urticaria and contact dermatitis from it use (25,26).

Vitamin B6 Pyridoxine, vitamin B6, is required for utilization of energy in ingested nutrients, production of red blood cells, and proper functioning of the nervous system. It is used to treat and prevent vitamin B6 deﬁ ciency resulting from poor diet, certain medications, and some medical conditions. There are no studies that indicate B6 suppplementation improves or reverses alopecia.

Copper Copper is a trace metal that has not been associated with hair growth or hair loss. There is information in the lay literature about its possible antioxidant effects in scavenging for radicals in McMichael PTR 01/21/08 Chapter 14

Alternative Treatments for Hair Loss 205 the body and possible anti-cancer effects. There are also reports that high levels of copper may be linked to liver and brain tumors. In addition, copper blood levels do not necessarily reﬂ ect tissue levels accurately. Although excess zinc ingestion may cause copper deﬁ ciency and hair loss, intake of copper is not known to induce hair growth.

Zinc Zinc defi ciency is not seen in normal healthy individuals. It may occur in acrodermatitis enteropathica, or in the setting of alcoholism, malabsorption, hemodialysis, sickle cell anemia, and parenteral nutrition. In a study of 16 patients with telogen effl uvium and 16 healthy age matched controls, there were no signifi cant differences in the two groups in their serum zinc levels (27). One study suggests that zinc levels are reduced in patients with alopecia areata, and that the ratio of copper to zinc levels may refl ect the severity of the underlying disease. These results have not been duplicated (28). A wide range of trace elements was studied in serum, erythrocytes, hair, and urine of Finnish patients with alopecia. The authors found no signifi cant differences except for copper content in serum of subtypes of patients with alopecia areata. The serum selenium content was low in a few patients, perhaps refl ecting the low selenium diet content of that population (29). It is interesting that individuals who take 30 mg or more of zinc a day can become defi - cient in copper. Copper defi ciency can, in turn, lead to hair loss. The topical application of Zinc in the form of zinc pyrithione shampoos has shown nominal improvement in androgenetic alopecia as compared with male patients treated with 5% topical minoxidil solution (30).

Soy Soy (Fig. 10) is a nutrient that supplies non-animal protein and amino acids. It also contains a host of other ingredients including the isoﬂ avones genistein, diadzein, and equol. It also contains ﬁ ber, copper, zinc, saponins, B vitamins, calcium, magnesium, iron, and omega-3 fatty acids. Soy contains phytoestrogens, which may to some extent substitute for post menopausal women’s endog- enous estrogen. It may promote “good breast and prostate health.” Its is usefulness in senile or

Figure 10 (See color insert.) Soy (Glycine max). McMichael PTR 01/21/08 Chapter 14

206 Jaworsky androgenetic alopecia is not known. Many beneﬁ cial claims of the anti-androgenic effects of soy are attributed to genistein and are based upon observation of rural Japanese. In this population there is a low rate of breast and prostate carcinoma and almost no male pattern alopecia. In the rural Japanese diet, 20–80 mg of genistein are consumed daily. For this reason, some recommend 300–500 mg of soy extract (not just protein) daily in divided doses (31). Although these observations are interesting, these claims have not yet been substantiated by controlled trials.

OTHER Shampoos Many over-the-counter shampoos claim they build body and create thickness. One such product is Nioxin® that claims to “create an optimum scalp environment” for maintenance of current hair growth and for regrowth. This product contains biotin, vitamin B coenzymes, saw palmetto, aloe, ginseng, and amino acids. Other products contain thickeners such as collagen and keratin. They can temporarily give the impression of thickened hair shafts above the level of the epidermis. They are best regarded as cosmetic agents (32).

Devices One marketed device claims to improve hairgrowth through photobiostimulation. It employs “low intensity laser light” and is to be used twice a day for 10 minutes. It has received 510K approval by the Food and Drug Administration (FDA). This approves a device as safe and comparable to one or more similar legal devices already on the market. Its effi cacy has yet to be adequately demonstrated. The HairMAX LaserComb® is advertised as using a laser diode of the red portion of the visible light spectrum at 660 nm wavelength. The mechanism of action is stated as “energizing and nourishing effects” that “make hair look healthy and vibrant” (33). The company claims that it will improve the growth of hair in 5 to 10 weeks. It is an expensive device ($395–545 USD) that has thus far received mixed reviews. Some of the positive responses are from respondents using other forms of hair loss remedies. FDA clinical trials with the device are underway (34). Of interest, there are a few reports in the literature of paradoxical hair growth after laser therapy for hair removal. In one report, hairgrowth was induced by treatment with an 810 nm diode laser intended for hair removal (35). The patient was of Fitzpatrick skin type III and was a bodybuilder. He did not disclose use of any dietary or hormonal supplements and had a “less than average response to hair laser treatment” in an adjacent site. The specifi cs of this response are not understood. One report of a pulsed infrared diode laser on 904 nm wavelength for alopecia areata in 16 patients with 34 resistant patches showed favorable results after one to two treatments (36). There is also one report of response to excimer laser therapy (308 nm xenon-chloride) in long standing alopecia areata after 17 sessions over three months (37). In the latter report, one half of the representative lesion was treated and showed regrowth while the untreated area did not. The possible usefulness of laser treatment in various alopecias is intriguing. The disparate wavelengths of laser in the above noted reports do not point to a specifi c mode of action. At the moment, this therapy is expensive and does not have a proven mechanism of action.

Mind-Altering Approaches The clinical existence of neurocutaneous pathways is routinely reaffi rmed in dermatological patients. Patients affected with eczema, psoriasis, lichen simplex chronicus, acne, and alopecia areata commonly correlate a fl are of their disorder with increased stress in their lives. This connection has been documented at the microscopic level. Egan et al showed the close association of axons with mast cells and epidermal Langerhans’ cells, supporting the theory that the peripheral nervous system plays an important role in modulating infl ammatory and immune reactions in the skin (38). It is, therefore, not surprising that modifi cation of perceived stress or the host’s reaction to the stress can potentially alter the clinical expression of dermatologic disorders. McMichael PTR 01/21/08 Chapter 14

Alternative Treatments for Hair Loss 207

Various approaches have been advocated in reduction of stress. They include biofeedback, behavior modifi cation, and relaxation techniques including muscle relaxation, aromatherapy, yoga, and guided imagery. Such techniques have been applied with success in patients with trichotillomania, where behavior modifi cation is key to resolution of the problem. Kohen reported using self-monitoring, hypnosis, and relaxation/mental imagery techniques to treat 5 patients with trichotillomania (39). Another 3 children were treated successfully with hypnotherapy. Two reported complete resolution in 8 weeks, and the third in 16 weeks (40). Hypnosis has also been used to improve alopecia areata (41). Aromatherapy can be viewed as a mind-altering intervention as well. The term aromatherapy was coined by French chemist René Maurice Gattefossé in the 1920’s to describe the practice of using essential oils taken from plants for healing. Most of the literature is composed of anecdotes and is based on folklore. Many claims made, including mental, emotional, and spiritual health, are not testable. There is, however, one double blind controlled trial that investigated the effi cacy of aromatherapy in patients with alopecia areata. Eighty-six patients were randomized into two groups. One received a mixture of essential oils [thyme, rosemary, lavender, and cedarwood (Figs 11–13)] in a mix of vehicle oils (grapeseed and jojoba oils) massaged into the scalp daily while the other received only the vehicle oils massaged daily. Nineteen of 43 patients in the treatment group responded, while only 6 of 41 in the vehicle-only group responded. Although less than half of the treatment group responded, this was deemed to be statistically signifi cant as compared with the control group (42). Many studies indicate that the perceived outcome of mind-altering treatments can signifi cantly impact on the actual outcome. They can be used to advantage in applicable settings in dermatology (43).

SUMMARY Although alternative therapies for alopecia and other ailments abound, their effi cacy in alopecia is for the most part questionable. One herb, saw palmetto, shows promise as an agent in androgenetic alopecia. Further studies need to confi rm the degree of effi cacy and standardized dosage.

Figure 11 (See color insert.) Thyme (Thymus vulgaris). McMichael PTR 01/21/08 Chapter 14

208 Jaworsky

Figure 12 Lavender (Lavandula angustifolia).

Baseline studies of hemoglobin and ferritin, especially in women with alopecia, are prudent for correction of any underlying defi cits. Systemic evaluation for underlying diseases as it pertains to clinical fi ndings is essential. Vitamins with trace metals to fulfi ll daily requirements but not in excess are prudent, in as much as dietary intake may vary considerably. The use of behavior modifi cation techniques, such as yoga, biofeedback, and relaxation techniques including aromatherapy, may have a place as an adjunct in appropriate individuals with alopecia.

Figure 13 Cedarwood (Juniperus virginiana). McMichael PTR 01/21/08 Chapter 14

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REFERENCES 1. Ishani A, MacDonald R, Nelson D, Rutks I, Wilt TJ. Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis. Amer J Med 2000; 109(8):654–664. 2. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altern Complement Med 2002; 8(2):143–152. 3. http://www.umm.edu/altmed University of Maryland Medical Center, Center for Integrative Medicine. 4. http://www.anagen.net 5. http://www.health.enotes.com/alternative-medicine-encyclopedia/hair-loss 6. Koch E. Extracts from fruits of saw palmetto (Sabal serrulata) and roots of stinging nettle (Urtica dioica): viable alternatives in the medical treatment of benign prostatic hyperplasia and associated lower urinary tracts symptoms. Planta Med 2001; 67(6):489–500. 7. http://www.uihealthcare.com 8. Blumenthal M, Busse WR, Goldberg A, et al. The complete German commission E monographes: therapeutic guide to herbal medicines. American Botanical Council, Austin, Texas 1998. 9. http://www.EDrugDigest.org 10. Treben M. Health from God’s Garden, herbal remedies and glowing health for well-being. Inner Traditions International, Rochester Vt. 1987. 11. www.sheabutter.com 12. Kantor J, Kessler LJ, Brooks DG, Cotsarelis G. Decreased serum ferritin is associated with alopecia in women. J Invest Dermatol 2003; 121(5):985–988. 13. Aydingoz I, Ferhanoglu B, Guney O. Does tissue iron status have a role in female alopecia? J Eur Acad Dermatol Venereol 1999; 13(1):65–67. 14. Boffa MJ, Wood P, Griffi ths CE. Iron status of patients with alopecia areata. Br J Dermatol 1995; 132(4):662–664. 15. Rushton DH, Ramsey ID. Nutritional factors and hair loss. Clin Exp Dermatol 2002; 27(5):396–404. 16. Rushton DH. Management if hair loss in women. Dermatol Clin 1993; 11(1):47–53. 17. Sinclair R. There is no clear association between low serum ferritin and chronic diffuse telogen hair loss. Br J Dermatol 2002; 147(5):982–984. 18. Trost LB, Bergfeld W, Calogeras E. The diagnosis and treatment of iron defi ciency and its potential relationship to hair loss, J Am Acad Dermatol 2006; 54(5):824–844 19. Olsen E. Iron defi ciency and hair loss: the jury is still out. J Am Acad Dermatol 2006; 54(5):903–905. 20. Frey J, Raby N. Lysine and collagen. Ann Biol Clin (Paris) 1991; 49(1):36–39. 21. Charles BM, Hosking G, Green A, Pollitt R, Bartlett K, Taitz LS. Biotin-responsive alopecia and developmental regression. Lancet 1979; 2(8134):118–120. 22. Williams ML, Packman S, Cowan MJ. Alopecia and periorifi cial dermatitis in biotin-responsive multiple carboxylase defi ciency. J Am Acad Dermatol 1983; 9(1):97–103. 23. Fujimoto W, Inaoki M, Fukui T, Inoue Y, Kuhara T. Biotin defi ciency in an infant fed with amino acid formula. J Dermatol 2005; 32(4):256–261. 24. Shelley WB, Shelley ED. Uncombable hair syndrome: Observations on response to biotin and occurrence in siblings with ectodermal dysplasia. J Am Acad Dermatol 1985; 13(1):97–102. 25. Schalock PC, Storrs F, Morrison L. Contact urticaria from panthenol in hair conditioner. Contact Dermatitis 2000; 43(4):223. 26. Roberts H, Williams J, Tate B. Allergic contact dermatitis to panthenol and cocamidopropyl PG dimonium chloride phosphate in a facial hydrating lotion. Contact Dermatitis 2006:55(6):369–370. 27. Arnaud J, Beani JC, Favier AE, Amblard P. Zinc status in patients with telogen effl uvium. Acta Dermato-Venererologica 1995; 75(3):248–249. 28. Tasaki M, Hanada K, Hashimoto I. Analyses of serum copper and zinc levels and copper/zinc ratios in skin disease. J Dermatol 1993; 20(1):21–24. 29. Mussalo-Rauhamaa H, Lakomaa EL, Kianto U, Lehto J. Elemental concenrtrations in serum, erythrocytes, haor and urine of alopecia patients. Acta Derm Venereol 1986; 66(2):103–109. 30. Berger RS, Fu JL, Smiles KA, et al. The effects of minoxidil, 1% pyrithione zinc and a combination of both on hair density: a randomized controlled trial. Br J Dermatol 2003:149(2):354–362. 31. www.stophairlossnow.co.uk 32. Bandaranayake I, Mirmirani P. Hair loss remedies-separating fact from fi ction. Cutis 2004; 73:107–114. 33. HairMax.com. 34. Leavitt ML. Hair loss treatments: a word of caution. Skin & Aging 2003; 11(3)80–87. 35. Bernstein EF. Hair growth induced by diode laser treatment. Dermatol Surg 2005; 31(5):584–586. 36. Waiz M, Saleh AZ, Hayani R, Jubiry SO. Use of the pulsed infrared diode laser (904 nm) in the treatment of alopecia areata. J Cosmet Laser Ther 2006; 8(1):27–30. 37. Raulin C, Gundogan C, Greve B, Gebert S. Excimer laser therapy of alopecia areata—side-by-side evaluation of a representative area. J Dtsch Dermatol Ges 2005; 3(7):524–526. McMichael PTR 01/21/08 Chapter 14

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38. Egan CL, Viglione-Schneck MJ, Walsh LJ, et al. Characterization of unmyelinated axons uniting epidermal and dermal immune cells in primate and murine skin. J Cutan Pathol 1998; 25(1):20–29. 39. Kohen DP. Hypnotherapeutic management of pediatric and adolescent trichotillomania. J Dev Behav Pediatr 1996; 17(5):328–334. 40. Cohen HA, Barzilai A, Lahat E. Hypnotherapy: an effective treatment modality for trichotillomania. Acta Paediatr 1999; 88(4):407–410. 41. Shenefelt PD. Biofeedback, cognitive behavioral methods and hypnosis in dermatology: is it all in your mind? Dermatol Ther 2003; 16(2):114–122. 42. Hay IC, Jamieson M, Ormerod AD. Randomized trial of aromatherapy. Successful treatment for alopecia areata. Arch Dermatol 1998; 134(11):1349–1352. 43. Shenefelt PD. Complementary psychocutaneous therapies in dermatology. Dermatol Clin 2005; 23(4):723–734. McMichael PTR 01/21/08 Chapter 15

15 Hirsutism and Hypertrichosis

Katherine R. Kerchner Department of Dermatology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, U.S.A. Amy J. McMichael Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

INTRODUCTION Throughout time, hair has served as a mark of beauty for both sexes. It is not until our perception of what is thought to be normal hair growth is altered by the appearance of unwanted excess facial or body hair, or the loss of much desired scalp hair, that we realize how much our appearance is reliant on hair. The existence, lack of, and distribution of hair continues to impact us socially, and can have many psychological implications (1). Moreover, maldistribution of hair can be a signal of several medical conditions that, if left unrecognized, could cause signiﬁ - cant harm to the patient (2).

HIRSUTISM Hirsutism is deﬁ ned as an excessive growth of coarse, terminal hairs in women, presenting in a characteristic male pattern (see Fig. 1) (2). This pattern of growth is in response to androgens exerting their effect at the level of the hair follicle. This is either caused by an increase in the actual amount of androgens being produced, excess androgens being circulated, or by an increase in the sensitivity of the androgen receptors at the hair follicle. Additionally, enhanced activity of 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone, which is the active form of the androgen, also leads to a hirsute state (3,4). Virilization refers to the presentation of hirsutism in addition to the wide variety of signs and symptoms associated with androgen excess such as acne, balding at the frontotemporal hairline, deepening of the voice, reduction in breast size, enlargement of the clitoris, increase in muscle mass, and amenorrhea or oligomenorrhea. Virilization can be the presenting sign of androgen-producing tumors or enzyme abnormalities, so it is essential to reﬂ ect on the various causes of hirsutism as a potential early sign of virilization (4,5).

Epidemiology Assessing the prevalence of hirsutism in the general population is diffi cult because of the subjective nature of the excessive hair growth. Opinions on what is considered excessive hair growth is determined by many factors, such as the extent of hair growth in surrounding friends and relatives, as well as racial and ethnic factors (4). Genetic factors determine not only hair growth characteristics within a racial group, but also of particular families within those racial groups (6). To incorporate some objectivity into the measurement of hirsutism, an objective assessment scale should be used. Many scales have been used, but the most commonly used is the modifi ed Ferriman-Gallwey Scoring System for hirsutism (see Fig. 2) (7). There are nine total body areas that are examined (lip, chin, chest, upper and lower back, upper and lower abdomen, upper arm, and thigh) and assigned a score from 0 (no hair) to 4 (frankly virile), and these are totaled to give a fi nal hormonal hirsutism score. A mild score is a total of 8–15, a moderate- severe Ferriman-Gallwey score is a total of more than 15. A cutoff of 8 is used to defi ne what is considered to be abnormally excessive body hair, which correlates with the 95th percentile in Ferriman and Gallwey’s original data. However, Ferriman himself later chose a value of 5 McMichael PTR 01/21/08 Chapter 15

212 Kerchner and McMichael

FIGURE 1 (See color insert.) Hirsutism: A female with increased terminal hair growth in a male distribution on the face. when defi ning hirsutism, while others have determined that a value of 3 or greater should be considered hirsute (see Fig. 2) (2,7,8). Housman, Feldman, McMichael, et al, incorporated a modifi ed Ferriman-Gallwey scale, an objective self-assessment tool used in measuring the presence and extent of excessive body hair. This self-assessment tool can be used by patients before seeing a physician to determine if there is a need for the evaluation of hirsutism. Alternatively, this self-assessment tool can be used by physicians to determine whether their patients have a realistic view of what they are describing as excessive body hair (9). The prevalence of hirsutism is anywhere from 2–8% of the U.S. population, depending on the chosen cutoff Ferriman-Gallwey score (10). A recent study of 633 women found that the prevalence and degree of facial and body terminal hair growth is similar in African American and Caucasian individuals (8). It is well known that East Asian, North Asian, and Southeast Asian (the so-called Mongoloid populations) have a greater paucity of hairs, as well as hirsutism, than do Caucasoids, or those of West Asian, or Middle Eastern descent (6). It is common knowledge that those of Hispanic origin also face diffi culties with hirsutism, though there is no published literature on prevalence in this population. The face and the lower abdomen are the most frequently affected areas in hirsute women (11). A study comparing U.S., Italian, and Japanese women with hyperandrogenic chronic anovulation found that, despite similar levels of LH and serum androgens, Japanese women were not hirsute. The premise behind this is that hirsutism in polycystic ovarian syndrome (PCOS) is secondary to skin 5α-reductase activity. Serum 3α-androstanediol glucuronide is a marker of skin 5α-reductase activity, and this was also much lower in Japanese women, as compared to Italian and North American women in this study (12). Unfortunately, serum levels of 3α-androstanediol glucuronide only have a role in the research setting because of the wide variations in the clinical assays used to measure it (4).

Etiology The underlying causes of hirsutism vary amongst different populations. Androgen-dependent hirsutism results in terminal hair growth, but only in areas of the body that necessitate the presence of androgens for hair growth. These areas include the face, neck, chest, abdomen, axillae, upper arms, inner thighs, and pubic regions. Some areas of the body, e.g., the scalp, eyebrows, and eyelashes, do not require androgens to produce terminal hairs, whereas others (the forearms, hands, and lower legs), are just simply less inﬂ uenced by androgen mechanisms (4,5). Until puberty, androgen-dependent hair is vellus, which is small, relatively straight, and lightly pigmented. Then, with puberty, the vellus hairs that are sensitive to androgens, become larger, curlier, and darkly pigmented. Androgen production commences around 8 years of age, which corresponds with adrenarche. Adrenarche is the moment in time in which the adrenal cortex begins to produce large amounts of adrenocortical hormones, notably, androgens. From McMichael PTR 01/21/08 Chapter 15

Hirsutism and Hypertrichosis 213 Source: From Ref. 2, with permission. Source: FIGURE 2 from 0 (no hair) to 4 The Ferriman-Gallwey scoring system for hirsutism. Each of the nine body areas most sensitive to androgen is assigned a score, (frankly virile), and these are summed to provide a hormonal hirsutism score. McMichael PTR 01/21/08 Chapter 15

214 Kerchner and McMichael

5α- REDUCTASE VELLUS HAIR

TESTOSTERONE DHT

TERMINAL HAIR

FIGURE 3 Conversion of testosterone to dihydrotestosterone (DHT) at the hair follicle. Source: From Refs. 4 and 5. adrenarche, and throughout adolescence, there is a gradual increase in androgen production that then begins to wane after the age of thirty (2,5). The role of androgens at the hair follicle is played out by the steroid hormones, testosterone and dihydrotestosterone (DHT). Free testosterone is the main form of testosterone that is active in the body. It must be converted locally, at the hair follicle, to DHT by the enzyme 5α-reductase, in order to be active at the hair follicle and induce terminal hair growth (Fig. 3). The sensitivity of the hair follicle to DHT is controlled by the levels of 5α-reductase in the skin. Thus, women with similar androgen proﬁ les may actually have completely different clinical presentations in the amount of hair, as well as the distribution of hair. This is important to remember, because those with normal androgen levels may be hirsute, and conversely, those with high androgen levels may not have hirsutism or other signs of virilization because of the differences in sensitivity of hair follicles to androgens among women (4,5).

Excess Androgen Production and Circulating Androgen Levels Hyperandrogenism is most often caused by PCOS (2). In 2003, an international consensus conference was held, and diagnostic criteria were established stating that the diagnosis of PCOS is made if two out of the following three criteria are met: (i) chronic oligoovulation or anovulation after excluding secondary causes; (ii) clinical or biochemical evidence of hyperandrogenism (but not hirsutism due to hair follicle sensitivity variation amongst patients); (iii) radiological evidence of polycystic ovaries. Clinical presentation is generally one of hirsutism, menstrual irregularities, or infertility (13,14). Other fi ndings often associated with PCOS that should trigger a clinician’s suspicion include obesity, the metabolic syndrome, early-onset female pattern alopecia, or insulin resistance. One should look for evidence of acanthosis nigricans, or ask about a family history of type 2 diabetes mellitus (2). Other causes of excess androgen production are uncommon. There are three major genetic enzyme defi ciencies which lead to excess androgen production. These include (i) 21α-hydroxylase defi ciency, (ii) 11β-hydroxylase defi ciency, and (iii) 3β-ol-dehydrogenase defi ciency. The classic forms often present in the neonatal period with ambiguous genitalia, and the non-classic forms often present with hirsutism. Androgen-secreting tumors (e.g., ovarian neoplasms) are rarely found, but can be a cause, and thus, one must remain thoughtful of this possibility. Cushing’s syndrome and disease, hyperprolactinemia, acromegaly, and thyroid dysfunction are also rare causes of hirsutism (2,4). It should also be noted that a small portion (approximately 3%) of testosterone circulates freely in the circulation. The remainder of the testosterone is bound to sex hormone-binding globulin (SHBG). Any factor (e.g., medications, anorexia nervosa, malnutrition, pregnancy) that impacts the levels of SHBG can alter the amount of free testosterone and can produce excess circulating androgens and ultimately hirsutism (2,4). In a study of 588 hirsute women, 6% (36 women) were found to have idiopathic hirsutism (15). Idiopathic hirsutism is defi ned as hirsute women who have normal ovulatory function and normal circulating androgen levels (16). See Table 1 for a list of the top causes of hirsutism and their approximate frequency.

Increased Sensitivity of the Hair Follicle to Androgens There are two types of 5α-reductase, type 1 and type 2. Recent studies have also suggested that the type 1 5α-reductase is implicated in the development of hirsutism (17). Also, gene mutations McMichael PTR 01/21/08 Chapter 15

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TABLE 1 Causes of Hirsutism and Their Approximate Frequency in Adult Hirsute Women Adrenal Congenital adrenal hyperplasia 1% 21-hydroxylase defi ciency (non-classic) <1% 11-hydroxlase defi ciency <1% 3β-hydroxysteroid dehydrogenase defi ciency <1% Cushing’s syndrome <1% Androgen-secreting adrenal tumors <1% Ovarian Severe insulin resistance 1% Androgen-secreting adrenal ovarian neoplasms <1% Combined adrenal and ovarian 95% Polycystic ovarian syndrome Idiopathic hirsutism (includes increased skin sensitivity to androgens) Exogenous androgens Anabolic steroids <1% Postmenopausal androgen therapy 1% Source: From Ref. 5, with permission.

in the polymorphic region of the androgen receptor could be responsible for increased sensitivity to androgens (4). There are studies that suggest that the qualitative differences in receptor function are secondary to changes in receptor size because of the variation in the number of trinucleotide repeats causing a change in the number of polyglutamine residues. This could result in altered receptor size and function, and could theoretically produce phenotypic variations, thus producing hirsutism (18).

Evaluation History A systematic approach to the diagnosis is important, and starts with a good history. Obtain- ing information about the onset of the hirsutism, how rapidly or chronically it progressed, the areas of increased hair identifi ed by the patient, familial patterns of hair growth, and prior treatments tried by the patient are all essential. Additionally, asking about a patient’s menstrual history and regularity may also prove benefi cial. A detailed medication history should also be obtained, particularly the use of any androgenic medications (e.g., anabolic and androgenic steroids). The fi rst priority is to rule out serious underlying disorders. Whenever there is rapid onset of hirsutism or virilization, an androgen-secreting tumor must be suspected. The chronic development of hirsutism is characteristic of a benign disorder, though some tumors can only produce moderate levels of androgens thus having milder presentations. Asking questions per- taining to personal and family history of obesity, insulin resistance, diabetes, and the metabolic syndrome may be helpful (2,4,5).

Physical Examination The physical examination should be directed at identifying the location and the amount of excess terminal hair. Additionally, virilizing features should be sought out such as androgenetic alopecia, acne, deepening of the voice, clitoral enlargement (visualization of the external genitalia will suffi ce; there is no need for a full pelvic examination), reduction in breast size, and enlarged muscle mass. Acanthosis nigricans is often associated with hyperinsulinemia and is not a sign of hyperandrogenism. However, hyperinsulinemia, as well as obesity, can be associated with polycystic ovarian syndrome, and may provide further direction in your evaluation (4,5). Signs of Cushing’s syndrome include central obesity, a buffalo hump, striae, and acanthosis nigricans. Lastly, using a scoring system is the only objective quantifi cation method for hirsutism. The modifi ed Ferriman-Gallwey tool is easy to use at baseline, and can then be compared at further visits to follow improvement or progression in the patient’s hirsutism (see Fig. 2). Additionally, the patient may use a customized form of this tool as described above in McMichael PTR 01/21/08 Chapter 15

216 Kerchner and McMichael order to assess the patient’s perception of clinical progress or use sequential photographs to monitor progress (3,4,7,9).

Laboratory Evaluation It is easy to order a battery of laboratory tests, so as to not overlook a serious disorder. Alter- natively, for some, just having clinical evidence of an ovulatory disorder is enough to warrant treatment initiation. The best tactic is probably somewhere in the middle. Following an approach that identifi es serious disorders, and provides important information is a good starting point. Our initial recommendations for laboratory evaluation are to obtain a free and total serum testosterone level, as well as a serum dehydroepiandrosterone sulfate (DHEAS) level as a cost effective way to fi nd the most common underlying problems. There is debate in the literature as to whether timing in the ovulatory cycle is important for interpretation of laboratry results. The ovary is the major source of testosterone, and DHEAS is almost entirely produced by the adrenal glands. Testosterone levels above 200 ng/dL, and DHEAS levels above 260 ug/dL, should raise concern for an ovarian or adrenal tumor, respectively. If a patient is not postmenopausal, and is anovulatory, a pregnancy test may be warranted. Additional testing may include a pelvic ultrasound (for evaluation of ovaries), or adrenal imaging techniques such as CT or MRI (2–5). Based on the patient’s history, or on fi ndings listed above, further workup for secondary causes of hirsutism may include a workup for thyroid dysfunction, a serum prolactin level, follicle-stimulating hormone (FSH) concentration, luteinizing hormone (LH), androstenedione level, or a fasting morning serum 17-hydroxyprogesterone level. Patients with PCOS will reveal a decrease in FSH, with a concomitant increase in LH, testosterone, androstenedione, and DHEAS. An elevated 17-hydroxyprogesterone level often occurs with congenital adrenal hyperplasia, most commonly 21-hydroxylase defi ciency. If Cushing’s syndrome is suspected, a dexamethasone-suppression test may help determine the source of androgen, by giving patients dexamethasone and measuring morning cortisol levels (2,4,5).

Management The fi rst goal in management is to identify and treat the underlying cause. Only when no cause can be identifi ed, e.g., the patient has normal ovulatory function, and normal androgen secretion, can we use the term the idiopathic hirsutism. It is, in fact, a diagnosis of exclusion (16). Obtaining optimal weight control can assist in the control of hirsutism since obesity is often linked with anovulation, insulin resistance, and higher levels of circulating androgens (4). Hir- sutism can be controlled with cosmetic and medical therapies. See Table 2 for a simplifi ed list of these methods. In some instances, a more permanent reduction in the amount of hirsutism can be maintained through physical measures (2). Typically, a combination of these methods is used to both prevent further hair growth (long-term goal), and cosmetically improve the appearance of the patient (immediate target).

TABLE 2 Mechanisms of Hair Removal Epilations Tweezing Waxing Sugaring Threading Depilation Chemical Hair removal gloves or stones Bleaching Electrolysis Laser hair removal Eﬂ ornithine cream Ovarian suppression Adrenal suppression Androgen blockade McMichael PTR 01/21/08 Chapter 15

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Physical/Cosmetic Treatments Hirsutism occurs as a prolongation of the anagen growth phase of the hair follicle (19). When a hair follicle is adequately injured, the hair follicle is unable to regenerate, and thus no new hair will regrow. This is the goal of permanent hair reduction methods such as electrolysis, thermolysis, and with multiple treatments, possibly LASER hair removal. Other techniques of hair removal are depilation and epilation. Depilation is defi ned as the removal of a portion of a hair, thus leaving the hair follicle intact. Examples of depilatories are depilatory creams and shaving (20). Depilatory creams can be irritating to the skin, leading to post-infl ammatory changes. Epi- lation is defi ned as the removal of the entire hair shaft, though the hair follicle remains intact, and thus new hair is capable of regrowing. Techniques of epilation include plucking or tweezing, and waxing (20). Such epilation has no effect on the duration of anagen, but does cause a shortening of telogen so that new hairs may regrow more quickly (21).

Bleaching Mild hirsutism can be treated with bleaching. This does not cause any injury to the hair follicle or hair shaft, but simply removes the pigment from the hair, resulting in hair lightening, so that the hair is not as noticeable to the eye. A variety of hair bleaches are available to the consumer: neutral oil bleaches, color oil bleaches, cream bleaches, and powder bleaches. Typically the bleaching agent is applied with a brush, swab or bottle. The active ingredient in hair bleaches is hydrogen peroxide. The preferred strength in a bleaching solution is 6%. The addition of a persulfate to boost the bleaching action of the hydrogen peroxide has resulted in generalized urticaria, asthma, syncope, and shock (20).

Cutting or Shaving This is one of the most long-standing and popular techniques in hair removal. It is fast, easy, and inexpensive. Studies have found that shaving/clipping of hair does not increase the rate of hair growth, though some do feel that the stubble present after shaving may be subjectively coarser. Thus, because of the after-effects such as stubble, razor bumps, cuts, and skin irritation, shaving is not always a well-liked method of hair removal by many women, particularly with facial hirsutism (20,22,23).

Hair-Removing Gloves/Pumice Stones This method is not well-liked by women in the United States. However, it has been used to reduce the excess hair and stubble associated with hirsutism. A glove made of ﬁ ne sanding paper is rubbed over the excess hair in a circular motion. Alternatively, a ﬁ ne pumice stone could be used. This can, of course, cause skin irritation if used too forcefully (20).

Plucking/Waxing/Sugaring/Threading All of these methods can be quite uncomfortable and, for this reason alone, may not be the best choice. Plucking (tweezing) is generally reserved for small areas of excess hair since it is a more tedious and time-consuming method of hair removal. Many are able to do this without consequences, but some contract inﬂ ammation, hyperpigmentation, scarring, ingrown hairs, and distorted follicles. Waxing is executed by application of a melted reusable solid wax or cold semisolid wax to the area of skin with excess hair. Once the wax hardens, it has the hair shaft embedded within the wax, and it is quickly peeled off of the skin, sometimes with an absorbent cloth or reinforced paper, taking the embedded unwanted hair shafts with it. Not only is this method uncomfortable, but it can also cause signiﬁ cant irritation or folliculitis, as well as potential allergic contact dermatitis and thermal burns (20,23). There have been case reports of erosions after waxing in areas previously treated with topical tretinoin, or in patients being treated with oral isotretinoin. Caution should be used not only with oral isotretinoin and topical tretinoin, but also with other chemicals that possess irritancy potential such as glycolic acid products (24,25). The method of sugaring removes unwanted hair in a similar manner as waxing. The mixture, instead of wax, is made of sugar, honey, and lemon, which is quite sticky and thus traps the unwanted hair as the paste hardens. Threading is a technique of hair removal using a wound-up piece of sewing thread. The hairs are plucked out by the scissoring action of a twisted thread, rather than wax or tweezers (23). McMichael PTR 01/21/08 Chapter 15

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Chemical Depilatories Chemical depilatory agents are composed of mercapten thioglycolic acid mixed with alkali. These agents work by dissolving the structure of the hair via the breaking down and hydrolyz- ing of disulﬁ de bonds (20,23). The hair shaft contains more disulﬁ de-containing amino acid cysteine than the keratin found in the epidermis, thus the chemical depilatory agents preferentially affect the hair shaft more than the surrounding skin. The chemical depilatory agent is applied to the area of unwanted hair as a paste, lotion, or cream, and is then removed after a certain time period. The hair becomes soft and broken-down, and is easily wiped away. The results are typically more long-lasting because the agent often penetrates into the hair follicle beneath the skin, therefore removing some of that portion of the hair shaft as well (23). It is often good to follow this treatment with a good moisturizer or topical corticosteroid in order to prevent an irritant dermatitis after the use of these agents (20). Additionally, a contact dermatitis can occur due to the fragrance or to the thioglycolate contained in the product

Galvanic electrolysis, Thermolysis, and the Blend Method Galvanic electrolysis, thermolysis, and the Blend Method are three permanent methods of excess hair removal, collectively referred to as electrolysis. Galvanic electrolysis uses galvanic current to destroy the hair follicles electrochemically. An electrolysis needle is inserted into a hair follicle, direct current is applied, and sodium hydroxide is formed from sodium chloride and water already in the hair follicles. The sodium hydroxide obliterates the surrounding tissue of the hair follicle, but preferentially spares the infundibulum because there is less salt and water in this region, and because the sebum in the infundibulum acts as an insulator from the current. Following follicular destruction, the electrologist removes the hair with forceps. This is repeated in many follicles in one treatment, but it takes more than one full minute to destroy a single hair follicle. Thermolysis uses high-frequency alternating current to produce heat within the electrolysis needle, which is directly passed to the surrounding follicular tissues. This technique is quicker than electrolysis, only a few seconds per hair follicle, but has the disadvantage of potential scarring since the infundibulum is not protected. The Blend Method combines both galvanic and high-frequency currents through a single electrolysis needle. This method is performed as quickly as thermolysis, but is not as painful as electrolysis. Most consider this to be the preferred method of electrolysis. Side effects include edema and erythema and postinﬂ ammatory hyper- and hypopigmentation in patients of darker skin types. Scarring typically does not occur if it is performed correctly and the current is not too high (23).

Laser Hair Removal There have not been any good long-term studies looking at the permanence of laser-assisted hair removal. A recent review of 11 randomized controlled trials looked at unwanted hair removal by laser systems and intense pulsed light (IPL) sources. It found an approximate 50% in hair reduction 6 months after treatment with alexandrite and diode lasers. Little evidence was found showing an effect with IPL, neodymium:YAG (Nd:YAG) or ruby lasers. However, none of the 11 trials were of high methodological quality, and the results may not show the true effi cacy of these devices. There are many non-randomized trials with longer follow-up times, which showed that all of the above lasers were effective at maintaining signifi cant hair reductions, though multiple treatments are necessary. Many of lasers have acquired Food and Drug Administration (FDA) approval to claim that they are able to provide “permanent hair reduction.” Permanent hair reduction is defi ned as prolonged, stable reduction in hair growth after a treatment regimen, which typically consists of numerous sessions (26). It is thought that lasers are effective at removing 50–90% of hairs. It is an expensive treatment and, though the safety profi le is encouraging, pigmentary changes and other undesirable effects can occur (27). A recent review found that pigmentary changes were often seen in association with shorter wavelengths and often occur in darker skin types. Also, it found that the Nd:YAG showed a lower incidence of these pigmentary changes, particularly in darker skin types (28). All of the hair removal lasers and IPL sources function with the same concept which is based on the theory of selective photothermolysis. With this theory, selected structures in the skin are targeted for destruction without damaging the surrounding skin structures. With hair McMichael PTR 01/21/08 Chapter 15

Hirsutism and Hypertrichosis 219 reduction as the goal, the selected target is the melanin pigment within the hair follicles, thus causing thermal damage to the hair follicle, preventing future hair growth within that follicle (26). Individuals with lower Fitzpatrick skin types are the best candidates for laser hair removal because they can use lower energy pulses than women of darker skin. Laser can still be used in women with darker skin, but built-in cooling devices and adjustment of energy levels are required to minimize the risk of dermatologic side effects (2).

Efl ornithine cream Efl ornithine cream was recently approved for the treatment of facial hair. It was found to signifi cantly reduce the amount of facial hair in a randomized, double blinded vehicle-controlled trial (29). The mechanism of action of efl ornithine is that it is an irreversible inhibitor of ornithine decarboxylase, which is a rate-limiting enzyme in the synthesis of polyamines, which are needed in order for the hair follicle matrix cells to proliferate, and hence have hair growth. A noticeable difference in hair growth is typically found after 4–8 weeks of twice a day treatment. The adverse effects thus far have been mild, including transient burning, stinging, or tingling at the site of application (29). A recent study showed that the combination of efl ornithine cream is not only safe to combine with laser hair removal treatments, but it also promotes a more rapid hair removal when combined with laser treatment (28,29).

Systemic Therapies The primary mechanisms behind systemic therapies are to suppress adrenal and ovarian androgen production, or to block the action of androgens at the skin level. Anti-androgens are the most effective; however, if the testosterone level is elevated (as it often is in PCOS), adding in an oral contraceptive pill (OCP) is often helpful. The goal of blocking the effect of androgens is to convert the excess terminal hairs back to those of the vellus or intermediate type (2,5,30–32). It typically takes approximately 6–12 months in order to see a successful effect from systemic therapies. Additionally, if systemic therapies are discontinued, previous symptoms typically recur (3,30,32).

Ovarian Suppression Ovarian suppression is best achieved with oral contraceptives. OCPs suppress the levels of free testosterone, and raise the levels of SHBG. Any combination OCP can be used, but those with nonandrogenic progestins (e.g., Yasmin, Ortho-Cyclen) are considered, by some, to be the best because of their potentially positive effects on lipids, acne, and hirsutism (32,33). Some think that OCPs can reduce the need for shaving by half. Since a major side effect of anti-androgen therapy is irregular menstruation, OCPs can be helpful in regulating menses if combined with anti-androgens. Potential side effects of OCPs include: irregular vaginal bleeding and venous thromboses, thus risks and benefi ts should be weighed in each individual patient. Consulting a gynecologist for their opinion, or for OCP management, is a reasonable step (2,5). Other than OCPs, systemic therapies for ovarian suppression can include cyproterone acetate, a progestin and antiandrogen, which is not currently available in the U.S., or gonadotropin-releasing hormone (GnRH) analogues. Cyproterone is used in low doses as a combination in agent in OCPs, or in a higher dose with simultaneous estrogen therapy or OCP. Adverse effects include weight gain, edema, decreased libido, nausea, male pseudohermaphroditism in a fetus, and hepatitis (2,5,32). GnRH analogues work via suppressing LH and FSH, and thus ovarian steroid secretion. GnRH analogues are very expensive, and because they suppress estrogen as well, estrogen replacement therapy is needed to prevent osteoporosis and other effects. A study found that the combination of GnRH and low dose oral contraceptive therapy was more effective than either agent alone in the treatment of hirsutism. Additionally, the low dose oral contraceptive therapy provided replacement of the estrogen that would have been suppressed on GnRH therapy alone (34). Another study compared the combination treatment of ethinyloestradiol and cyproterone acetate (EO-CA) cyclically, with the GnRH analogue gose- relin, for 6 months in women with PCOS and hirsutism. The study found that the group treated with EO-CA had a signifi cant reduction in hirsutism, where the GnRH-treated group had no signifi cant reduction in hirsutism. However, the group treated with GnRH showed improved insulin sensitivity, whereas the EO-CA group did not (35). Because of the expense, however, the McMichael PTR 01/21/08 Chapter 15

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GnRH therapies should be reserved for select cases. Cyproterone acetate is available in Canada, Mexico, and Europe (2,32).

Adrenal Suppression In patients with increased adrenal androgens, such as in congenital adrenal hyperplasia, it is often helpful to use glucocorticoids such as dexamethasone or prednisone (2,3,5,32). Cyproter- one acetate has weak glucocorticoids properties. Other causes of increased adrenal androgens include PCOS, Cushing’s syndrome, and adrenal tumors. These, however, are not best managed with glucocorticoids (32). The addition of dexamethasone, either alone or in combination with spironolactone, may be useful to prolong the duration of remission of hirsutism in women with hyperandrogenism who are treated with antiandrogens. The adverse effects of glucocorticoids are well known and must be considered when used for this indication (36).

Antiandrogens In addition to progestin and anti-adrenal properties, cyproterone acetate has anti-androgen properties through competitive inhibition of androgen-receptor binding. Again, in women who possess a uterus, combination therapy with estrogen must be used. Spironolactone, which was originally used as a potassium-sparing diuretic, was found to have antiandrogen properties via competitive binding of the androgen receptor, suppression of adrenal androgen biosynthesis, and increased clearance of testosterone with increased conversion of androgen to estrogen. It is the gold standard against which all other anti-androgens are compared. Side effects associated with spironolactone include irregular menses (unless simultaneous use of an OCP is employed), hyperkalemia (especially in renal insuffi ciency or in patients with increased serum potassium on other medications), hypotension, nausea, decreased libido, liver dysfunction, and male pseudohermaphroditism. It is typically used in combination with an OCP in dosage ranges from 50–200 mg per day in two divided doses (2,4,5). A Cochrane review found that spironolactone 100 mg per day was superior to placebo, fi nasteride 5 mg per day, and cyclic cyproterone acetate (12.5 mg) up to 1 year after the conclusion of treatment (37). Flutamide is a highly specifi c and potent pure antiandrogen that was originally used in the treatment of prostatic carcinoma. The drug’s actions are mediated via nonsteroidal competitive inhibition of androgen-receptor binding and by decreasing adrenal androgen production. It does not have glucocorticoid, progestin, androgenic, or estrogenic activity. Adverse effects include nausea, gastralgia, dry skin, fatigue, breast tenderness, male pseudohermaphroditism in a fetus, and hepatotoxicity. Close liver function monitoring is required, and patient’s are typically simultaneously on OCP’s. Dosages typically range from 125–250 mg twice per day, and it can be quite costly in some countries (2,3,38–40). Studies have suggested that fl utamide is superior to spironolactone in the effi cacy of the treatment of hirsutism (40,41). There have been other studies, at lower doses of fl utamide and spironolactone than are often used, that show that fl utamide, spironolactone, and fi nasteride are similar in effi cacy at 6 months (42).

Other Therapies Finasteride inhibits 5α-reductase directly at the hair follicle. It is without serious side effects in women who are not pregnant, so it is only used in women who are using a reliable method of birth control, or who are not of child-bearing potential. There is a lack of long-term data in terms of adverse effects in women treated with this medication. Thus far, the results are mixed on whether fi nasteride is as effective as the other antiandrogens. It seems that the disparate results may be secondary to differences in hirsute women or differences in the methods of measuring hair growth (32,42–44). Future studies may show that the combination of fi nasteride with other antiandrogens, specifi cally spironolactone, to be more effective that either agent alone, in the management of hirsutism (32,45). Ketoconazole inhibits several enzymes in the androgen production pathway. Typically, dosing is started at 400 mg per day and titrated up to 1200 mg per day. Unfortunately, side effects are severe including alopecia, dry skin, abdominal pain, nausea, fatigue, headache, vaginal spotting, and hepatotoxicity. Ketoconazole is contraindicated in pregnancy and, because of the associated severe side effects and risks, it is typically not used in the treatment of hirsutism. However, it can be reserved for those that do not respond to any other option (3). McMichael PTR 01/21/08 Chapter 15

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In addition to OCP’s, PCOS is often treated with insulin sensitizers, such as metformin, which promote ovulation (and hence more regular menstrual cycles) and decrease the level of androgens by approximately 20%. Unfortunately, hirsutism is not usually improved with these agents (2,46).

HYPERTRICHOSIS Hypertrichosis is the growth of hair that is considered excessive for the age, sex, or ethnicity of an individual on any area of the body. There are two methods of classifying hypertrichosis: the distribution of the hair on the body (generalized or localized/regional), and the cause of the hypertrichosis (congenital or acquired). The hair in hypertrichosis is longer than is typically seen for that portion of the body, and can be vellus-like or terminal-like, depending on the cause (see Fig. 4). Hypertrichosis can be a severe cosmetic alteration, but it may also signify an underlying systemic disease. It is important to be familiar with the various causes of hypertrichosis, as well as how to manage this entity (47,48).

Etiology There are two primary mechanisms that encompass hypertrichotic hair growth. Unfortunately, the triggers of these mechanisms are still largely not understood, so we continue to classify hypertrichosis based on clinical presentation, rather than on actual pathophysiology (47). The fi rst mechanism involved in hypertrichosis is that there is a switch from vellus to terminal hair growth in regions of the body that do not typically possess terminal hair. This is similar to hirsutism, which is excess hair growth in females caused by hyperandrogenism in a male-pattern distribution. In hypertrichosis, the switch of vellus hair to terminal hair can occur in either sex and in any area of the body that does not typically have terminal hair, not necessarily in a male-pattern distribution (47). A common theory behind this switch from vellus to terminal hair is that androgens may infl uence a fi broblast transfer that leads to an increase in the volume of the papillary dermis. This increase in volume theoretically leads to a marked increase in follicle size and anagen length (49). The second mechanism involves the hair cycle itself. The hair cycle differs in various parts of the body. Over the scalp, hair spends a longer portion of time in anagen than do hair follicles on other parts of the body with shorter hair. In hypertrichosis, the hair follicle undergoes an anagen phase that is longer than normal for that particular location of the body (47,49). There- fore, if a therapy could selectively induce catagen, or stop a prolonged telogen phase, a therapy for hypertrichosis and even for hirsutism would be born (49). There are many drugs which may cause hypertrichosis. Examples include minoxidil, diazoxide, phenytoin sodium and cyclosporine (48,50). The mechanism of hair growth with many of these medications is that they cause hyperpolarization of the potassium channels of the hair follicle, which ultimately leads to increased growth (51). Other drugs can be associated with hypertrichosis, though not to the extent of the above mentioned medications. These

FIGURE 4 Hypertrichosis. McMichael PTR 01/21/08 Chapter 15

222 Kerchner and McMichael

TABLE 3 Causes and Syndromes Associated with Hypertrichosis Hypertrichosis as a primary feature Drug-induced Localized congenital hypertrichosis Localized acquired hypertrichosis Congenital hypertrichosis lanuginosa Congenital generalized hypertrichosis Gingival ﬁ bromatosis with hypertrichosis Osteochondrodysplasia with hypertrichosis (Cantú syndrome) Hypertrichosis, pigmentary retinopathy, and facial anomalies Hypertrichosis as a secondary feature Fetal exposure syndromes (associated with alcohol, hydantoin, valproate, minoxidil) Lipoatrophic diabetes Congenital porphyrias (sun-exposed areas) Stiff skin syndrome Downs syndrome Rubenstein-Taybi syndrome Hurler syndrome (and other mucopolysaccharidoses) Morogu syndrome Leprechaunism (Donohue syndrome) Winchester syndrome Schynzel-Giedion syndrome Hypertrichosis with acromegalic features POEMS syndrome Source: From Refs. 47 and 48.

include oral contraceptives, systemic corticosteroids, and occasionally other drugs such as psoralens, latanoprost (drops cause localized trichomegaly), acetazolamide, and streptomycin sulfate (47,48).

Clinical Features Generalized Hypertrichosis There are many syndromes associated with generalized hypertrichosis as a primary or a secondary diagnostic feature. See Table 3 for a list of many of these disorders (47,52–55).

Localized Congenital Hypertrichosis Hypertrichosis cubiti, or hair elbows, is associated with long vellus hairs over the extensor surface of the elbows and the surrounding areas bilaterally. It becomes prominent during childhood and resolves partially or completely in adolescence. This is thought of as a type of nevoid hypertrichosis, even though there is no underlying pigment or hamartoma. Other similar disorders include hypertrichosis of the auricle (presents during childhood or adolescence), hypertrichosis of the eyebrows (presents after adolescence), hairy polythelia (presents as a tuft of hair along the mammary line), and anterior cervical hypertrichosis (presents as a tuft of hair just above the laryngeal prominence and it can be associated with neuropathies) (47,48,52,54).

Other Causes Other causes of localized congenital hypertrichosis occur in association with underlying plexi- form neuroﬁ bromas, spinal dysraphism (when it presents over the sacral midline it is referred to as a “faun tail”), congenital melanocytic nevi, and occasionally in association with a Becker’s nevus (47,52,54).

Localized Acquired Hypertrichosis Localized acquired hypertrichosis is often found in association with repeated trauma, irritation, inﬂ ammation and friction. Examples associated with this type of hypertrichosis include eczema, lichen simplex chronicus, sack bearers, occlusion under a cast or splint. It has also been McMichael PTR 01/21/08 Chapter 15

Hirsutism and Hypertrichosis 223 seen at sites of vaccinations, and after contact with psoralens, anthralin, mercury or iodine-containing topical agents, and potent ﬂ uorinated corticosteroids (47,54).

Management When hypertrichosis is secondary, addressing the underlying cause (e.g., withdrawing the causative drug, treating the underlying disease manifestation) is the fi rst step in management, and often results in resolution of the hypertrichosis. If the hypertrichosis is primary, the issue of management becomes psychosocial and one of cosmetic appearance. Management of primary hypertrichosis entails the same physical/cosmetic treatment options as those used for hirsutism. These include permanent hair reduction methods such as laser hair removal, galvanic electrolysis, thermolysis, and the Blend Method. Other treatments include bleaching, depilatories, and epilatories. Overall, the most effi cient treatments are probably laser hair removal (when the hair is thick enough for effective treatment) and the use of topical efl ornithine cream. Over- all, patients with localized hypertrichosis are often more satisfi ed with the available treatment options than are those with generalized hypertrichosis (53).

REFERENCES 1. Sonino N, Fava GA, Mani, E, et al. Quality of life of hirsute women. Postgrad Med J 1993; 69:186–189. 2. Rosenfi eld RL. Hirsuitism. N Engl J Med 2005; 353:2578–2588. 3. Hock DL, Seifer DB. New treatments of hyperandrogenism and hirsutism. Obstet Gynecol Clin North Am 2000; 27:567–581. 4. Ploufe L. Disorders of excessive hair growth in adolescent. Obstet Gynecol Clin North Am 2000; 27:79–99. 5. Rittmaster, RS. Hirsutism. Lancet 1997; 349:191–195. 6. Hamilton J. The hirsute female: racial and genetic predisposition. Clin Obstet Gynecol 1964; 10 1075–1084. 7. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21:1440–1447. 8. DeUgarte CM, Woods KS, Azziz R, et al. Degree of facial and body terminal hair growth in unselected black and white women: toward a populational defi nition of hirsutism. J Clin Endocrinol Metab 2006; 91:1345–1350. 9. Housman TS, Derrow AE, Snively BM, et al. Women with excessive facial hair: a statistical evaluation and review of impact on quality of life. Cosmetic Derm 2004; 17(3):157–165. 10. Knochenhauer ES, Key, TJ, Azziz R, et al. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern united states: a prospective study. J Clin Endocrinol Metab 1998; 83:3078–3082. 11. Hines G, Moran C, Azziz R, et al. Facial and abdominal hair growth in hirsutism: a computerized evaluation. JAAD 2001; 45:846–850. 12. Carmina E, Koyama T, Lobo R. Does ethnicity infl uence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 1992; 167:1807–1812. 13. Lanham MS, Lebovic DI, Domino SE. Contemporary medical therapy for polycystic ovary syndrome. Int J Gynaecol Obstet 2006; 95:236–241. 14. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19:41–47. 15. Carmina E. Prevalence of idiopathic hirsutism. European J of Endo 1998; 139:421–423. 16. Azziz R, Carmina E, Sawaya M. Idiopathic hirsutism. Endocr Rev 2000; 21:347–362. 17. Mestayer C, Berthaut I, Portois MC, et al. Predominant expression of 5α-reductase type 1 in pubic skin from normal subjects and hirsute patients. J Clin Endocrinol Metab 1996; 81:1989–1993. 18. Legro R, Shahbahrami B, Kovacs B, et al. Size polymorphisms of the androgen receptor among female Hispanics and correlation with androgenic characteristics. Obstet Gynecol 1994; 83:701–706. 19. Paus R. Control of the hair cycle and hair diseases as cycling disorders. Curr Opin Dermatol 1996; 3:248–258. 20. Wagner R. Physical methods for the management of hirsutism. Cutis 1990; 45:319–326. 21. Ebling FJ. Hair. J Invest Dermatol 1976; 67:98–105. 22. Lynfi eld YL, Macwilliams P. Shaving and hair growth. J Invest Dermatol 1970; 55:170–172. 23. Liew SH. Unwanted body hair and its removal: a review. Dermatol Surg 1999; 25:431–439. 24. Goldberg NS, Zalka AD. Retin-A and wax epilation. Arch Dermatol 1989; 125:1717. 25. Romo ME. Isotretinoin and wax epilation. Br J Dermatol 1991; 124:393. McMichael PTR 01/21/08 Chapter 15

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26. Haedersdal M, Gotzsche PC. Laser and photoepilation for unwanted hair growth. Cochrane Database Syst Rev 2006; 4. 27. Lim SP, Lanigan SW. A review of the adverse effects of laser hair removal. Lasers Med Sci 2006; 21:121–125. 28. Smith SR, Piacquadio DJ, Littler C, et al. Efl ornithine cream combined with laser therapy in the management of unwanted facial hair growth in women: a randomized trial. Dermatol Surg 2006; 32:1237–1243. 29. Wolf JE, Shander D, Schrode K, et al. Randomized, double-blind clinical evaluation of the effi cacy and safety of topical efl ornithine HCl 13.9% cream in the treatment of women with facial hair. Int J of Dermatol 2007; 46:94–98. 30. Kokaly W, McKenna TJ. Relapse of hirsutism following long-term successful treatment with oestrogen-progestogen combination. Clin Endocrinol 2000; 52:379–382. 31. Azziz R. The evaluation and management of hirsutism. Obstet Gynecol 2003; 101:995–1007. 32. Moghetti P, Toscano V. Treatment of hirsutism and acne in hyperandrogenism. Best Pract Res Clin Endocrinol Metab 2006; 20:221–234. 33. Derman R. Androgen excess in women. Int J Fertil 1996; 41:172–176. 34. Heiner JS, Greendale GA, Judd HL, et al. Comparison of a gonadotropin-releasing hormone agonist and a low dose oral contraceptive given alone or together in the treatment of hirsutism. J Clin Endocrinol Metab 1995; 80:3412–3418. 35. Dahlgren E, Landin K, Janson PO. Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome. Hum Reproduct 13:2706–2711. 36. Carmina E, Lobo RA. The addition of dexamethasone to antiandrogen therapy for hirsutism prolongs the duration of remission. Fertil Steril 1998; 69:1075–1079. 37. Farquhar C, Lee O, Jepson R. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst Rev 2003; 4:CD000194. 38. Marcondes JA, Minnani SL, Kirschner MA, et al. Treatment of hirsutism in women with fl utamide. Fertil Steril 1992; 57:543–547. 39. Motta T, Maggi G, D’Alberton A, et al. Flutamide in the treatment of hirsutism. Int J Gynecol Obstet 1991; 36:155–157. 40. Cusan L, Dupont A, Labrie F, et al. Treatment of hirsutism with the pure antiandrogen fl utamide. J Am Acad Dermatol 1990; 23:462–469. 41. Cusan L, Dupont A, Labrie F, et al. Comparison of fl utamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertil Steril 1994; 61:281–287. 42. Moghetti P, Tosi F, Castello R, et al. Comparison of spironolactone, fl utamide, and fi nasteride effi cacy in the treatment of hirsutism: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2000; 85:89–94. 43. Venturoli S, Marescalchi O, Flamigni C, et al. A prospective randomized trial comparing low dose fl utamide, fi nasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism. J Clin Endocrinol Metab 1999; 84:1304–1310. 44. Fruzzetti F, Bersi C, Genazzani AR, et al. Treatment of hirsutism: comparisons between different antiandrogens with central and peripheral effects. Fertil Steril 1999; 71:445–451. 45. Kelestimur F, Everest H, Sahin Y, et al. A comparison between spironolactone and spironolactone plus fi nasteride in the treatment of hirsutism. Eur J Endocrinol 2004; 150:351–354. 46. Morin-Papunen LC, Koivunen RM, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998; 69:691–696. 47. Wendelin, DS, Pope DN, Mallory SB. Hypertrichosis. J Am Acad Dermatol 2003; 48:161–179. 48. Vashi RA, Mancini AJ, Paller AS. Primary generalized and localized hypertrichosis in children. Arch Dermatol 2001; 137:877–884. 49. Krause K, Foitzik K. Biology of the hair follicle: The basics. Semin Cutan Med Surg 2006; 25:2–10. 50. Jankovic SM, Jankovic SV. The control of hair growth. Dermatol Online J 1998; 4:2. 51. Bondeson J, Miles AE. The hairy family of Burma: a four generation pedigree of congenital hypertrichosis lanuginose. J R Soc Med 1996; 89:403–408. 52. James W, Berger T, Elston D. Diseases of the skin appendages: hypertrichosis. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia: Elsevier, 2006:769–771. 53. Trueb RM. Causes and management of hypertrichosis. Am J Clin Dermatol 2002; 3:617–627. 54. Camacho-Martinez, F. Hypertrichosis and hirsutism. In: Bolognia J, Jorizzo J, Rapini R, eds. Dermatology. 1st ed. Edinburgh: Mosby, 2003:1051–1053. 55. Tay YK, Bellus G, Weston W. What syndrome is this? Gingival Fibromatosis-hypertrichosis syndrome. Pediatr Dermatol 2001; 18:534–536. 56. Wyatt JP, Anderson HF, Cordoro KM, et al. Acquired hypertrichosis lanuginosa as a presenting sign of metastatic prostate cancer with rapid resolution after treatment. J Am Acad Dermatol 2007; 56: S45–S47. McMichael PTR 01/21/08 Chapter 16

16 Light-Assisted Hair Removal

Brian Zelickson and Lydia Sahara Department of Dermatology, University of Minnesota, Minneapolis, Minnesota, U.S.A.

INTRODUCTION Since the fi rst hair-removal laser system was cleared by the U.S. Food and Drug Administration (FDA) in 1995, many technological advances have been made in this fi eld. Today, photoepilation is one of the most effective methods of achieving long-term hair reduction. This procedure has rapidly become an integral part of dermatology. In order to understand this procedure, one must have knowledge of hair biology, lasers and light sources. In this chapter, the basics of photoepilation are reviewed. LASER is an acronym for light amplifi cation by the stimulated emission of radiation. The four major components of a laser system are a power source, an active medium, an optical resonator, and a delivery system. The power source supplies energy to excite the molecules within the medium. A population inversion occurs when majority of the molecules within a medium are in the excited state. This is an essential step for the production of laser light. The medium can be a gas, liquid, solid or a semiconductor. Lasers are often named after their medium, which also determines the primary emission wavelength. The optical resonator provides a feedback mechanism in which laser energy can return to the medium and stimulate more excited molecules to emission. Its main function is to multiply the number of passes through the medium, generating a highly directional and intense light beam. Finally, the delivery system guides the light energy from the laser onto the skin (Fig. 1). As a result of this amplifi cation process, light energy emitted by lasers has three unique properties: it is identical in wavelength (monochro- maticity), phase (coherence), and direction (collimation) (1). These qualities are ideal for targeting specifi c chromophores within the skin. Intense pulsed light (IPL) has also been cleared by the FDA for hair removal. In the past decade, this device has become increasingly popular due to its versatility in assuming the function of various lasers. IPL is a broad spectrum light source that contains many different wavelengths. Filters are used to narrow the spectrum of light emitted and can be changed depending upon the clinical situation.

BIOLOGY OF THE HAIR FOLLICLE Laser hair removal is based on the theory of selective photothermolysis where pigment within the hair shaft and the follicle is the targeted chromophore (substance that absorbs light). The type, diameter, color, and depth of hair determine its response to laser treatment. To understand the interactions between light and hair follicles, it is important to be familiar with the basic biology of hair.

Hair Cycle In humans, the hair growth cycle is asynchronous. Each hair follicle has its own rhythm independent of its neighboring follicles. The proportion and duration of follicles in anagen (growth), catagen (regression), and telogen (rest) are determined by the body location. Approximately 85–90% of scalp follicles at any given time are in anagen, which lasts for 2–6 years (2). In contrast, only about 20% of all hair follicles on the legs are in anagen, which persists for 19–26 weeks (3).

Types of Hair There are two major types of hair based on the shaft length and diameter: vellus and terminal. Vellus hairs are short and ﬁ ne, measuring less than 30µm. While primary vellus hairs are McMichael PTR 01/21/08 Chapter 16

226 Zelickson and Sahara

FIGURE 1 Components of a laser. non-pigmented, secondary vellus hairs or miniaturized terminal hairs are pigmented. Like terminal hair, a vellus hair undergoes the full hair cycle, though its anagen phase is much shorter. Terminal hairs are long and pigmented with diameter ranging from 50–120 µm depending on the ethnicity of the individual (2).

Hair Color Hair color is genetically determined by the type and the quantity of melanin in the hair shaft. The human melanocyte produces two forms of melanin: (i) eumelanin which predominates in brown and black hair; (ii) pheomelanin which predominates in blond and red hair. Gray hair contains a decreased number of melanocytes in the hair bulb while senile white hair has no pigment-producing melanocytes. Dark hair also contains larger and more heavily pigmented melanosomes. In the ultraviolet and visible region of the spectrum, the absorption of eumelanin is higher than that of pheomelanin. Furthermore, follicular melanocytes manufacture larger melanosomes in comparison with those in the epidermis. They also have longer dendrites and lower keratinocyte to melanocyte ratio (1:5 versus 1:25) (4). In a typical hair follicle, only the melanocytes that reside in the superior portion of the infundibulum and upper part of the hair bulb are pigmented. Melano- cytes in other areas of the follicle are relatively amelanotic. The hair bulb undergoes signiﬁ cant changes with each hair cycle. Melanogenesis in follicular melanocytes only takes place during stage III to VI of anagen. In fact, the ﬁ rst sign of anagen termination is the retraction of melanocyte dendrites in the bulb. At the onset of catagen, melanin synthesis ceases and the entire pigmentary unit of the hair bulb undergoes involution by apoptosis.

Depth of Hair Follicle The depth of the hair follicle also varies with the hair cycle. In terminal hair, the bulb of an anagen follicle is situated deepest in the skin at the level of subcutaneous fat (1–5 mm). The bulb of vellus hair lies more superﬁ cially in the dermis (<1 mm). The bulge, which functions as a reservoir for pluripotent epithelial stem cells, is constant in depth throughout the hair cycle (1.5 mm). During catagen and telogen, the hair bulb gradually condenses to a region just below the bulge and maintains its position until early anagen. Because of the proximity of the bulb to the bulge in early anagen, this is in theory the best time to damage the hair follicle. This concept will become more apparent as the targets of photoepilation are discussed in the next section.

TARGET OF LASER HAIR REMOVAL Theory of Selective Photothermolysis For many years, medical application of electromagnetic radiation (EMR) has been based on the theory of selective photothermolysis. The idea is to destroy the targeted tissue completely without damaging the surrounding structures. To achieve this, the duration of EMR exposure

(pulse width, Tp) must be shorter than the time for the heated target to lose half of its heat by diffusion (thermal relaxation time, TRT) (5).

Tp < TRT If the above condition is met, the heat produced within the target due to absorption of radiation should not ﬂ ow out of the tissue until it has been injured completely. The longer a McMichael PTR 01/21/08 Chapter 16

Light-Assisted Hair Removal 227

TABLE 1 Laser Terms in Dermatology Terms Deﬁ nition Units Chromophore Substance that absorbs light N/A Pulse width Duration of light exposure to the skin msec Thermal relaxation time Time required for a heated target to lose half of its heat by diffusion Thermal damage time for a Time required for irreversible target injury with msec uniform target sparing of surrounding tissue Thermal damage time for a Time required for the outermost part of a target to msec non-uniform target reach the desired damage temperature by heat diffusion from chromophore Photon A particle of light N/A Power Rate of energy delivery J/sec or W Irradiance Power delivered per unit area W/cm2 Fluence Energy delivered per unit area J/cm2

tissue is exposed to laser energy, the more thermal energy will spread to the adjacent tissues. Thus, pulse widths are generally matched to the size of the target in order to prevent injury to the unintended surrounding tissue (Table 1).

Extended Theory of Selective Photothermolysis For laser hair removal, the target chromophore is melanin, which has the highest concentration in the hair shaft and the bulb. Damage of the stem cells in the bulge is also thought to be crucial in obtaining permanent results. These cells, however, do not possess suffi cient quantity of melanin to absorb light energy and must rely on heat transfer from nearby structures. Although the exact follicular structure required for long-term photoepilation is unclear, important targets include the stem cells in the region of the bulb and the bulge as well as the microvasculature around the dermal papillae. Therefore, the extended theory of selective photothermolysis was proposed to describe this type of heat transmission, in which light energy is applied to obliter- ate a non-uniformly distributed target. In a follicle, the heavily pigmented melanosomes in the hair shaft and the bulb are responsible for light absorption. Heat diffusion then expands in the shape of a cylinder from these chromophores to involve the bulge and the blood vessels around the dermal papillae (6). To allow thermal diffusion to adjacent structures to occur, suffi cient heat must be deposited into the chromophore (Fig. 2). This is in contrast to the standard theory of selective photothermolysis, where destruction of the chromophore without damaging the surrounding tissues is desirable. The time it takes to achieve this type of irreversible injury is called thermal damage time (TDT) for a uniform target. For a non-uniform target such as the hair follicle, it is defi ned as the time it takes for the outermost part of a target to reach the desired damage temperature through heat diffusion from the chromophore. Given the considerations above, a longer pulse width will be more effi cient in gradually heating the chromophore and maintaining heat transfer to nearby tissues until TDT is reached. The pulse width should also be longer than the TRT for adequate heat diffusion to occur. How- ever, it must be shorter than or equal to the TDT to achieve selective tissue injury. Therefore, the theory of extended selective photothermolysis asserts that the optimal pulse width for permanent laser hair removal falls between the TRT and TDT.

TRT < Tp ≤ TDT

CHARACTERIZATION OF LIGHT AND LASER ENERGY Light interacts with the skin in several ways. It can be absorbed, transmitted, scattered or reﬂ ected. For laser and light application, only light energy that is absorbed can generate heat and cause injury to the skin. The ideal laser or light should maximize absorption by the chromophore and minimize other light-tissue interactions such as transmission, scattering and McMichael PTR 01/21/08 Chapter 16

228 Zelickson and Sahara

FIGURE 2 Heat diffusion from chromophore to target.

reﬂ ection. To achieve this objective, it is necessary to have a general understanding of the physical properties of these devices.

Wavelength The optimal wavelength or wavelengths depend on the absorption and depth of the chromophore. Melanin absorption peaks around 330 to 340 nm, which is in the ultraviolet region of the EMR spectrum. It then gradually diminishes over the visible range and stabilizes in the infrared region (Fig. 3). The depth of tissue penetration is directly correlated with wavelength so longer wavelengths will travel deeper into the skin. Since pigmented anagen follicles are deep within the dermis, wavelengths in the ultraviolet spectrum may not reach them. Wavelengths in the visible and infrared region are more effective. Furthermore, substantial melanin is located in the lower epidermis, which may be more susceptible to injury with shorter wavelengths during photoepilation. To target patients with black hair and dark skin, lasers with longer wavelengths and IPL with ﬁ lters that eliminate shorter wavelengths (λ eliminated < 695 nm) are generally preferred.

FIGURE 3 Absorption spectrum of melanin. McMichael PTR 01/21/08 Chapter 16

Light-Assisted Hair Removal 229

Pulse Width As previously stated, pulse width is the duration of laser exposure to the skin. It is determined according to the size of the target. A short pulse duration will generate heat in a more localized area, which is suitable for treating smaller lesions. In contrast, a long pulse duration is necessary to destroy a large target. Therefore, pulse width is closely related to the selectivity of thermal injury. Short pulse widths are generally more selective. However, since heat must be transferred from the melanized bulb to the bulge, longer pulse widths (Tp = 10–40 msec) are more efﬁ cacious in photoepilation. Longer pulse durations also prevent epidermal injury in patients with Fitzpatrick type IV to VI skin. Because the TRT of epidermis is approximately 3–10 msec, pulse widths longer than 10 msec permit more time for the epidermis to cool by heat diffusion.

Spot Size The spot size is the diameter of the laser beam incident on the skin surface. Whenever a laser pulse is delivered, some beam broadening occurs where photons (particles of light) at the periphery are scattered away from the collimated beam of light. Consequently, fewer photons are transmitted to the target at the edge of a laser beam. This phenomenon is called edge effect (Fig. 4). For a large spot size, the edge effect is small since the probability of the dispersed photons scattering back into the collimated beam of light is high. This creates more energy transfer to the target, resulting in greater tissue impact. In contrast, the edge effect is signiﬁ cant for a small spot size. After several scattering events, photons at the edge of the laser beam may not carry sufﬁ cient energy to cause a tissue effect by the time they arrive at the target. Because of the edge effect, a larger spot size is more effective in delivering energy to deeper structures within the skin. It also increases the dermal to epidermal damage ratio.

Fluence Laser energy is measured in joules (J). Power is the rate of energy delivery to the skin, which is measured in joules per second (J/sec) or watts (W). Irradiance is the power delivered per unit area, which is measured in watts per centimeter squared (W/cm2). When pulse width and irradiance have been established, the amount of energy delivered per unit area (ﬂ uence) can be calculated. Fluence (J/cm2) = Irradiance (J/sec/cm2) x Pulse width (sec)

COOLING OF THE EPIDERMIS Melanin in the skin and hair follicle both act as chromophores for the laser. This can lead to one of the major risks in laser hair removal, which is damage to the pigmented melanocytes in the epidermis and subsequent scarring. There are several ways to prevent this problem. First, it is important to avoid treating patients who are tanned because their epidermal melanocytes are primed to increase melanin production. Secondly, one can choose a relatively long wavelength

FIGURE 4 Edge effect of scattering. McMichael PTR 01/21/08 Chapter 16

230 Zelickson and Sahara

FIGURE 5 Contact cooling device with sapphire window. and pulse duration as discussed above. Finally, cooling the epidermis is imperative especially in individuals with Fitzpatrick skin type IV to VI.

Timing of Cooling Cooling can be done at any point during photoepilation. When performed before and in conjunction with the procedure, its main function is to protect the pigmented epidermis (7). Pre-cooling is preferred for short pulse widths (Tp <5 msec) while parallel cooling is favored for longer pulse widths (Tp = 5–10 msec) (8). Post-cooling limits thermal injury to the structures surrounding the hair follicle. Ice packs immediately after treatment can reduce erythema, edema and pain.

Methods of Cooling Heat can be extracted from the skin during photoepilation via various methods. The simplest way is to apply a thick aqueous gel to the skin prior to the procedure. This is called passive cooling and allows some heat in the stratum corneum to be transferred to the gel. Evapora- tive cooling with cryogenic spray immediately before pulse delivery is ideal for preserving the epidermis while targeting superﬁ cial dermal structures. When a liquid is transformed into a gas, the process of evaporation draws heat from the epidermis and decreases its temperature. Therefore, minimal epidermal damage will occur when the laser pulse arrives. Direct skin contact cooling with a cold substance such as a transparent ﬂ uid encased in glass or sapphire window can also lower the skin temperature, especially in the dermo-epidermal junction. The glass or sapphire act as a heat conductor for a circulating water source, which constantly removes the heat from the skin surface (Fig. 5). Compared with other techniques, these systems are able to extract heat more rapidly since a fresh supply of water is cooling the window continuously. The contact time is generally shorter for sapphire window because it conducts heat better than glass. Lastly, cold air cooling at the site of light exposure has been shown to protect the epidermis and provide analgesia. This technique delivers a stream of cool air about –20 to –30°C through a tube in an adjustable quantity to the skin surface. This type of contact-less cooling has several advantages. First, there is no medium to interfere with the laser beam. It also offers even, consistent cooling in body parts where the skin topography is irregular (9). Cold air cooling devices are built into some lasers and light sources while others operate independently such as the Zimmer system (Zimmer MedizinSystems; Irvine, California, U.S.A.).

HAIR-REMOVAL LIGHT SOURCES Lasers Four types of lasers with wavelengths ranging from the visible to the infrared are commonly used for hair removal. The ruby laser emits light in the red region of the visible spectrum (694 nm) and was one of the ﬁ rst lasers introduced for photoepilation. However, it has become less McMichael PTR 01/21/08 Chapter 16

Light-Assisted Hair Removal 231

TABLE 2 Wavelengths of Hair-Removal Lasers Laser Wavelength Ruby 694 nm Alexandrite 755 nm Diode 810 nm Nd:YAG 1064 nm popular in recent years due to its short wavelength and superfi cial penetration, which poses greater risk to the epidermal melanin. The alexandrite (755 nm) and diode (810 nm) laser both emit light in the near-infrared area. They are comparable in effi cacy, but the alexandrite laser with its shorter wavelength is generally considered superior in treating light and fi ne hairs. The neodymium:yttrium aluminum garnet (Nd:YAG) laser has the longest wavelength (1064 nm) among the hair removal lasers. This enables it to target structures deep in the dermis while sparing the melanin in the epidermis. Because Nd:YAG has the safest profi le in treating patients with Fitzpatrick type IV to VI skin, it is quickly becoming the laser of choice for this population. For photoepilation, lasers with longer pulse durations are superior in heating the large chromophore and allowing thermal diffusion to the rest of the follicle. Long-pulsed Nd:YAG has been shown to give more permanent results as compared to the quality-switch (Q-switch) Nd:YAG, which emits light with short pulse widths in the nanosecond range (Table 2).

Intense Pulsed Light IPL provides a broad range of wavelengths, encompassing the ultraviolet, visible and infrared regions of the spectrum. Its source is a xenon fl ashlamp, which emits light from 370 to 1800 nm when unfi ltered (10). However, cut-off fi lters can be placed to eliminate certain areas of the spectrum to maximize the wavelengths absorbed by the chromophore. IPL, therefore, can target a variety of chromophores depending on the wavelengths eliminated by the fi lters. For light-assisted hair removal, emission in the visible to infrared region is desirable (λ > 695 nm). There are also some disadvantages associated with a broad band source. IPL emits an inconsis- tent spectrum from pulse to pulse, which can lead to variable depth of penetration. The large hand piece and large spot size limit its maneuverability over the concavity and convexity of the skin. Furthermore, since light divergence is greater with IPL, contact with the skin must be maintained at all times (Fig. 6). Current IPL sources are not ideal for Fitzpatrick skin type IV to VI because the cut-off fi lters do not yet eliminate all of the shorter wavelengths, which can be damaging to dark skin.

Photodynamic Therapy Photodynamic therapy (PDT) is currently FDA cleared for treating actinic keratosis and is used off-label for acne vulgaris and skin rejuvenation. Aminolevulinic acid (ALA) is ﬁ rst applied

FIGURE 6 Intense pulsed light handpiece. McMichael PTR 01/21/08 Chapter 16

232 Zelickson and Sahara topically to the skin, which is metabolized intracellularly to protoprophyrin IX. This is followed by the illumination of a visible light source to activate the protoprophyrin IX, a natural photo- sensitizing molecule. Cytotoxic free oxygen radicals are then generated to destroy the targeted tissue (11). Because ALA tends to accumulate in the sebaceous glands, PDT may selectively target the hair follicles. This mechanism provides a potential advantage in that it does not depend on melanin as a chromophore, making PDT versatile for all hair colors.

GUIDELINES FOR LASER HAIR REMOVAL Indications Photoepilation is indicated for hypertrichosis, hirsutism and ingrown hairs. While many patients seek treatment for cosmetic purposes, the underlying medical cause of these conditions should ﬁ rst be excluded. Hypertrichosis is excessive hair growth in any part of the body and can be secondary to medication, malnutrition, trauma and hereditary disorders. In contrast, hirsutism implies an increase of hair growth in androgen-dependent sites in women. There is often a genetic predisposition, but abnormalities of endocrine origin must be considered. Chronic inﬂ ammation of the hair follicles associated with ingrown hairs is common in women who shave their bikini areas and in the beard area of men (pseudofolliculitis barbae). Laser hair removal can ameliorate these conditions.

Patient Selection The ideal patient for photoepilation has dark, coarse hair and Fitzpatrick type I or II skin. Dark skin is generally associated with higher incidence of adverse side effects. However, by choosing lasers with long wavelengths and pulse durations combined with proper epidermal cooling, individuals with thick, black hair and dark skin can now be treated more safely. For patients with Fitzpatrick type III skin, the color and type of hair as well as cutaneous response to injury should be considered in selecting a laser. Light sources with short wavelengths are more effective for light and thin hair though blond or white hair does not respond well to laser and IPL treatments. Other contraindications include photosensitivity, history of keloid formation, active infection at the site of treatment and pregnancy.

Pretreatment Care Because epidermal melanin absorbs in the same spectrum as the hair follicle, it is essential to avoid tanning before the procedure. Use of sunscreen and hydroquinone several weeks prior can further inhibit epidermal melanin stimulation. Since the hair shaft must be preserved as a chromophore, waxing, plucking and electrolysis should be avoided. Shaving and trimming do not remove the hair shaft are therefore permitted. Acyclovir can be prescribed for patients with history of herpes simplex at the site of photoepilation (12). Prior to the treatment, the skin should be cleansed to remove all cosmetics. To provide patient comfort and reduce pain, a topical anesthetic can be applied an hour before the procedure. Grids can also be drawn on the skin with a white marker to minimize pulse overlap. If there is any concern that the patient may not respond well to laser therapy, a test patch should be considered.

Choice of Settings Once a light source has been chosen, several parameters need to be determined depending on the clinical situation: spot size, pulse width, ﬂ uence and method of cooling. General recommendations for spot size, pulse width and ﬂ uence are outlined below.

Spot Size As previously discussed, large spot size carries more laser energy deeper into the skin. These characteristics enhance the efﬁ cacy of photoepilation. Large diameters also increase the speed of treatment, which is beneﬁ cial when treating a sizeable area such as the back or the leg. McMichael PTR 01/21/08 Chapter 16

Light-Assisted Hair Removal 233

Pulse Width

For a given energy level, shorter pulse durations (Tp <15 msec) are generally more effective for thin, light hair but are more likely to harm the epidermis. Longer pulse durations allow heat to diffuse from the thinly pigmented epidermis while promoting continuous absorption of the thick follicle. This protects the epidermis, making long pulse widths superior for dark skin.

However, excessively long pulse durations (Tp > 40 msec) have not been shown to increase the efﬁ cacy of laser therapy.

Fluence Fluence is the parameter most associated with complications related to photoepilation. Although higher ﬂ uences are more effective in obtaining permanent results, they are also more likely to overheat the epidermis and the tissue adjacent to the follicle. Vulnerable sites include the chin due to its increased follicle density and the pigmented genital region. Therefore, it is advisable to start with the lowest effective ﬂ uence then step up gradually.

Treatment Endpoints In laser hair removal, the ideal outcome is vaporization of the hair shaft with minimal alteration of the surrounding skin. Perifollicular edema, which occurs within minutes after exposure to a laser pulse, is also considered a good treatment endpoint because it indicates injury to the hair follicle. Edema expanding beyond the follicle, however, suggests dermal damage. Mild transient erythema is normal after laser procedures, but this may represent injury to the epidermis if it becomes extensive and persistent. Perifollicular edema and mottled erythema are common and usually resolved several hours after the procedure. Other signs of epidermal damage include discoloration, blistering and complaints of pain from the patient. These undesirable side effects can be avoided by decreasing the ﬂ uence, increasing the pulse width at a constant energy level and providing adequate cooling.

Post-treatment Care Cooling with ice packs after photoepilation can decrease erythema, edema and pain. Topical corticosteroids can also control infl ammatory reactions. To prevent post-infl ammatory hyperpigmentation, sun exposure should be minimized by using sunscreen. These measures are especially important in patients with dark skin to minimize complications. Hair shedding usually occurs during the fi rst few weeks after treatment. Regrowth of hair with smaller diameters after photoepilation is a good prognostic indicator of long-term hair reduction. The interval between each session should be approximately four to eight weeks depending on the hair cycle of the treated site. Compared to follicles on the trunk and extremities, those on the face have shorter telogen phase with more rapid progression to anagen so a more frequent treatment schedule is appropriate. In all anatomical locations, multiple sessions are necessary to achieve permanent results.

COMPLICATIONS The incidence of complications in laser hair removal is low. Most are related to unintended injury to the epidermis and resolve spontaneously without permanent sequelae. Adverse reactions are more common in sun-exposed areas as well as during spring and summer months, indicating that tanning may be associated with worse outcomes. Sun-protected sites such as the axillae and inguinal folds tend to have the least side effects (13). In addition, complications are most likely to occur in dark-skinned patients treated with short wavelength lasers.

Transient Adverse Effects Acute transient adverse effects last from hours to days with no associated long-term consequences. Superﬁ cial blistering and crusting are signs of epidermal damage and may indicate inappropriate high ﬂ uences or inadequate cooling. Crusting appears to be more common in McMichael PTR 01/21/08 Chapter 16

234 Zelickson and Sahara patients treated with ruby and alexandrite lasers. Reticulate erythema is a rare side effect that presents both clinically and histologically as livedo reticularis. It has been reported in patients treated with diode lasers. The most common site appears to be on the legs. Potential risk factors include a history of chilblains and treatment with high ﬂ uences. Reticulate erythema is self- limited but may persist from few months to more than a year (14). Other short-term side effects include folliculitis, purpura and thrombophlebitis.

Pigmentary Alterations As expected, pigmentary alterations of the skin are more frequently seen in patients with dark skin. Hyperpigmentation is usually reversible, resulting from laser-stimulated melanin production. In contrast, hypopigmentation may be permanent, representing thermal damage to the melanocytes in the epidermis (15). Depigmentation of the hair shaft can also occur after photoepilation. Both temporary and permanent leukotrichia have been reported. The follicular melanocytes in these patients are thought to be more sensitive to heat, which results in the destruction of the melanocytes with partial damage to the stem cells in the hair follicles. This allows regeneration of the hair shaft but not the melanin. Leukotrichia may resolve after several months especially in younger patients (16).

Permanent Adverse Effects Permanent adverse effects after laser treatments are rare. These include permanent changes to skin texture such as atrophy and scarring, as well as pigmentary alterations such as leukotrichia, hyper-, and hypopigmentation.

Paradoxical Hypertrichosis A rare adverse effect of light-assisted hair removal that has been recognized recently is paradoxical hypertrichosis. This can be seen with all devices. Patients with skin type III to V and black hair appear to be at the greatest risk. The etiology of this process is unclear. However, many of the affected patients were treated with suboptimal ﬂ uences, which may have stimulated the hair follicles. Light epilation may also synchronize the hair cycle by converting reversibly injured follicles to anagen. This may falsely give the appearance of hypertrichosis by increasing the hair density (17).

CONCLUSION Photoepilaton is an effective and reliable method of removing unwanted hair. Given recent technological advances and research in this fi eld, laser and IPL systems are expected to continue to improve in their effi cacy and safety. In the past, individuals with dark skin have experienced signifi cant complications related to thermal damage of the epidermis. However, current lasers with longer wavelengths and pulse durations combined with cooling devices enable these patients to be treated with minimal side effects. For patients with blond or white hair who presently do not respond to photoepilation, light sources using an exogenous chromophore such as PDT to target the hair follicles are being investigated. Although adverse reaction to light-assisted hair removal is uncommon, good clinical judgment with thorough understanding of laser and light technologies are essential in achieving the best outcome.

REFERENCES 1. Lui H, Anderson RR. Radiation sources and interaction with skin. In: Lim H, Hoenigsmann H, Hawk J, eds. Principles and Practice of Photodermatology. New York: Taylor & Francis Group, 2007:27–38. 2. Paus R, Peker S. Biology of hair and nails. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 1st ed. Vol. 1. Philadelphia: Mosby, 2003:1007–1032. 3. Lepselter J, Elman M. Biological and clinical aspects in laser hair removal. J Dermatol Treat 2004; 15:72–85. 4. Ross EV, Ladin Z, Kreindel M, et al. Laser hair removal: theoretical considerations in laser hair removal. Dermatol Clin 1999; 17(2):333–355. McMichael PTR 01/21/08 Chapter 16

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5. Altshuler GB, Anderson RR, Manstein D, et al. Extended theory of selective photothermolysis. Lasers Surg Med 2001; 29:416–432. 6. Ross EV. Extended theory of selective photothermolysis: a new recipe for hair cooking? Lasers Surg Med 2001; 29:413–415. 7. Drosner M, Adatto M. Photo-Epilation: guidelines for care from the European Society for Laser Dermatology (ESLD). J Cosmet Laser Ther 2005; 7(1):33–38. 8. Hirsch RJ, Anderson RR. Principles of laser-skin interactions. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 1st ed. Vol. 2. Philadelphia: Mosby, 2003:2143–2151. 9. Raulin C, Breve B, Hammes S. Cold air in laser therapy: fi rst experiences with a new cooling system. Lasers Surg Med 2000; 27:404–410. 10. Ross EV. Laser versus intense pulsed light: competing technologies in dermatology. Lasers Surg Med 2006; 38:261–272. 11. Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid. Am J Clin Dermatol 2003; 4(10):699–708. 12. Liew, SH. Laser hair removal: guidelines for management. Am J Clin Dermatol 2002; 3(2):107–115. 13. Lim SPR, Lanigan SW. A review of the adverse effects of laser hair removal. Lasers Med Sci 2006; 21:121–125. 14. Lapidoth M, Shafi rstein G, Amitai DB, et al. Reticulate erythema following diode laser-assisted hair removal: a new side effect of a common procedure. J Am Acad Dermatol 2004; 51:774–777. 15. Lanigan SW. Incidence of side effects after laser hair removal. J Am Acad Dermatol 2003; 49:882–886. 16. Radmanesh M, Mostaghimi M, Yousefi I, et al. Leukotrichia developed following application of intense light for hair removal. Dermatol Surg 2002; 28:572–574. 17. Alajlan A, Shapiro J, Rivers JK, et al. Paradoxical hypertrichosis after laser epilation. J Am Acad Dermatol 2005; 53:85–88. McMichael PTR 01/21/08 Chapter 16 McMichael PTR 01/21/08 Chapter 17

17 Allergic Contact Dermatitis

Sharone K. Askari Department of Dermatology, St. Louis University Hospital, St. Louis, Missouri, U.S.A. Erin M. Warshaw Department of Dermatology, University of Minnesota and VA Medical Center, Minneapolis, Minnesota, U.S.A.

INTRODUCTION Allergic contact dermatitis (ACD) to haircare products is not uncommon. The most common allergens found in hair products include: hair dyes, fragrances, preservatives, bleaches, emulsi- ﬁ ers, permanent wave solutions, hair straighteners, and styling agents. This chapter details the epidemiology, clinical characteristics, and main allergens within each group. In addition, less commonly reported agents such as shampoos, conditioners, hair removers, sunscreens, topical minoxidil, and hair accessories also are discussed. Useful information on the diagnosis, treatment, and management of allergic contact dermatitis due to hair products is provided.

EPIDEMIOLOGY In the general population, adverse reactions to personal care products, including haircare products are common. A recent study involving 3,800 patients in the United Kingdom showed that 23% of women and 13% of men reported an adverse reaction to a personal care product over a one-year period. Even more surprising, the same study demonstrated that approximately 51% of women and 38% of men have experienced an adverse reaction at some stage in their lives (1). Therefore, prevalence is likely to be under-reported to the medical community, as most patients discontinue the suspected product and do not report these reactions to their physicians (2). Practitioners also need to consider the possibility of allergic contact reactions to cosmetics, including hair products, more often in their differential diagnosis. A study by the North Ameri- can Contact Dermatitis Group (NACDG) of 13,000 patients discovered that for those patients diagnosed as having cosmetic contact dermatitis, less than half were initially thought to be due to cosmetics by either the dermatologist or the patient (3). Unfortunately, there are few studies on the epidemiology of allergic contact dermatitis exclusively due to hair products. Recently, the Information Network of Departments of Der- matology (IVDK), a consortium consisting of 40 dermatology departments in Germany, Aus- tria, and Switzerland, published one of the most valuable studies on the prevalence of allergic reactions specifi cally due to haircare products. The network performed a total of 77,901 dermatologic consultations for suspected cases of allergic contact dermatitis between the period of 1995–2002, and hair products were suspected in 2,506 patients (3.2%). The overwhelming majority of these patients were female (92.9%), and consisted of 1,217 consumers and 884 current or previous hairdressers. The average age of the female consumer was 46 years and approximately 15% had a history of eczema, while the average female hairdresser was 24 years old and almost one-third had a history of atopy. It is also important to note that certain racial groups have higher rates of sensitization to different allergens. While a study by Deleo and colleagues involving 9624 patients patch tested between 1992–1998 found similar overall rates of irritant and allergic contact dermatitis, there were statistically signifi cant differences in sensitization rates for specifi c allergens between whites and blacks. They found that whites had higher rates of sensitization to formaldehyde, glutaraldehyde, formaldehyde-releasers, lanolin, and balsam of Peru. However, blacks exhib- ited higher rates of sensitization to p-phenylenediamine and cobalt chloride. These differences may be related to genetic factors, but are most likely due to differences in allergen exposure in different races (200). McMichael PTR 01/21/08 Chapter 17

238 Askari and Warshaw

Hairdressers have a signifi cantly higher risk of developing allergic contact dermatitis to hair products due to their occupational exposure. This was clearly evident in the IVDK study, which showed that 48% of the individuals suspected of having an allergic reaction to hair products were hairdressers (4). Similarly, another study from Italy of 209 hairdressers evaluated between 1990–1999 showed that 43.8% had a positive patch-test reaction to one or more antigens in the hairdressing series (5). Other studies have shown that ACD to hair products among hairdressers is on the rise. In Spain, Valks and colleagues compared 300 hairdressers patch- tested with a standard series and specifi c hairdressing products between 1994–2003 with 300 hairdressers patch-tested between 1980–1993. They discovered not only a signifi cant increase in suspected cases of occupational ACD (48.8% to 58%), but the positive patch-test rate among this group signifi cantly increased from 58.8% to 78.3% (p < 0.05) (6).

TYPES OF CONTACT REACTIONS The two major types of contact dermatitis are irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). In this chapter, we focus on allergic contact reactions to hair products. How- ever, some allergens found in hair products may also cause contact urticaria and photoallergy. Contact urticaria classically presents as urticarial wheals and is much less common than contact dermatitis. Photoallergy, a subtype of allergic contact dermatitis, is caused by the exposure to an antigen in conjunction with UVA radiation; diagnosis is made by photopatch testing. These four categories of adverse reactions are summarized in Table 1. It is important to realize that these reactions are not mutually exclusive, and may occur simultaneously in a particular patient. Furthermore, some antigens may cause several different types of reactions.

Irritant Contact Dermatitis (ICD) Irritant contact dermatitis is a nonspecifi c response to chemicals or physical agents that disrupt the normal epidermal barrier. Damaged skin lacks the proper oils and moisture, thus allowing irritants to penetrate more deeply and cause further damage by triggering infl ammation. It is estimated that approximately 80% of all contact reactions are irritant reactions (7,8). Clinically, irritant contact dermatitis is often well demarcated with a “glazed” appearance, but there may also be erythema, itching, swelling, blistering and scaling. Initially, irritant reactions are usually confi ned to the site of contact with the irritant. If the dermatitis is prolonged or severe, it may also spread later to previously unaffected areas, although this is uncommon. The severity of ICD can be highly variable and depends on many factors, including amount and strength of the irritant, length and frequency of exposure, and skin susceptibility. Irritant contact dermatitis can affect any individual given suffi cient exposure to irritants, but those with a history of atopic dermatitis are particularly susceptible.

Allergic Contact Dermatitis ACD is a type IV delayed hypersensitivity reaction, resulting from contact with a specifi c allergen to which a patient has developed a specifi c sensitivity. It was fi rst described in 1895 by Jadassohn. There are two main steps in developing allergic contact dermatitis: induction and elicitation. During the induction phase, also known as sensitization, an allergen penetrates the

TABLE 1 Summary of Contact Reaction Types Type of reaction ACD ICD Contact urticaria Photoallergic Mechanism Cell-mediated, type IV Direct toxic effect 2 subtypes: UVA and cell-mediated, –immunologic: type IV IgE mediated, type I –nonimmunologic: unclear Diagnosis Closed patch-testing Diagnosis of RAST, SPT, OPT (use test) Photopatch testing exclusion Abbreviations: ACD, allergic contact dermatitis; ICD, irritant contact dermatitis; RAST, radioallergosorbent test; SPT, skin prick test; OPT, open patch testing. McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 239 epidermis and is processed by antigen-presenting cells (Langerhans cells, dendrocytes, and macrophages). The processed antigen is presented to a T lymphocyte, which then undergoes blastogenesis in a regional lymph node. A subset of these T cells differentiates into memory cells, while others become effector T cells that are released into the bloodstream. This initial phase generally takes between 10–14 days. In the elicitation phase, the sensitized person is again exposed to the antigen, which is processed by an antigen-presenting cell and presented to circulating effector T lymphocytes, which produce lymphokines and cytokines. These factors mediate the infl ammatory response that usually develops in 24 to 72 hours after the second exposure (8). Acute ACD classically presents as intensely pruritic papules and vesicles on an erythematous base, while chronic ACD may manifest as xerosis, fi ssuring, and lichenifi ed eczematous plaques (9). Most allergens applied to the hair or scalp may cause dermatitis of the neck, forehead, lateral cheeks, ears, eyelids and hands. The eyelids are often the fi rst body part to show signs of allergic reaction since the skin is particularly sensitive to allergens and irritants (10). The upper trunk and shoulders may also be affected by allergens in hair products (11). Interestingly, ACD to hair products rarely affects the scalp. This is hypothesized to occur because the scalp has a relatively thick epidermis and may therefore be more resistant to penetration of allergens (10). Some exceptions to this rule include allergens in permanent hair dyes (para-phenylenediamine) or permanent waves (glyceryl monothioglycolate), which may cause severe scalp reactions with edema and crusting. Some permanent wave products (ammonium thioglycolate) may also result severe irritant reactions and scalp burns when applied improperly (10).

Contact Urticaria Contact urticaria generally develops within minutes after exposure to an antigen. Symptoms may range from localized reactions (itching, burning, tingling, erythema, wheals, rhinitis, burning, and conjunctivitis) to more severe systemic manifestations (wheezing, angioedema, anaphylaxis, and death). These reactions are much less common than contact dermatitis (12). There are three subtypes of contact urticaria: nonimmunologic, immunologic, and an unknown mechanism. Some common substances found in haircare products known to cause contact urticaria are listed in Table 2.

Nonimmunologic Contact Urticaria (NICU) Nonimmunologic reactions are much more common than immunologic contact urticarial reactions. These reactions usually remain well localized with no systemic symptoms. No prior exposure is necessary, but the severity of reaction depends on the concentration of the antigen and location of use. The mechanism of NICU is not fully understood and these reactions often cannot be suppressed with antihistamines, implying that other mediators are involved, such as prostaglandins. However, nonsteroidal anti-inﬂ ammatory drugs have been shown to suppress NICU reactions to sorbic acid (13) and benzoic acid (14).

Immunologic Contact Urticaria (ICU) ICU is an immediate, Type I, IgE-mediated reaction. Although these reactions are less common than NICU reactions, they are more prevalent in atopics (12). After the fi rst exposure with an inciting antigen, antibody-producing cells produce specifi c IgE and IgG4, which can bind to both mast cells and basophils. Subsequent exposure results in the release of infl ammatory mediators (15). These reactions can extend beyond the localized site of contact and may result in systemic symptoms (conjunctivitis, rhinitis, and anaphylaxis). ICU is best diagnosed with radioallergosorbent testing (RAST), skin prick testing, scratch testing, or open patch testing (use testing) in the presence of resuscitation equipment.

Unknown Mechanism Substances found in this group produce reactions with features of both nonimmunologic and immunologic reactions. These agents may produce a generalized histamine release without a speciﬁ c immunologic basis (16). McMichael PTR 01/21/08 Chapter 17

240 Askari and Warshaw

TABLE 2 Substances Found in Haircare Products Known to Induce Contact Urticariaa Nonimmunologic (NICU) Immunologic (ICU) Unknown mechanism Acetic acid Alcohols Ammonium persulfate Alcohols Ammonia Paraphenylenediamine Ammonium persulfate (10) Ammonium persulfate (155) Balsam of Peru Balsam of Peru (56) Benzoic acid Benzoic acid Cinnamic acid Benzyl alcohol (56) Cinnamic aldehyde Benzophenone Formaldehyde Butylhydroxytoluene (56) Propylene glycol (88) Diethyltoluamide Sodium benzoate Formaldehyde Sorbic acid Henna Lanolin alcohols (56) Menthol Parabens Paraphenylenediamine (155) Polyethylene glycol (PEG-8) Polysorbate 60 Salicylic acid Sodium sulﬁ de Sodium coco hydrolyzed animal protein (100) Vanillin (14) aSome authorities classify these allergens as unknown mechanism. Source: From Ref. 10 and other sources indicated.

Photoallergic Contact Reactions These reactions are a subtype of allergic contact dermatitis and are elicited by the exposure of an allergen in conjunction with UVA radiation (15). Photoallergic reactions should always be suspected when reactions occur in a sun-exposed distribution. Photoallergens include sunscreens (such as benzophenones and oxybenzone), fragrances (musk ambrette, 6-methylcou- marin, sandalwood oil) and antibacterial agents (triclosan and dichlorophene) (17). Diagnosis of photocontact dermatitis is made by photopatch testing; interested readers may ﬁ nd reviews (17) on this topic helpful.

CONTACT ALLERGENS Most allergens found in personal haircare products are listed in the cosmetic screening series (Table 3) and hairdressing series (Table 4). The IVDK study clearly demonstrated the effectiveness of the hairdressing series, which detected 80% of allergic contact reactions to hair products among consumers (non-occupational contact dermatitis) and 93% of allergic reactions found in hairdressers (occupational contact dermatitis) (4). Allergens found in hair products responsible for allergic contact reactions may be categorized by:

Hair dyes (p-phenylenediamine, p-toluenediamine, p-aminophenol, pyrogallol) Fragrances (fragrance mix, balsam of Peru, hydroxymethyl pentylcyclohexene carboxaldehyde) Preservatives (methyldibromoglutaronitrile/phenoxyethanol, methylisothiazolinone/methylchloroisothiazolinone, formaldehyde, and paraben mix) Hair bleaching agents (ammonium persulfate) Emulsiﬁ ers (lanolin alcohol, cetearyl alcohol) Permanent waves (glyceryl monothioglycolate)

The most common sensitizers in the IVDK study are listed in Table 5. Speciﬁ c allergens are discussed in greater detail below. McMichael PTR 01/21/08 Chapter 17

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TABLE 3 Cosmetic Screening Series Allergen Concentration (%) 1,2-Dibromo-2,4-dicyanobutane 0.3 2(2-Hydroxy-5-methylphenyl) benzotriazol (Tinuvin P) 1.0 2,6-Ditert-butyl-4-cresol (BHT) 2.0 2-Bromo-2-nitropropane-1,3-diol (Bronopol) 0.25 2-Hydroxy-4-methoxybenzophenone 10.0 2-Phenoxyethanol 1.0 2-tert-Butyl-4-methoxyphenol (BHA) 2.0 4-Chloro-3,5-xylenol (PCMX) 0.5 4-Chloro-3-cresol (PCMC) 1.0 Abitol 10.0 Amerchol L 101 50.0 Benzyl alcohol 1.0 Benzyl salicylate 2.0 Cetyl alcohol 5.0 Chlorhexidine digluconate 0.5b Chloroacetamide 0.2 Clioquinol (5-chloro-7-iodo-quinolinol) 5.0 Cocamidopropyl betaine 1.0b Diazolidinylurea (Germall II) 2.0 Dimethylaminopropylamine 1.0b DMDM hydantoin 2.0b Dodecyl gallate 0.25 Ethylenediamine dihydrochloride 1.0 Hexahydro-1,3,5-tris (hydroxyethyl)triazine (Grotan BK) 1.0b Hexamethylenetetramine (Hexamin) 2.0 Imidazolidinylurea (Germall 115) 2.0 Iodopropynyl butylcarbamate 0.1 Isopropyl myristrate 20.0 Methylchlorothiazolinone/methylisothiazolinone 0.02b Methyldibromoglutaronitrile/Phenoxyethanol 1.5 Octyl gallate 0.25 Paraben mixa 16.0 Phenyl salicylate (Salol) 1.0 Phenylmercuric acetate 0.01b Polyoxyethylenesorbitan monooleate (Tween 80) 5.0 Propyl gallate 1.0 Propylene glycol 5.0 Quaternium 15 (Dowicil 200)a 1.0 Sodium-2-pyridinethiol-1-oxide (Sodiumomadine) 0.1b Sorbic acid 2.0 Sorbitan monooleate (Span 80) 5.0 Sorbitan sesquioleate 20.0 Stearyl alcohol 30.0 Tea tree oil 5.0 tert-Butylhydroquinone 1.0 Thimerosal (Merthiolate) 0.1 Triclosan (Irgasan DP 300) 2.0 Triethanolamine 2.0 aThese allergens are commonly found in standard series. bAll allergens are tested in petrolatum as the vehicle, unless identiﬁ ed with b which are tested in water. Source: From Ref. 156.

HAIR DYES Hair coloring is commonly used worldwide to change hair color, add highlights, or disguise gray hair. In the United States alone, it is estimated that over 50 million consumers color their hair (12). According to the IVDK study performed in Europe, hair dyes (such as p-phenylenediamine, p-toluenediamine, and p-aminophenol) were the most common sensitizers among all haircare products (Table 5). A few studies have tried to determine the prevalence of ACD to hair dyes in the general population. Sosted and colleagues (18) recently performed a retrospective McMichael PTR 01/21/08 Chapter 17

242 Askari and Warshaw

TABLE 4 Hairdressing Screening Series Allergen Concentration (%) 2,5-Diaminotoluene sulfate 1.0 2-Bromo-2-nitropropane-1,3-diol (Bronopol) 0.25 2-Nitro-4-phenylenediamine 1.0 3-Aminophenol 1.0 4-Aminophenol 1.0 4-Chloro-3,5-xylenol (PCMX) 0.5 4-Chloro-3-cresol (PCMC) 1.0 4-Phenylenediaminea 1.0 Ammonium persulfate 2.5 Ammonium thioglycolate 2.5b Balsam of Perua 25.0 Captan 0.5 Chloroacetamide 0.2 Cl+Me-isothiazolinonea (Kathon CG, 200 ppm) 0.02b Cobalt chloridea 1.0 Cocamidopropylbetaine 1.0b Diazolidinylurea (Germall II) 2.0 Formaldehydea 1.0b Glyceryl monothioglycolate 1.0 Hydrogen peroxide 3.0b Hydroquinone 1.0 Imidazolidinyl urea (Germall 115) 2.0 Nickel sulfatea 5.0 Quaternium-15a (Dowicil 200) 1.0 Resorcinol 1.0 Zinc pyrithione (Zinc omadine) 1.0 aAllergens also present in standard series. bAll allergens are tested in petrolatum as the vehicle, except those marked b which are tested in water. Source: From Ref. 156. study of 4,000 randomly selected Danish individuals. Approximately 5% reported an adverse reaction to a hair dye compatible with allergic contact dermatitis, but only one in six of these affected individuals reported these reactions to their healthcare provider. Therefore, many allergic reactions to hair dyes occur but often are underreported. There are four main types of hair dyes: permanents dyes, semi-permanents/temporary dyes, hair restorers, and vegetable dyes. Each hair dye category has a speciﬁ c duration and mechanism of action (19). Table 6 provides a current list of hair dyes reported in the literature to cause allergic contact dermatitis.

Permanent Dyes Permanent dyes are the most popular type of hair dye in the United States because of the variety of colors available (10). Unfortunately, they are also the most common class to elicit allergic contact reactions (4). Permanent dyes are formed within the hair cortex and can therefore withstand more than ten washings. These dyes generally involve a mixture of color intermediates and hydrogen peroxide in a viscous lotion base. This mixture is applied to the hair immediately after mixing. The mechanism of action involves two steps. First, the hydrogen peroxide bleaches the original hair melanin, thus allowing for better coloring. Second, oxidation of the primary intermediate dyes by hydrogen peroxide results in highly reactive benzoquinone mono- and di-imines, which rapidly react with other compounds present known as couplers. The choice of intermediates and reaction conditions determine a wide variety of colors. The entire process is usually completed within 15 minutes (19). The most common hair dye allergy is caused by para-phenylenediamine (PPD) and derivatives of PPD, which are found in both permanent and semi-permanent dyes. According to the IVDK study in Europe, PPD was the most common sensitizer among all haircare products, causing allergic reactions in 15.4% of individuals suspected to have ACD to hair cosmetics (Table 5) (4). In the latest report from the North American Contact Dermatitis Group (NACDG), of the 4,913 patients patch tested between 2001–2002, PPD allergy was present in 4.8% of all McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 243

TABLE 5 IVDK Study Results. Female Consumers and Hairdressers Patch Tested to Hairdresser Series and Selected Allergens from the Standard Series of the GCD Group (1995–2002) Adjusted prevalencea (95% CI) Allergen Hairdressers Consumers p-Phenylenediamine 18.7 (15.4–22.0) 15.4 (13.2–17.1) p-Toluenediamine 22.3 (18.8–25.9) 13.9 (11.7–16.2) Fragrance mix 13.2 (9.7–16.7) 9.0 (7.3–10.7) p-Aminophenol 5.0 (3.3–6.8) 7.2 (5.4–8.9) Balsam of Peru 6.9 (4.3–9.6) 6.9 (5.4–8.3) Pyrogallol 3.8 (2.2–5.4) 4.8 (3.3–6.2) m-Aminophenol 3.0 (1.6–4.4) 4.6 (3.2–6.1) Ammonium persulfate 18.4 (15.7–21.0) 4.4 (3.0–5.7) Lanolin alcohol 2.1 (0.8–3.4) 2.6 (1.3–6.7) MDGN + PE 9.7 (6.1–13.2) 2.4 (1.3–5.0) GMTG 13.5 (11.0–16.0) 1.9 (1.0–2.9) Cocamidopropyl betaine 3.2 (1.4–6.8) 1.9 (1.1–2.8) MCI/MI 3.8 (2.0–5.7) 1.6 (0.9–2.4) HMPPC 3.7 (0.0–7.5) 1.6 (0.2–3.0) Formaldehyde 1.5 (0.3–2.8) 1.5 (0.8–2.3) Paraben mix 0.001 NA 0.7 (0.2–1.2) Cetearyl alcohol 0.3 (0.0–0.6) 0.2 (0.0–0.5) a Adjusted for age. Abbreviations: CI, confi dence interval; NA, not available; GCDG, German Contact Dermatitis Group; GMTG, glyceryl monothioglycolate (glyceryl thioglycolate); HMPPC, hydroxymethyl pentylcyclohexene carboxaldehyde (Lyral); IVDK, Information Network of Departments of Dermatology; MCI/MI, methylisothiazolinone/methylchloroisothiazolinone (Kathon CG); MDGN + PE, methyl-dibromo glutaronitrile + phenoxyethanol (Euxyl K400). Source: From Ref. 4. patients patch tested and it was the thirteenth most common overall allergen (20). Some believe that even Oscar Wilde suffered from contact dermatitis from a PPD-based hair dye (21). Allergic contact dermatitis to PPD characteristically involves the scalp, hairline, face, eyelids, ears, and shoulders (11). Allergic reactions are signifi cantly more common in home dye kits than professional treatments by hairdressers (2). Although most hair dyes rarely contain concentrations greater than 2% (22), PPD is one of the most potent contact allergens known (2). In fact, concentrations greater than 10% are known to actively sensitize almost all individuals (22). Furthermore, sensitization rates for PPD may vary among different racial groups. Dickel and colleagues showed that blacks have signifi cantly higher sensitization rates of PPD (10.6%) when compared to whites (4.5%; p=.006). These differences in sensitization rates may be due to variation in allergen exposure among different racial groups or interindividual variations in the N-acetylation capacities of human skin for PPD (199). Although allergic contact reactions to PPD are more common, contact urticaria and anaphylaxis may also occur (23,24). Belton and Chira reported a 68-year-old woman with a history of anaphylaxis to a hair dye containing PPD, who died due to anaphylaxis upon reexposure to a different hair dye that also contained PPD (25). There have also been several reported cases that have suggested allergic reactions to the dyed hair itself (10). However, fully developed (oxidized) PPD is not allergenic and PPD-sensitized patients generally do not need to cut their hair if recently dyed with PPD (11). Therefore, most of these case reports are probably due to improperly dyed hair, resulting in unoxidized, residual antigens (10). Although most cases of PPD allergy result in erythematous and eczematous reactions to the face and hairline, ACD to PPD may occasionally result in hair loss or unusual presentations. Tosti and colleagues reported two cases of telogen effl uvium secondary to hair dye allergy. One of these reports involved a 50-year-old woman who developed an acute and severe eczematous dermatitis of the scalp, neck, face, and ears fi ve days after using a hair dye. Diffuse hair loss followed, involving more than 70% of her scalp. Subsequent patch testing demonstrated an intense reaction to para-phenylenediamine (26). The possibility of extensive and irreversible follicular damage after repeated use of hair dyes in allergic patients has also McMichael PTR 01/21/08 Chapter 17

244 Askari and Warshaw

TABLE 6 Permanent, Semipermanent, and Temporary Hair Dyes Reported to Cause ACD Allergen References Conc. vehicle 2,4-Diaminophenol (2) 2.0, petb 2, 7-Naphthalenediol (157) 0.1, aqc 2-Aminomethyl-p-aminophenol HCL (158) 1.0, aqc 2-Chloro-p-phenylenediamine (159) 1.0, petc 2-Nitro-p-phenylenediamine (2,34,159–161) 1.0, peta,b 3-Nitro-p-hydroxyethylaminophenol (162) 1.35, alcc 4-Amino-3-nitrophenol (163) 2.0, petc Basic Blue 99 (163,164) 0.5, petb Basic Red 22 (35) 1.0, petb Disperse Brown 1 (29) 1.0, peta,b Disperse Orange 3 (2,29,35,160,165) 1.0, peta,b HC Red B54 (36) 1.0, petc HC Yellow 7 (36) 1.0, petc Hydroquinone (166) 1.0, peta,b m-Aminophenol (2,167) 1.0, peta,b, 2.0, petb N-Phenyl-p-phenylenediamine (29) 0.25, petb o-Aminophenol (168) 1.0, 2.0, 10.0, petb p-Aminophenol (2,29,167) 1.0, peta , 2.0, petb p-Phenylenediamine (26,29,160,161,169)d 1.0, peta,1.0, petb Resorcinol (26,161,169,170) 1.0, peta , 2.0, petb Solvent Red 1 (171) 0.5, petb Toluene-2,5-diamine (2,26,28,159,161,167) 1.0, peta,b, 2.0, petb aAllergen available from Chemotechnique Diagnostics (Patch Test Catalogue 2005). bRecommended concentrations by DeGroot (Patch Testing: Test Concentrations and Vehicles for 3700 Chemicals, 2nd Edition). cConcentration taken from the documented reference. dMultiple reports Abbreviation: ACD, allergic contact dematitis. Source: From Ref. 33. been reported (27). Erythema multiforme-like eruptions due to PPD allergy from hair dye has also been described (28). PPD was shown by Koopmans and Brynzeel to serve as a good screening agent for hair dye allergy since it cross-reacts with many para-compounds used in permanent and semi-permanent hair dyes, such as p-toluenediamine sulphate and p-aminophenol. However, it is not an effective screening agent for allergy to disperse dyes (azo compounds), which are mainly used in textiles and some permanent and semi-permanent dyes (29). Therefore, PPD-sensitive patients must avoid both permanent and semi-permanent hair dyes, and certain textile dyes (30). PPD-sensitive patients must use alternative dyes, such as lead oxide dyes, henna, and temporary dyes (31). Open patch testing with a hair dye 48 hours prior to coloring has been shown to be an excellent tool for preventing severe reactions and is recommended, but rarely implemented (10,32). There are many other hair dyes that may cause allergy. Sosted and colleagues (33) evaluated 229 hair dyes using a model based on the analysis of the chemical structure and ability of dyes to form an antigenic complex, thus predicting sensitization potentials in humans. Based on these predicted sensitization potentials and the prevalence of use in Europe, the authors proposed a hair dye screening series, which is listed in Table 7.

Semipermanent and Temporary Dyes Semipermanent dyes can withstand 4 to 5 washings and are usually formulated in a shampoo base. These dyes generally have a small molecular size, allowing them to penetrate into the hair cortex (19). They generally consist of derivatives of nitroanilies, nitrophenylenediamines, and nitroaminophenols (12). Despite being used widely, semipermanent dyes rarely cause sensitization, probably because they remain on the hair for only a short period of time (34). Perno and Lisi reported a 48-year-old woman who presented with large, erythematous, pso- riasiform patches on her neck, upper trunk, and wrists, which began two days after using a McMichael PTR 01/21/08 Chapter 17

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TABLE 7 Proposed Hair Dye Screening Series Allergens 1-Hydroxyethyl-4,5-diaminopyrazole sulfate 1-Naphthol 2,4,5,6-Tetraaminopyrinidine 2,4-Diaminophenoxyethanol HCl 2,7-Naphthalenediola 2-Amino-3-hydroxypyridine 2-Amino-6-chloro-4-nitrophenol 2-Methyl-5-hydoxyethylaminophenol 2-Methylresorcinol 3-Nitro-p-hydroxyethylaminophenol 4-Amino-2-hydroxytoluene 4-Amino-3-nitrophenola 4-Amino-m-cresol 4-Chlororesorcinol 4-Hydroxypropylamino-3-nitrophenol Acid Violet 43 Disperse Violet 1 HC Blue 2 HC Red 3 m-Aminophenola N,N,-bis(2-hydroxyethyl)-p-phenylenediamine o-Aminophenola p-Aminophenola Picramic acid p-Methylaminophenol p-Phenylenediaminea Resorcinola Toluene-2,5-diaminea a Documented to cause allergic contact dermatitis. Source: From Ref. 33. semipermanent hair dye. Patch testing showed a positive reaction to three nitro semipermanent dyes (34). Temporary dyes generally last only until the next washing and can be found in hair color setting lotions (19). They generally consist of mild, organic acids and dyes that coat the hair shaft (10), such as Basic Red 22 (35) and HC Yellow 7 (36).

Hair Restorers (Metallic Dyes) Hair restorers are usually used by men to gradually darken their hair and conceal graying. The most common ingredient is lead acetate with colloidal sulfur or sodium thiosulfate (19). These agents deposit black lead oxides and sulﬁ des, which progressively coat the hair shaft. Others hair restorers include basic dyes, bismuth citrate, indolamine, and indophenols. As a group, these agents are generally harmless to the hair (12). A literature search revealed that there has been only one case report of contact dermatitis to lead acetate. Edwards described a 70-year-old man who developed a pruritic, papulo-vesicular eruption of the scalp, forehead, cheeks, and upper torso shortly after using a lead acetate dye. Patch testing to lead acetate (0.5 pet) was positive (37).

Vegetable Hair Dyes There are several vegetable hair dyes including henna, indigo leaves, chamomile ﬂ owers, and powdered walnuts. Henna is the most commonly used vegetable dye and is produced from powdered leaves of Lasonia inermis. The active ingredient is lawsone (2-hydroxy-1,4-napthoquinone), which results in a reddish color that usually persists for a few weeks (19). Henna hair dye may be used alone or combined with other coloring agents, such as p-phenylenediamine (38). When pure henna is used, the dying process may take six or more hours. However, the same cosmetic effect can be achieved within 30 minutes when henna is combined with PPD (39). McMichael PTR 01/21/08 Chapter 17

246 Askari and Warshaw

Allergic reactions to pure henna hair dyes are very rare. Ortiz and colleagues reported a 30- year-old female who developed severe erythema, edema, and pruritus of the forehead, eyelids, ears and scalp within hours of using a natural henna hair dye. She had used the same dye two months prior and had developed intense pruritus of the scalp without evidence of dermatitis. Patch testing showed a positive reaction to pure henna, but a use test to pure henna was negative (40). Oztas and colleagues also reported a 38-year-old woman who developed severe angioedema involving her eyelids, face, forehead, scalp, and tongue within four hours of using a commercial henna hair dye. Patch testing revealed a positive reaction to both natural henna (1% aq) and PPD (41). There have also been two reports of palpebral eczema due to pure henna hair dye (42,43). Henna can also be found in many products besides hair dyes. It may be found in a variety of shampoos, conditioners, and other products that do not alter the color of the hair, especially in Europe (44). Temporary henna tattoos are also becoming increasingly popular, especially among teenagers who view them as attractive and harmless (45). Many tattoo makers use “black henna,” which may contain PPD in order to hasten the dye process, enhance darkness, and increase longevity of the tattoo (30). In the United States, it is illegal to import henna tattoo dyes that contain PPD. Unfortunately, cosmetic samples used exclusively by professionals, such as salons and fair booths, do not require ingredient declarations (45). Brancaccio and colleagues (46) demonstrated that some black henna tattoo dyes can contain up to 15.7% PPD by high performance liquid chromatography. Practitioners should be aware of PPD sensitization via “black henna” tattoos as this is a potentially important historical clue in patients who subsequently react to PPD-containing hair dyes. Jasim and colleagues (30) reported a 15-year-old boy with a previous history of a blistering reaction to black henna tattoo. After this patient was re-exposed to a PPD containing hair dye, he developed severe facial edema that progressed to respiratory difﬁ culties requiring intu- bation. The application of PPD for twenty minutes resulted in severe blistering at 24 hours.

Fragrances According to the IVDK study, fragrances were the second most common category found in hair products to cause allergic contact dermatitis (Table 5). The NACDG found that approximately 10% of all individuals patch tested had a positive reaction to a fragrance (20). A similar fi nding was seen among patients suspected to have an allergy to hair products (9%) (4). Currently, it is estimated that there are more than 5,000 different fragrances used in cosmetics, including haircare products (11,47). The most common markers for fragrance allergy are fragrance mix, balsam of Peru, and hydroxymethyl pentylcyclohexene carboxyaldehyde (Lyral) (4). The standard fragrance mix consists of seven chemicals and one natural extract: eugenol, isoeugenol, geraniol, cinnamal, hydroxycitronellal, alpha-amyl cinnamic aldehyde, cinnamic alcohol, and oak moss absolute. In the IVDK study, fragrance mix was responsible for causing positive reactions in 11.4% of patients suspected of having an allergy to a hair product (4). Studies have shown that this mix can detect between 70–80% of all individuals with a fragrance allergy (48). Balsam of Peru, (Myroxylon pereirae), is a natural mixture of aromatic chemicals including cinnamic aldehyde, cinnamic alcohol, methyl cinnamate, benzyl cinnamate, benzyl benzoate, benzoic acid, benzyl alcohol, and vanillin (31). Balsam of Peru is also a common allergen found in hair products, ranking fi fth in the IVDK study (Table 5). It acts not only as a fragrance, but also as an antibacterial, antifungal, and antiscabetic agent (11). Studies have shown that balsam of Peru can detect up to 50% of fragrance-sensitive individuals (49). Furthermore, Larsen and colleagues (50) found that patch testing with four fragrances (balsam of Peru, narcissus oil, sandalwood oil, and ylang-ylang oil), in addition to the fragrance mix, detected approximately 96% of individuals with fragrance allergies. Hydroxymethyl pentylcyclohexene carboxaldehyde (HMPPC or Lyral) is another emerging sensitizer, especially in Europe where it has been reported to affect up to 2.7% of the population (51). Absolute and synthetic jasmine has also reported to be helpful in detecting additional cases of fragrance allergy (52). In general, allergies to fragrances are very diffi cult to manage for several reasons. First, fragrances are diffi cult to avoid since they are ubiquitous, especially in hair products. Second, there McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 247 are many covert sources of fragrances. For example, cosmetic manufacturers are not required by law to list specifi c fragrances, since they are considered trade secrets. Rather, they are only required to place “fragrance” or “perfume” on the ingredient label (31). “Unscented” cosmetics may contain a masking fragrance designed to hide the natural odor of the product (53). Third, fragrances that function as preservatives or emollients can legally be included in a “fragrance-free” product (54). Dual functioning agents are less common sensitizers and include benzyl alcohol, benzal- dehyde, ethylene brassylate, cyclopentadecanolide (55), essential oils, fl ower plant extracts, and fl avorings. Finally, patients also need to be advised that there may be extensive cross-reactivity among fragrances (56). A suggested fragrance screening series is listed in Table 8.

Botanicals Botanicals have become popular ingredients in haircare products since many consumers believe they are “natural” and therefore “non-allergenic” (57). Botanicals are plant extracts that are used principally for their medicinal properties, but many botanicals, including essential oils, are also used as fragrances (56). Although little is known about the prevalence of allergic reactions to botanicals (11), it is mentioned here to stress the importance of avoiding botanicals in fragrance-sensitive individuals. There is no screening allergen or mix for botanicals currently available (58). Simpson patch tested 140 patients suspected of contact dermatitis to 47 commonly used botanical extracts and divided these patients into two groups. The “high-risk” group consisted of 21 patients with a history of botanical use and whose dermatitis could not be explained by routine patch testing. The control group consisted of 119 patients who were being evaluated for contact dermatitis but had no history of botanical use. The high-risk group showed a statistically signiﬁ cant higher rate of relevant botanical allergies (47.6%) when compared to the control group (3.4%) (58). The proposed botanical screening tray suggested by the authors of this study is listed in Table 9. Kiken and Cohen (59) also reviewed botanical extracts known to cause ACD; these botanicals included: aloe, arnica ﬂ owers, centella asiatica, chamomile, cucumber, peppermint, rosemary, sage, stinging nettles, and witch hazel. A literature search revealed only one report of

TABLE 8 Fragrance Screening Series Allergen Concentration (%) Amyl cinnamaldehyde 2.0 Benzyl alcohol 1.0 Benzyl salicylate 2.0 Cananga oil 2.0 Cinnamic alcohol 2.0 Cinnamic aldehyde 1.0 Eugenol 2.0 Geraniol 2.0 Geranium oil, bourbon 2.0 Hydroxycitronellal 2.0 Isoeugenol 2.0 Jasmine absolute, Egyptian 2.0 Jasmine synthetic 2.0 Lavender absolute 2.0 Lyral 5.0 Methyl anthranilate 5.0 Musk ketone 1.0 Musk moskene 1.0 Musk xylene 1.0 Narcissus absolute 2.0 Oakmoss absolute 2.0 Rose oil, Bulgarian 2.0 Sandalwood oil 2.0 Vanillin 0.0 Ylang-ylang oil 2.0 All allergens are tested in petrolatum. Source: From Ref. 156. McMichael PTR 01/21/08 Chapter 17

248 Askari and Warshaw

TABLE 9 Proposed Botanical Screening Tray Allergen Concentration (%) Cananga oil 2.0 Compositae mix 6.0 Dandelion 2.5 Geranium oil (Bourbon) 2.0 Lavender (absolute) 2.0 Lichen acid mix 0.3 Neroli 4.0 Rose oil (Bulgarian) 2.0 Sandalwood oil 2.0 Spearmint oil 5.0 Tea tree oil 5.0 Ylang-ylang oil 2.0 All allergens are tested in petrolatum. Source: From Ref. 58. botanical allergy linked to hair products. Mozelsio reported a 38-year-old male who developed an immediate hypersensitivity reaction after topical application of tea tree oil to psoriatric lesions on his legs. Prick testing showed a positive reaction to tea tree oil. Interestingly, the patient had no prior exposure to tea tree oil except for his haircare products (60).

Preservatives Preservatives are widely used in hair products to prevent microorganism growth, which can lead to product degradation and potentially cause consumer infections. According to the IVDK study, preservatives were the third largest category of allergens responsible for allergic contact dermatitis in hair products (Table 5). There are approximately 60 major preservatives used in cosmetics, including haircare products (12). The ﬁ ve major classes of preservatives used in the United States, along with the number of cosmetic products preserved in 2003 within each class, are listed in Table 10.

TABLE 10 Classiﬁ cation of the Major Preservatives Found in Cosmetics and Number of Cosmetic Products Contained in Each Preservative Class in the United States (2003) Preservative groups Number of cosmetic products 1. Paraben esters 17,336 methyl-4-hydroxybenzoate (methyl paraben) ethyl-4-hydroxybenzoate (ethyl paraben) propyl-4-hydroxybenzoate (propyl paraben) butyl-4-hydroxybenzoate (butyl paraben) 2. Formaldehyde and formaldehyde releasers formaldehyde (methanal) 118 1-(3-chloroallyl)-3,5,7-triaza-1-azoniaadamantane chloride (Quaternium-15, Dowicil 200) 516 imidazolidinyl urea (Germall 115) 2,038 diazolidinyl urea (Germall II) 725 2-bromo-2-nitropropane-1,3-diol (Bronopol, BNPD) 168 dimethyloldimethyl hydantoin (DMDM hydantoin, Glydant) 993 3. Isothiazolinones 2-methyl-5-chloro-4-iothiazolin-3-one/2-methyl-4- 699 isothiazolin-3-one (MCI/MI, Kathon CG, Euxyl K100) 4. 1,2-dibromo-2,4,-dicyanobutane (Methyldibromoglutaronitrile, 95 MDBGN, Tektamer 38. When associated with phenoxyethanol: Euxyl K400) 5. 3-Iodo-2-propynyl-butylcarbamate (IPBC, Glycasil, Troysan 172 KK-108a, Biodocarb C450) Source: Modiﬁ ed from Ref. 66. McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 249

Although paraben esters are the most commonly used preservatives, allergy to parabens is rare. Formaldehyde and formaldehyde-releasing preservatives are responsible for most preservative allergies in a wide variety of sources. Based on the IVDK study (Table 5), the most common preservative allergies found in hair products were: methyldibromoglutaronitrile/ phenoxyethanol (MDGN+PE, Euxyl K400), methylisothiazolinone and methylchlorothiazolinone (MI/MCI= Kathon CG), and formaldehyde and formaldehyde releasers (4). A suggested preservative screening series is provided in Table 11.

Methyldibromoglutaronitrile/Phenoxyethanol (MDGN+PE, Euxyl K400) Euxyl K400 is a 4:1 mixture of methyldibromoglutaronitrile (MDGN) and 2-phenoxyethanol (PE). It is effective against bacteria, fungi, and yeasts (7). As documented by the NACDG, there has been a steady increase in prevalence to this compound in North America from 1.5 % (1994–6) to 5.8% (2001–2), making it the eleventh most common allergen in patients referred for patch testing (20). Most cases of allergy to Euxyl K400 are to MDGN (61); phenoxyethanol is an extremely rare sensitizer (20). Leave-on products are largely responsible for most reactions, but ACD may also result from rinse-off products (62). In order to reduce sensitization to Euxyl K400, the maximum allowable concentration of MDGN found in “leave-on” products has been restricted to 0.025% (63). Armstrong and colleagues reported an 18-year-old woman who presented with a six month history of severe scalp eczema in association with mild eczema of the axillary, pre-sternal,

TABLE 11 Suggested Preservative Screening Series Allergen Concentration (%) 2,6-di-tert-Butyl-4-cresol (BHT) 2.0 2-Bromo-2-nitropane-1,3-diol 0.25 2-Chloracetamide 0.2 2-Phenylphenol (o-phenylphenol) 1.0 3,3,4,5-Tetrachloro salicylanilide (TCS) 0.1 3,4,4-Trichlorocarbanilide (TCC Triclocarban) 1.0 3,4,5-Tribromosalicylanilide (TBS) 1.0 3-tert-Butyl-4-methoxyphenol (BHA) 2.0 4-Chloro-3,5-xylenol (PCMX) 0.5 4-Chloro-3-cresol (p-Chloro-m-cresol, PCMC) 1.0 Amidoamine 0.1a Benzalkonium choloride 0.1a Benzyl alcohol 1.0 Bithionol 1.0 Chlorhexidine digluconate 0.5a Chloroquinaldol 5.0 Cocamide DEA 1.0a Diazolidinyl urea 2.0 DMDM hydantoin 2.0a Dodecyl gallate 0.25 Ethylenediamine tetraacetic acid disodium dehydrate 1.0 (Disodium EDTA) Methyldibromoglutaronitrile/phenoxyethanol 1.5 Glutaraldehyde 0.2b Hexachlorophene 1.0 Hexahydro 1,3,5-tris (2-hydroxy-ethyl) triazine (Grotan BK) 1.0a Imidazolidinyl urea 2.0 Octyl gallate 0.25 Phenylmercuric acetate 0.01a Propyl gallate 1.0 Sodium metabisulﬁ te 1.0 Sodium omadine (sodium 2-pyridinethiol-1 oxide) 0.1a Sorbic acid 2.0 Thimerosal (Merthiolate) 0.1 Triclosan (Irgasan DP) 2.0 All allergens are tested in petrolatum as the vehicle, except those marked aallergen tested in water; ballergen is emulsiﬁ ed with sorbitan sequioleate 5%. McMichael PTR 01/21/08 Chapter 17

250 Askari and Warshaw interscapular, and inguinal region. The distribution was consistent with seborrheic dermatitis, however the severity of scalp involvement was unusual. After conventional therapy failed, the patient was discovered to have a positive patch reaction to MDGN, which was found in patient’s hair conditioner and hair mousse (64).

Methylisothiazolinone and Methylchlorothiazolinone (MI/MCI; Kathon CG) Kathon CG is the brand name preservative of a mixture of 2-methyl-5-chloro-4-isothiazolin-3- one and 3-methyl-4-isothiazolin-3-one (ratio of 3:1) (65). It is effective against a wide range of fungi, yeasts, and gram-positive and negative bacteria. The most common products to cause allergy are leave-on products such as moisturizing creams and lotions (66). In the United States, it is regulated to no greater than 7.5 ppm in leave-on products and 15 ppm in rinse-off products (67). When concentrations exceed 200 ppm, Kathon CG is an irritant. Although isothiazolinones share a similar chemical structure, cross-reactions are uncommon (68).

Formaldehyde and Formaldehyde Releasers Formaldehyde, or methanal, is rarely used in cosmetics since it a frequent sensitizer, irritant, and possible carcinogen (69). In fact, formaldehyde use is prohibited in cosmetics in both Japan and Switzerland (70). However, formaldehyde can still be found in shampoos and haircare products in the United States (11). Although the cosmetic industry has dramatically reduced their use of formaldehyde over the years, there continue to be occult sources of free formaldehyde. These include gradual degradation of formaldehyde releasers, impurities from raw materials, and slow release from plaster containers (10). Therefore, formaldehyde may still be present in products labeled “formaldehyde-free.” Many suppliers may also use formaldehyde to transport detergents to manufacturers, who may not be aware that it has been incorporated into their products, especially in body and hair shampoos (71). There have also been reports of formaldehyde being detected in cosmetics that were released from plastic tubes externally coated with melamine or carbamide-formaldehyde resin (72). Formaldehyde releasers are among the most effective preservatives, especially against gram-negative bacteria (73). Formaldehyde-releasing preservatives all contain an easily detach- able formaldehyde moiety, which is gradually released into the product and may induce sensitization. Approximately 50% of formaldehyde-sensitive patients also react to one or more formaldehyde-releasing preservatives (74) and therefore some experts believe that formaldehyde-sensitive patients should avoid all formaldehyde-releasing preservatives (75).

Quaternium-15 Quaternium-15 is one of the most potent formaldehyde releasers since it has the greatest potential for formaldehyde release (76). It is effective against yeasts, molds, and bacteria, especially against Pseudomonas aeruginosa (77). Most products, such as shampoos and conditioners, contain concentrations between 0.02–0.3%. A study by Parker and Taylor evaluated 89 patients allergic to quaternium-15, and determined that haircare products accounted for exposure in one-third of the patients. Furthermore, 55% of these patients were also allergic to formaldehyde (78). Quaternium-15 sensitive patients do not need to avoid other quaternary ammonium compounds (73) nor additives that have similar names (such as quaternium-11).

Bronopol (2-Bromo-2-nitropropane-1,3-diol) Bronopol is effective against both gram-positive and gram-negative bacteria, fungi, and yeasts. It is also particularly effective against P. aeruginosa (10). Concentrations usually range between 0.01–1% in shampoos and emulsions, and formulations greater than 1% are usually irritating. There has been a steady decline in the use of bronopol over the past 15 years (66). Fransway demonstrated that 70% of bronopol-sensitive patients had no reaction to formaldehyde or other formaldehyde releaser (74).

Diazolidinyl Urea Diazolidinyl urea (Germall II) is one of the newest formaldehyde releasers and provides excellent coverage against both gram-positive and gram-negative bacteria. It is often combined with parabens for optimal antifungal activity (known as Germaben II). Concentrations in personal McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 251 products generally range between 0.1–0.5% (66). Allergy may develop to the molecule itself or to free formaldehyde (79). Cross reactions with imidazolidinyl urea are common (10,66).

Imidazolidinyl Urea Imidazolidinyl urea (Germall 115) is the most commonly used preservative after parabens and is one of the weakest sensitizers among formaldehyde releasers (56). It is effective against both gram-positive and gram-negative bacteria (10), but is often combined with parabens for increased coverage against yeast and fungi (known as Germaben). Sensitization appears more related to the entire molecule and less to the release of formaldehyde. Concentrations vary between 0.03–0.2% in cosmetics (66).

Dimethyloldimethyl Hydantoin (DMDM Hydantoin) DMDM hydantoin, also known as Glydant, is a broad-spectrum preservative and is widely used in shampoos (7). Most formulations range between 0.1–1% and contain between 20–200 ppm free formaldehyde (80). In a study of 35 individuals allergic to formaldehyde, De Groot and colleagues demonstrated that 57% reacted to DMDM hydantoin (81).

Parabens Parabens, which include a family of alkyl esters, are the most commonly used group of preservatives (66). In 1995, a European study showed that parabens were found in 99% of all leave-on products and 77% of rinse-off products (82). Parabens are effective against fungi and gram-positive bacteria (10,83), and are generally used in concentrations ranging from 0.1–0.8% (66). Although parabens are the most common preservative used in hair products, they are one of the weakest sensitizers (12). Cross reactions commonly occur within the paraben esters (83), and may rarely occur with other para amino compounds such as para-aminobenzoic acid (PABA), paraphenylenediamine, benzocaine, and sulfonamides (69). Cooper and Shaw reported a 74-year-old-woman who developed severe itching and erythema of the face and scalp, and eyelid edema, which was attributed to a paraben allergy from a tar shampoo (84). In 1973, Fisher noted that individuals allergic to parabens often have false-negative patch test reactions when paraben patches were tested on normal intact skin of the back, and those with positive patch test reactions to parabens may sometimes continue to use parabens on other intact and uninvolved skin without any adverse reactions (85). Fisher offered two possible explanations for this “paraben paradox”: (a) patch testing is being performed on normal skin and (b) the concentration of the vehicle ingredient is too low (85). Other theories have also been proposed (86).

Other Preservatives Iodopropynyl butylcarbamate (IPBC) is very effective against fungi, Staphylococcus aureus, and various gram negative bacilli. Currently, there are only a handful of reports documenting allergic reactions to IPBC (87). IPBC may be found in shampoos, moisturizing lotions, and creams (7). Propylene glycol is a popular vehicle and solvent with antimicrobial properties and is used in some “preservative-free” hair products and topical medications, such as minoxidil. In certain products, the amount of propylene glycol may be as high as 70%. It has been shown that concentrations greater than 25% have antibacterial (E. coli, Pseudomonas) and antifungal activity (Candida albicans, Bitryrosporum obiculare) (10). Funk and Maibach classiﬁ ed reactions to propylene glycol into four types: irritant contact dermatitis, allergic contact dermatitis, nonimmunologic contact urticaria, and subjective or sensory irritation (88). The data on the prevalence of allergic sensitization to propylene glycol are problematic, as different studies have utilized different patch test concentrations, and have used various criteria for the interpreting results (89). Products that contain greater than 10% propylene glycol are more likely to cause irritant reactions and be misinterpreted as allergic contact dermatitis (10). Gonzalo and colleagues recommended that allergic reactions to propylene glycol should be conﬁ rmed by repeated patch testing, dilutions, and repeat open application testing (ROAT) (89). Propylene glycol is commonly found in corticosteroid creams, gels, ointments, and lotions. Consequently, propylene McMichael PTR 01/21/08 Chapter 17

252 Askari and Warshaw glycol allergy should be suspected when a patient complains of worsening dermatitis after corticosteroid use (90). Fisher recommends substituting glycerin for patients allergic to propylene glycol (91). Benzyl alcohol acts not only as a preservative, but may also serve as a fragrance and local anesthetic. Benzyl alcohol is also known as benzene methanol, phenyl methanol, and phenyl carbinol. Although it is increasingly used in hair dyes to produce deeper shades, it is a rare sensitizer (10). In fact, Fransway reported a positive patch rate of less than 1% (83). Benzyl alcohol may cross-react with balsam of Peru (10). Sorbic acid is used as an alternative preservative in some hair products. It is a rare sensitizer, but may induce nonimmunologic urticaria and cause facial ﬂ ushing and stinging (16). Sorbic acid may cross-react with potassium sorbate (10). Triclosan, also known as Irgasan DP- 300, is an anti-bacterial agent and preservative used in shampoos and soaps. However, allergy to this preservative is rare (10). Other preservatives reported as allergens include: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, propyl gallate (12), chloroacetamide (12), and t-butyl hydroquinone (92).

Bleaches Hair bleaches, such as ammonium persulfate, are commonly used for lightening darker shades of hair. There are two main types of hair bleaches: hydrogen-peroxide and zinc formaldehyde sulfoxylate bleaches. Hydrogen peroxide based bleaches are more common and may also include ammonium persulfate as a “booster,” resulting a more potent bleach (93). Multiple components are mixed together and result in a viscous paste that is applied to the hair for 10–40 minutes, depending on the desired amount of bleaching. The hair is then thoroughly washed. Zinc formaldehyde sulfoxylate bleaches are primarily used to bleach artiﬁ cially dyed hair (19). According to the IVDK study, ammonium persulfate was the eighth most common cause of allergic contact dermatitis from hair products (Table 5). Ammonium persulfate may also cause irritant contact dermatitis and Type I reactions (94), and immediate reactions more common than delayed reactions (95). The mechanism of these immediate reactions is unclear, but it appears that some are IgE mediated (96) and can be quite severe, resulting in asthma and even vascular collapse. Brubaker reported a 54-year-old woman with a history of bleaching her hair with ammonium persulfate for 25 years without any problems, who developed generalized erythema and urticaria followed by shock after bleaching her hair. Use testing was positive to ammonium persulfate within 15 minutes (97). Care must also be taken during closed patch testing. Perfetti and colleagues reported an anaphylactoid reaction to ammonium persulfate in a 21-year-old hairdresser who experienced severe bronchial obstruction within 90 minutes of closed patch testing (98). Although ammonium persulfate can be found in hair lighteners in concentrations as high as 60%, the Cosmetic Ingredient Review (CIR) expert panel recently cautioned that urticarial reactions may be more common at concentrations greater than 17.5% (99). Ammonium persulfate may also cross react with potassium persulphate (100).

Emulsifi ers Emulsifi ers are commonly found in skincare products, cosmetics, and topical medications. These agents enhance the miscibility of aqueous and fatty components. As a general rule, emulsifi ers can be mildly irritating but rarely sensitize (10,101). Although emulsifi er allergies are not common, they may be an important cause of adverse reactions to cosmetics and topical medications, which can be easily overlooked. Tosti and Gerra studied 737 patients suspected of having a cosmetic or medicament-related contact dermatitis and determined that 5.3% had a positive patch test to emulsifi ers (102). Triethanolamine (2.5% pet) was the most frequent sensitizer, but other emulsifi ers included: cetyl stearyl alcohol (Lanette O), sorbitan sesquioleate (Arlacel 83), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monooleate (Tween 80), and Amerchol L101 (lanolin derivative). It was also determined that patients with emulsifi er allergies generally have a higher prevalence of positive patch test reactions to other ingredients found in topical preparations, especially to lanolin and parabens (102). Further- more, patch testing with the actual products were frequently found to be negative. These fi nd- McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 253 ings suggest the importance of testing for emulsiﬁ ers when suspicious of topical preparations even when the suspected product results a negative patch test and other clinically relevant reactions have been found (102). Lanolin is a commonly used emulsiﬁ er and emollient in cosmetics and topical medications (10). It is a natural product derived from the sheep’s wool and is a complex mixture of hundreds of esters of alcohol and fatty acids with a wide variation of purity (103). The prevalence of lanolin allergy is controversial. The primary sensitizer is believed to be in the wool-wax lanolin alcohols and patch testing is performed to 30% wool-wax alcohols (pet) (56), however the exact allergenic fraction is not known (10). Matthieu and Dockx have suggested that Amerchol L101, a commercially available product from the hydrolysis of wool fat, may actually be a more sensitive screening agent for lanolin allergy (104). However, there is a general agreement that lanolin allergy is more frequently seen from topical therapeutic medications in patients with leg ulcers and stasis dermatitis, while cosmetic lanolin allergy is uncommon from application to normal skin (56). There is also a lanolin paradox, which is similar to the paraben paradox. This paradox states that lanolin found in topical therapeutic agents sensitize a high proportion of patients, whereas the same lanolin may be safely used in cosmetics. Furthermore, patients sensitive to lanolin from topical therapeutic agents may tolerate lanolin-containing cosmetics when applied to normal, unaffected skin (105,106).

Permanent Waves, Hair Straighteners, and Hair Removers Cold Waves: Ammonium Thioglycolate Individuals with fi ne and thin hair often use permanents to give the illusion of a fuller head of hair. The term cold waves stems from the fact that heat is not necessary in this process. Cold permanent waves involve several steps: First, the hair is treated with an alkaline shampoo, thus allowing the hair to be more permeable to the waving fl uid. Next, the hair is set in curls and an alkaline waving solution (usually an alkaline thioglycolate) is applied, which disrupts the strong disulfi de bonds of the keratin fi laments and lasts for approximately 10–20 minutes. Then, the waving fl uid is removed by use of a towel while the hair remains in the curlers. Finally, acidic hydrogen peroxide solution is applied and neutralizes the waving fl uid, thus restoring the sulfur-sulfur bridges in the curled position (19). Since the 1930s, ammonium thioglycolate has been used in cold wave solutions for salon and home use. If applied improperly, ammonium thioglycolate can cause acute irritant dermatitis and extensive hair damage including hair breakage and loss (10,12), but true allergic reactions are rare (10,100).

Acid Perm Waves: Glyceryl Monothiogylocolate Because cold wave permanents containing thioglycolic acid are alkaline and irritating, most salons today use a gentler process known as acid waves. The term “acid” is a misnomer since most acid perms are actually alkaline and the pH varies among manufacturers (107). Most acid wave products are based on glyceryl monothioglycolate (19). According to the IVDK study, glyceryl monothioglycolate was responsible for 1.9% of reactions in hair products (Table 5). It was very popular in the 1980s in many Western countries. In 1995, however, most German producers of professional hair cosmetics discontinued the use of glyceryl monothioglycolate because of its strong sensitizing potential (100). Glyceryl monothioglycolate is especially problematic since it may remain on hair for up to three months (108) and can penetrate intact rubber gloves (10). In fact, allergic reactions to glyceryl monothioglycolate are more common in hairdressers than consumers (109). Plastic laminate gloves (known as “4H gloves”) may provide protection to hairdressers (10). Engasser reported a 25-year-old hairdresser with both ACD and Type I allergies to glyceryl monothioglycolate (110). Cross reactions between ammonium thioglycolate and glyceryl monothioglycolate are rare (10). Alternatives are available for patients sensitive to glyceryl monothioglycolate and include sulfi tes and cysteamine hydrochloride. Sulfi te waves, used primarily at home, have a more pleas- ant odor, but provide weaker curls and require more time. Most adverse reactions to sulfi te waves have been irritant reactions, but there have been occasional reports of allergic contact reactions (10). Fisher described a 36-year-old woman who developed an eczematous eruption McMichael PTR 01/21/08 Chapter 17

254 Askari and Warshaw over her scalp, forehead, and occipital region after forty-eight hours of her second exposure to a permanent containing sodium bisulﬁ te; subsequent patch testing was positive to sodium bisulﬁ te (2% pet) (111). Cysteamine hydrochloride (CHC) is another permanent-wave ingredient that is thought to be less damaging since the reaction occurs at a relatively neutral pH. Although there have been a few causes of allergic contact reactions in hairdressers (112), a recent literature search showed no reported cases of allergy in consumers since its introduction in the United States in 1993. CHC is an excellent alternative for individuals allergic to glyceryl monothioglycolate.

Hair Straighteners Straightening hair is accomplished by three main steps. First, straightening fl uid, such as sodium hydroxide, sodium bisulfi te, or ammonium thioglycolate, is applied for 15 minutes. Next, the hair is mechanically straightened by intermittent combing for 15–20 minutes. Finally, the hair is rinsed with water and neutralizing fl uid for 3–5 minutes. Neutralizing agents usually consist of either non-alkaline shampoos, sodium bicarbonate, or hydrogen peroxide (19). Straighteners can be irritating due to their high alkalinity and can seriously damage hair if used excessively (113).

Hair Removers (Substituted Thiols, Thioglycolates, and Efl ornithine Hydrochloride) Depilatories are often used by patients susceptible to pseudofolliculitis barbae. Barium sulfi de depilatories are often irritating and malodorous, but most modern depilatories use substituted thiols, which act more slowly but are less irritating (i.e., calcium thioglycolates). Efl ornithine hydrochloride cream, a prescription depilatory, reduces unwanted facial hair by inhibiting ornithine decarboxylase (12). Hickman and colleagues demonstrated that efl ornithine HCl 13.9% cream can be irritating with exaggerated use, but did not appear to cause allergic or photoallergic contact dermatitis (114).

Shampoos, Conditioners, Leave-In Products, and Sunscreens Shampoo ingredients (such as cocamidopropyl betaine) were the sixth most common category responsible for ACD from hair products in the IVDK study (Table 5). Shampoos clean hair by removing dirt, scale, sebum, and microorganisms by use of anionic, cationic, amphoteric, and/ or nonionic surfactants (12,19). The use of conditioners and after-shampoo products improve the appearance, fullness, feel, luster, and manageability of hair. It has been assumed that anionic surfactants within many shampoos leave the hair with many negatively charged sites. The active ingredients of most conditioners are usually positively charged molecules, which neutralize the negatively charged hairs. There are also several shampoos that include conditioning agents, usually referred to as “2-in-1 shampoos.” However, formulation of this class of shampoos is difﬁ cult since the anionic surfactants can inactivate cationic conditioners. The use of silicone conditioners, such as dimethicone copolyol, are more compatible with anionic detergents since silicone carries no charge. Some experts have suggested that these silicone-based 2-in-1 shampoos result in increased loss of hair, but there has been no clear evidence supporting this claim (19). Other commonly used conditioning agents include: quaternium compounds, hydrolyzed proteins, polymers, lipids, and glycols (12). Most shampoos are diluted several times with water and have very short contact time with the scalp. Therefore, there are very few serious side effects. However, when ACD to a shampoo occurs, it characteristically affects the ears, eyelids, edges of the scalp, neck and shoulders (19). Allergens reported in shampoos include surfactants, fragrances, preservatives, and antidandruff agents. A list of reported allergens found in shampoos is summarized in Table 12.

Surfactants Cocamidopropyl Betaine (CAPB) Cocamidopropyl betaine is the most commonly used amphoteric surfactant in cosmetics including hair products (12). According to data submitted to the FDA by the cosmetic industry, CAPB was found in 6.4% of all personal care products in 1994 (115). According to the McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 255

TABLE 12 Reported Allergens in Shampoos Allergen Purpose Conc. (%) Vehicle Ref. Benzophenone-3 Sunscreen 2.0 pet 133 Captan Antidandruff agent 0.1 pet 128 Cetrimonium bromide (cetrimide) Conditioner 0.01 aq 172 Cinnamic alcohol Fragrance 2.0 pet 19 Cocamide DEA Nonionic surfactant 0.5 pet 120 Cocoamidopropyl betaine Detergent 1.0 aq 124 Coco-betaine Amphoteric detergent 2.0 aq 123 Decyl glucoside Nonionic surfactant 2.0 aq 173 EDTA Prevents oxidation 0.1, 1.0 aq 174 Formaldehyde Preservative 1.0 aq 175,176 Lauramide DEA Nonionic surfactant 1.0 pet/aq 120 Linalool Fragrance 30.0 pet 19 Miranols (imidazole derivatives) Amphoteric surfactant 1.0 aq 177 Methyldibromo glutaronitrile (MDGN) Preservative 0.3 pet 64 Paraben mix Preservative 1.0 pet 84 Potassium cocohydrolyzed animal protein Detergent 5.0 & 30.0 aq 178 Selenium sulﬁ de Antidandruff agent 2.0 pet 179 Sodium laureth sulfate Amphoteric surfactant 1.0 aq 123,180 Sodium pyrithione Antidandruff agent 0.3 aq 181 TEA PEG-3 cocamide sulfate Amphoteric detergent 1.0 aq 124 Triethanolamine poly-peptide oleate Surfactant 10.0 aq 182 Zinc pyrithione Antidandruff agent 1.0 pet 93,126,127,183,184 Abbreviations: EDTA, (disodium) ethylenediamine-tetraacetic acid; MDGN, methyl-dibromo glutaronitrile. Source: Modiﬁ ed from Ref. 19.

IVDK study, CAPB was the eleventh most common ingredient in hair products responsible for allergic contact reactions (4). There have been many reports of allergic contact reactions to CAPB, with over 70 published cases of allergic contact dermatitis to cosmetic products (115). However, it is diffi cult to interpret CAPB patch test results since CAPB may also cause irritant reactions, resulting in false-positive readings (10). To complicate matters even more, the specifi c component of CAPB responsible for these allergic reactions is unclear. Depending on the purity of CAPB, various amounts of reactants and intermediates can remain as impurities, such as amidoamine, dimethylaminopropylamine (DMAPA), monochloroacetic acid, sodium chloride and coconut fatty acids (115–117). Foti and colleagues demonstrated that ten patients previously shown to be allergic to CAPB from one source, were later shown to have no reactions when patch tested from a different source with greater purity. However, all patients were shown to have a reaction to pure amidoamine (0.5 and 0.25% aq) and DMAPA (1% aq), and they concluded that CAPB allergy is due to both of these impurities (118). Furthermore, it is diffi cult to manage patients with CAPB allergy since cross-reactivity with other coconut derived products is largely unknown (119). Other surfactants reported to cause ACD in hair products are cocamide DEA, lauramide DEA (120,121), cocamidopropyl hydroxysultaine (122), cocobetaine (123), and TEA-PEG-3 cocamide sulfate (124).

Antidandruff Shampoos Zinc Pyrithione (Vancide ZP, Zincon) Zinc pyrithione has both bactericidal and fungicidal properties, and is especially useful in the treatment of dandruff and hyperproliferative diseases such as scalp psoriasis and seborrheic dermatitis (125). Pereira and colleagues reported an allergic reaction from zinc pyrithione in a shampoo and identiﬁ ed seven other cases from the literature (126). Nielsen reported a 35-year- old woman with a history of stable scalp psoriasis for ﬁ ve years who developed acute dermatitis of the scalp after using a shampoo containing zinc pyrithione. Her second exposure resulted in widespread dermatitis of the scalp, upper trunk, axillae, and hands (127). Jo et al. reported a 43-year-old woman with stable psoriasis for 25 years, who developed scaly erythematous McMichael PTR 01/21/08 Chapter 17

256 Askari and Warshaw patches and plaques on her scalp, trunk, and extremities. Patch testing was positive to zinc pyrithione (125). Zinc pyrithione may cross-react with piperazine and ethylenediamine (10).

Captan (N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide, Vanicide 89 RE) Captan is primarily used as a fungicide and bacteriostat, especially in antidandruff shampoos. Epstein reported a 41-year-old man who used a hair product containing Dangard, a modiﬁ ed captan, and presented with acute dermatitis in a sun-exposed distribution. His reaction was most severe on his scalp and forehead, but also present on the lower parts of his face and neck. The reaction began shortly after having sun exposure. Photopatch testing conﬁ rmed Dangard as the responsible allergen (128). In 1992, however, captan was removed from the NACDG screening series due to high rate of false-positive reactions (10).

Conditioners Niinimaki et al showed that conditioners containing protein hydrolysates, which are used to “repair” broken hair, may cause contact urticaria, especially in patients with atopic dermatitis (129). Pasche et al reported a 41-year-old woman who developed contact urticaria associated with systemic symptoms (rhinitis, wheezing, and dyspnea) after two minutes of applying a hair conditioner. Prick testing was positive to “hydrolyzed proteins,” which contained a quaternary ammonium, stearyl trimethylammonium chloride, and hydrolyzed bovine collagen. The authors concluded that the bovine collagen protein was the most likely allergen (130). Schalock and colleagues reported a 53-year-old woman who presented with facial edema, erythema, and pruritus within one minute after applying a new hair conditioner. This progressed to diffuse pruritus of her trunk with gradual improvement over one hour after washing off the hair conditioner. Prick testing was positive to panthenol, which is a common conditioning agent found in haircare products (131).

Leave-in Hair Products (Hair spray, Foams, and Gels) Hair sprays allow styled hair to be kept in place by applying a fi lm polymer around the hair fi lament. Styling foams are similar, but also include a foam builder to produce a mousse. Styl- ing gels consist of a fi lm polymer and a thickener, and may contain titanated mica for glitter effects (19). Various allergens reported to cause allergic contact dermatitis in haircare products, excluding shampoos and dyes, are summarized in Table 13.

Sunscreens Some haircare products such as hair sprays, dyes, and shampoos may contain sunscreens to protect the hair color from degradation by sunlight (10), and may occasionally cause allergic contact dermatitis (132). The most common sunscreen allergens include the benzophenones, oxybenzone, octyl dimethyl PABA, and the dibenzoylmethanes such as avobenzone (PARSOL 1789) (17). These sunscreens can cause both allergic contact and photoallergic contact dermatitis. Nedorost (133) reported two cases of contact dermatitis and photocontact dermatitis to benzophenone-3 (2-hydroxy-4-methoxy-5 acid benzophenone) in haircare products. In the ﬁ rst case, a 38-year-old woman presented with a 2–3 year history of intermittent burning and pruritic facial erythema. Photopatch testing revealed a strong reaction to benzophenone-3, which was found in her shampoo and facial moisturizer. The second case involved a 57-year-old woman with a one-year history of peri-oral itching and erythema along with a three-day history of erythematous swelling over her face and the anterior neck with a demarcation at her collar line, which developed after sitting in the sun. Further evaluation showed positive patch and photopatch test reactions to benzophenone-3, which was discovered in both her lip balm and shampoo.

Topical Medications Minoxidil Topical minoxidil is a hypertrichotic agent used to treat androgenetic alopecia, and is available in 2% and 5% formulations. Overall, topical minoxidil has a favorable safety proﬁ le, but there have been many reports of both irritant and allergic reactions to both minoxidil and its vehicle, propylene glycol. There has also been at least one reported case of photoallergic contact derma- McMichael PTR 01/21/08 Chapter 17

Allergic Contact Dermatitis 257

TABLE 13 Reported Allergens Found in Hair Preparations (Excluding Shampoos and Dyes) Allergen (purpose) Hair product Conc. (%) Vehicle Ref. Ammonium persulfate (bleaching Hair bleach 2.5 pet 93,185 agent) Ammonium thioglycolate (waving Permanent wave 2.5 pet 186 agent) Benzoin (resin) Hair lacquer 10.0 pet/alc 19 Butylated hydroxyanisole (BHA; Hair cream 2.0 pet 187 antioxidant) Chloroacetamide (preservative) Hairdressing 0.2 pet 188 Compound tincture of benzoin (fragrance) Permanent wave 10.0 pet/alc 19 Cyclohexanone-formaldehyde resin Hair lacquer spray 1.0 acet + pet 189 D&C Yellow No. 11 (color) Hair cream 0.1 pet 190 D-Panthenyl ethyl ether (moisturizer) Hair lotion 30.0 pet 191 Diazolidinyl urea (preservative) Hair gel 1.0 pet 192 Dimercaprol chelating agent) Permanent wave 10.0 aq 186 Eugenol (fragrance) Hair cream 2.0 pet 19 Glutaral (glutaraldehyde; preservative) Hair conditioner 1.0 pet 193 Glyceryl thioglycolate (waving agent) Acid permanent wave 2.5 pet 107–109 Hexamidine isethionate (preservative) Hair lotion 0.15 aq 194 Hinokitiol (B-thujaplicin; hair growth Hair liquid 0.1 aq 195 stimulant) Laurylpyridinium chloride Hair conditioner 0.1 aq 196 (conditioner) Methyldibromo glutaronitrile (MDGN; Hair conditioner 0.3 pet 64 preservative) Methylisothiazolinone and methylc- Hair conditioner 100 ppm aq 19 hloroisothiazolinone (MI/MCI; preservative) Panthenyl ethyl ether (hair-conditioning Hair lotion 30.0 pet 191 agent) Procaine hydrochloride (local anesthetic Hair lotion 1.0 pet 197 and hair-growth promoter) Pyridoxine dioctanoate (antiseborrheic) Hair liquid 1.0 pet 195 Sodium bisulﬁ te Cold permanent wave 2.0 pet 111 Thioglycerin (depilatory) Depilating cream 10.0 aq 19 Zinc pyrithione (antidandruff) Medicated hair cream 1.0 pet 198 Source: Modiﬁ ed from Ref. 19.

titis (134). The most common complaint among users is scalp pruritus and scaling, which may be due to seborrheic dermatitis, irritant contact dermatitis, or allergic contact dermatitis (135). Although these reactions are clinically similar, it is critical to differentiate these reactions for optimal treatment. Recent studies indicate that most reactions to topical minoxidil are likely due to propylene glycol. As mentioned earlier, there are two available formulations of minoxidil, 2% and 5% solutions. When compared to the 2% solution, the 5% solution contains 2.5 times more propylene glycol. This may explain why phase III clinical trials showed that the 5% solution had three times more adverse reactions than the 2% solution (135). In the literature, ACD to topical minoxidil have been reported to occur between 0–11%, but the vehicle used during patch testing in these studies has been variable, thus resulting in a wide range (136). For this reason, some authors consider minoxidil to be a vehicle-dependent contact allergen, a term ﬁ rst used by Whitmore, who described a 34-year-old man who developed dermatitis of the scalp while using 2% minoxidil solution, which normally contains alcohol, propylene glycol, and water. Interestingly, the patient had a positive patch reaction only when 2% minoxidil was tested with propylene glycol as the vehicle. However, there was no reaction seen to propylene glycol (20% aq) or 2 % minoxidil tested in alcohol or petrolatum (136). A review of the current literature revealed a similar pattern as seen by Whitmore. In patients reported to have ACD to therapeutic solutions of minoxidil, most reactions are seen McMichael PTR 01/21/08 Chapter 17

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TABLE 14 Recommended Patch Testing for Suspected Allergic Contact Dermatitis to Minoxidil Recommended antigens Minoxidil solution (actual product) 10% Propylene glycol (aq) 2% minoxidil (aq) 2% minoxidil (10% propylene glycol) 2% minoxidil (70% isopropyl alcohol) 70% Isopropyl alcohol (aq) when minoxidil is tested with propylene glycol as the vehicle, and only a few of these patients also have been shown to be allergic to minoxidil in alcohol (137–139). However, there have been no reported cases of positive reactions to minoxidil in petrolatum (136), even when the concentration of minoxidil was increased to 5% in petrolatum (140). These ﬁ ndings suggest that propylene glycol is critical in enhancing skin penetration of minoxidil and eliciting sensitization. Due to this phenomenon of vehicle-dependent allergy, testing with multiple vehicles during patch testing is crucial in order to determine the true culprit. Some patients with reactions to one minoxidil preparation may tolerate minoxidil in a different vehicle. Friedman et al. tested 11 patients suspected of allergic contact dermatitis to minoxidil solution. He determined that nine patients were actually allergic to propylene glycol, four were allergic to minoxidil, and one was allergic to butylene glycol. If propylene glycol is the suspected allergen, propylene glycol with butylene glycol (135), glycerin, or polysorbate may be substituted (141,142). Other authors have recommended the use of hexylene glycol and polyethylene glycol 400 (PEG 400) as an alternative vehicle (143). Tables 14 and 15 provide a helpful guide for the evaluation and possible alternatives for patients suspected of having allergy to topical minoxidil.

Wigs and Accessories In general, allergic contact dermatitis to synthetic hairs or wigs is rare. Crichlow and Warin reported a 36-year-old woman with a history of alopecia universalis who was treated with 2.5% diphencyprone and later developed severe scalp eczema, which extended to her arms and legs. Diphencyprone treatment was discontinued, but scalp eczema in a band-like pattern persisted, suggestive of ACD to her wig. Patch testing was positive to para-phenylenediamine, which was thought to be due to unreacted p-phenylenediamine remaining on dyed parts of the wig since the dermatitis cleared when she was switched to a wig without dyes (144). Some wig linings and adhesives may also irritate the scalp. Shehade and Beck reported a 60-year-old woman who developed mild eczema involving the frontal hair line and nape of the neck. Patch testing revealed positive reactions to several disperse dyes, which were present in her wig lining (145). Contact dermatitis has also been reported to disperse blue 124 and 106 in colored bindis (146). Practitioners should also be aware of nickel allergy from hair accessories. As conﬁ rmed by the most recent NACDG report in 2001–2002, nickel continues to be the most common contact

TABLE 15 Interpretation of Patch Testing Results and Possible Alternative Treatments for ACD Minoxidil Patch testing results Diagnosis Alternatives Minoxidil (aq): + Minoxidil ACD Consider systemic androgen mondulators Propylene glycol: + Propylene glycol ACD Vehicle substitution with: hexylene glycol, PEG 400, butylene glycol, glycerin, or polysorbate Minoxidil (prop glycol ): + Propylene glycol: – Minoxidil (aq): – Vehicle-dependent ACD Consider replacing propylene glycol (as above) All negative: No allergy. Consider irritant contact reaction Consider adjunct use of topical or seborrheic dermatitis corticosteroids Source: Adapted from Refs. 135, 136. McMichael PTR 01/21/08 Chapter 17

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allergen (with a positive patch test reactions in 16.7% of patients) (20). Prolonged contact with hairpins, bobby pins, and curlers may cause localized scalp dermatitis in nickel-sensitive patients (10). Sommer and Wilkinson reported a 14-year-old girl with recurrent pustular eczema of the retroauricular region and anterior scalp which was discovered to be secondary to a nickel- containing headband (147). Baxter and Wilkinson (148) reported a 33-year-old woman with a two year history of localized pruritus and eczema on her central forehead secondary to a nickel-containing bindi. Lembo and colleagues reported a 55-year-old man with vesicular lesions arranged on his forehead in contact areas with his hat; subsequent patch testing showed a positive reaction to PPD which was thought to be possibly present in the hat band (149).

DIAGNOSIS/MANAGEMENT Patch Testing: Detection of Allergen(s) Allergic contact dermatitis is conﬁ rmed by patch testing. Prepared screening panels such as the T.R.U.E. (thin-layer rapid use epicutaneous) test, which consists of 23 commonly encountered allergens, has been shown to identify approximately 25% of all relevant contact allergens (150). However, in the IVDK study, the hairdressing series (Table 4) was shown to be far more superior for individuals suspected of having allergy to hair products and was able to detect the responsible allergen in over 80% of consumers and 92% of hairdressers (4). There are also larger standard series which can be manually prepared, which include: (a) the North American Contact Dermatitis Standard Screening Series (65 allergens) and (b) Mayo Clinic’s Standard Series (73 allergens) (11). However, the most recent NACDG study of 4,913 patients who were patch tested between 2001–2, found that 16.7% of the patients had a relevant reaction to an allergen not in the NACDG standard series (20). This illustrates the importance of patch testing with the different screening panels discussed in this chapter (Tables 2, 7, 9–12 and 16). It is not only important to use different screening panels, but it is also valuable to patch test to several suspected products (151). In general, “leave-on” hair products (such as mousses, gels, and hairsprays) are safe for closed patch testing at full strength. However, “rinse-off” products (such as shampoos and conditioners) are typically diluted 1:50 or 1:100. Patch testing to irritating substances (such as hair dyes and permanent wave solutions) should only be performed in reference to standard concentrations. References such as De Groot et al. (152) specify chemical concentrations and vehicles used in testing different allergens, including irritating agents. Some cosmetic manufacturers will also supply patch test kits of individual ingredients in a suspected product. If patch-testing results are not helpful and the physician is clinically suspicious of contact urticaria, immediate testing may be performed by applying the diluted agent in increasing concentrations to unaffected skin on the volar aspect of the forearm for 15–20 minutes with interval readings taken over the next 45 minutes (14). Another method is skin-prick testing. All testing for contact urticaria should only be done where emergency resuscitation facilities are available since there have been reports of anaphylactic reactions during testing (10).

Management of Allergic Contact Dermatitis There are four major components necessary in the management and treatment of allergic contact dermatitis: avoidance of the allergen(s), alleviation of pruritus, treatment of inﬂ ammation, and restoration of the normal skin barrier (153).

Avoidance of the Allergen(s) Avoidance of the allergen(s) and patient education is the primary goal in the management of allergic contact dermatitis, but this is often diffi cult to implement. After patch testing has identifi ed a specifi c allergen, the physician must determine both the source of the suspected allergen and confi rm that the allergen contacted the affected area, which is known as clinical relevance (7). If clinical relevance is established, the patient must be educated about the allergen, the syn- onyms, and cross-reacting allergens. It is also helpful to provide patients with “exposure lists,” which list commonly used products that contain both the responsible allergen and cross-reacting McMichael PTR 01/21/08 Chapter 17

260 Askari and Warshaw agents. This process can be overwhelming for the patient. Therefore, it is equally important to provide patients with a list of products. A useful tool is www.contactderm.org, which allows practitioners to enter speciﬁ c allergens and provides a database with a customized list of safe products that do not contain any of the entered allergens.

Alleviation of Pruritus Pruritus can be controlled by the use of antihistamines. Less-sedating antihistamines include cetirizine, loratadine, and fexofenadine. Doxepin is especially useful for refractory pruritus when taken at bedtime (153).

Treatment of Inﬂ ammation Most cases of ACD are treated with the use of topical corticosteroids. For hair-bearing regions such as the scalp, solutions are the preferred vehicle of treatment. In general, it is preferable to prescribe topical corticosteroids that contain fewer preservatives such as ointments rather than creams (7). It is important to be cognizant of ACD to preservatives and vehicles found in topical corticosteroids, as well as to the steroid itself (154). Potent topical corticosteroids, especially when used for long periods of time, may cause striae, atrophy, and even adrenal axis suppression. In severe cases of ACD, a three-week taper of oral prednisone (40–60 mg) may be given, however it is important to note that rebound dermatitis may occur if the steroid taper is shorter than three weeks (7). Alternatives to corticosteroids include topical immunomodulators (such as pimecrolimus and tacrolimus), which inhibit the release of inﬂ ammatory cytokines from T lymphocytes and mast cells. These agents have no risk of skin atrophy, striae, or tachyphylaxis and are ideal for sensitive regions such as the face and intertriginous areas. The most commonly reported side effects include transient skin burning or stinging (8).

Restoration of the Normal Skin Barrier Restoration of the normal skin barrier is usually performed by prolonged and aggressive application of moisturizers. It is generally recommended to apply a thick cream or ointment several times a day, preferably with emollients that contain few potential allergens or irritants. For intensive therapy, the affected area may be occluded with plastic wrap (or a shower cap for the scalp) after a heavy layer of emollient or topical corticosteroid is applied (153).

SUMMARY There are many haircare products that can cause allergic contact dermatitis. The most common allergens include hair dyes, fragrances, preservatives, bleaches, emulsiﬁ ers, permanent wave solutions, hair straighteners, shampoos, and conditioners. Currently, there are limited data on allergy in hair products. More research is needed to further elucidate risk factors, responsible allergens, and appropriate product substitutions.

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79. de Groot AC, Bruynzeel DP, Jagtman BA, Weyland JW. Contact allergy to diazolidinyl urea (Germall II). Contact Dermatitis 1988; 18(4):202–205. 80. Fransway AF. The problem of preservation in the 1990s. I. Statement of the problem, solutions of the industry, and the current use of formaldehyde and formaldehyde-releasing biocides. American Journal of Contact Dermatitis 1991; 2:6–23. 81. de Groot AC, van Joost T, Bos JD, van der Meeren HL, Weyland JW. Patch test reactivity to DMDM hydantoin. Relationship to formaldehyde allergy. Contact Dermatitis 1988; 18(4):197–201. 82. Rastogi SC, Schouten A, de Kruijf N, Weijland JW. Contents of methyl-, ethyl-, propyl-, butyl- and benzylparaben in cosmetic products. Contact Dermatitis 1995; 32(1):28–30. 83. Fransway AF. The problem of preservation in the 1990s. III. Agents with preservative function independent of formaldehyde release. American Journal of Contact Dermatitis 1991; 2:145–174. 84. Cooper SM, Shaw S. Allergic contact dermatitis from parabens in a tar shampoo. Contact Dermatitis 1998; 39(3):140. 85. Fisher AA. Paraben dermatitis due to a new medicated bandage: the “paraben paradox”. Contact Dermatitis 1979; 5(4):273–274. 86. Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermatitis 2005; 16(2):57–66; quiz 55–56. 87. Bryld LE, Agner T, Menne T. Allergic contact dermatitis from 3-iodo-2-propynyl-butylcarbamate (IPBC) - an update. Contact Dermatitis 2001; 44(5):276–278. 88. Funk JO, Maibach HI. Propylene glycol dermatitis: re-evaluation of an old problem. Contact Dermatitis 1994; 31(4):236–241. 89. Gonzalo MA, de Argila D, Garcia JM, Alvarado MI. Allergic contact dermatitis to propylene glycol. Allergy 1999; 54(1):82–83. 90. Fowler JF. Contact allergy to propylene glycol in topical corticosteroids. American Journal of Contact Dermatitis 1993; 4:37. 91. Fisher AA. Reactions to popular cosmetic humectants. Part III. Glycerin, propylene glycol, and butylene glycol. Cutis 1980; 26(3):243–244, 269. 92. Le Coz CJ, Schneider GA. Contact dermatitis from tertiary-butylhydroquinone in a hair dye, with cross-sensitivity to BHA and BHT. Contact Dermatitis 1998; 39(1):39–40. 93. Fisher AA, Dooms-Goossens A. Persulfate hair bleach reactions. Cutaneous and respiratory manifestations. Arch Dermatol 1976; 112(10):1407–1409. 94. Fisher AA. The persulfates: a triple threat. Cutis 1985; 35(6):520, 523–5. 95. Calnan CD, Shuster S. Reactions to Ammonium Persulfate. Arch Dermatol 1963; 88:812–815. 96. Aalto-Korte K, Makinen-Kiljunen S. Specifi c immunoglobulin E in patients with immediate persulfate hypersensitivity. Contact Dermatitis 2003; 49(1):22–25. 97. Brubaker MM. Urticarial reaction to ammonium persulfate. Arch Dermatol 1972; 106(3):413–414. 98. Perfetti L, Galdi E, Biale C, Garbelli N, Moscato G. Anaphylactoid reaction to patch testing with ammonium persulfate. Allergy 2000; 55(1):94–95. 99. Pang S, Fiume MZ. Final report on the safety assessment of Ammonium, Potassium, and Sodium Persulfate. Int J Toxicol 2001; 20(Suppl 3):7–21. 100. Kanerva L. In: Handbook of Occupational Dermatology. Berlin, New York: Springer, 2000. 101. Hannuksela M. KM, Pirila V. Contact sensitivity to emulsifi ers. Contact Dermatitis 1976; 2:201–204. 102. Tosti A, Guerra L, Morelli GR, Bardazzi F. Prevalence and sources of sensitization to emulsifi ers: a clinical study. Contact Dermatitis 1990; 23:68–72. 103. Kligman AM. The myth of lanolin allergy. Contact Dermatitis 1998; 39(3):103–107. 104. Matthieu L, Dockx P. Discrepancy in patch test results with wool wax alcohols and Amerchol L- 101. Contact Dermatitis 1997; 36(3):150–151. 105. Wolf R. The lanolin paradox. Dermatology 1996; 192(3):198–202. 106. Kligman AM. Lanolin allergy: crisis or comedy. Contact Dermatitis 1983; 9(2):99–107. 107. Storrs FJ. Permanent wave contact dermatitis: contact allergy to glyceryl monothioglycolate. J Am Acad Dermatol 1984; 11(1):74–85. 108. Morrison LH, Storrs FJ. Persistence of an allergen in hair after glyceryl monothioglycolate- containing permanent wave solutions. J Am Acad Dermatol 1988; 19(1 Pt 1):52–59. 109. Tosti A, Melino M, Bardazzi F. Contact dermatitis due to glyceryl monothioglycolate. Contact Dermatitis 1988; 19(1):71–72. 110. Engasser P. Type I and type IV immune responses to glyceryl thioglycolate. Contact Dermatitis 2000; 42(5):298. 111. Fisher AA. Dermatitis due to sulfi tes in home permanent preparations. Part II. Cutis 1989; 44(2):108–109. 112. Landers MC, Law S, Storrs FJ. Permanent-wave dermatitis: contact allergy to cysteamine hydrochloride. Am J Contact Dermat 2003; 14(3):157–160. 113. Wickett RR. Permanent waving and straightening of hair. Cutis 1987; 39(6):496–497. 114. Hickman JG, Huber F, Palmisano M. Human dermal safety studies with efl ornithine HCl 13.9% cream (Vaniqa), a novel treatment for excessive facial hair. Curr Med Res Opin 2001; 16(4): 235–244. McMichael PTR 01/21/08 Chapter 17

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115. Fowler JF, Fowler LM, Hunter JE. Allergy to cocamidopropyl betaine may be due to amidoamine: a patch test and product use test study. Contact Dermatitis 1997; 37(6):276–281. 116. Angelini G, Foti C, Rigano L, Vena GA. 3-Dimethylaminopropylamine: a key substance in contact allergy to cocamidopropylbetaine? Contact Dermatitis 1995; 32(2):96–99. 117. Pigatto P, AS. B, F. C. Contact dematitis to cocamidopropyl betaine is caused by residual amines: relevance, clinical characteristics, and review of the literature. American Journal of Contact Dermatitis 1995; 6:13–16. 118. Foti C, Bonamonte D, Mascolo G, et al. The role of 3-dimethylaminopropylamine and amidoamine in contact allergy to cocamidopropylbetaine. Contact Dermatitis 2003; 48(4):194–198. 119. Shaffer K, Hordinksy MK, Warshaw EM. Allergenicity and cross-reactivity of coconut derivatives. Dermatitis 2004; 15:103. 120. de Groot AC, de Wit FS, Bos JD, Weyland JW. Contact allergy to cocamide DEA and lauramide DEA in shampoos. Contact Dermatitis 1987; 16(2):117–118. 121. Fowler JF, Jr. Allergy to cocamide DEA. Am J Contact Dermat 1998; 9(1):40–41. 122. Guin JD. Reaction to cocamidopropyl hydroxysultaine, an amphoteric surfactant and conditioner. Contact Dermatitis 2000; 42(5):284. 123. Van Haute N, Dooms-Goossens A. Shampoo dermatitis due to cocobetaine and sodium lauryl ether sulphate. Contact Dermatitis 1983; 9(2):169. 124. Andersen KE, Roed-Petersen J, Kamp P. Contact allergy related to TEA-PEG-3 cocamide sulfate and cocamidopropyl betaine in a shampoo. Contact Dermatitis 1984; 11(3):192–193. 125. Jo JH, Jang HS, Ko HC, et al. Pustular psoriasis and the Kobner phenomenon caused by allergic contact dermatitis from zinc pyrithione-containing shampoo. Contact Dermatitis 2005; 52(3):142–144. 126. Pereira F, Fernandes C, Dias M, Lacerda MH. Allergic contact dermatitis from zinc pyrithione. Contact Dermatitis 1995; 33(2):131. 127. Nielsen NH, Menne T. Allergic contact dermatitis caused by zinc pyrithione associated with pustular psoriasis. Am J Contact Dermat 1997; 8(3):170–171. 128. Epstein S. Photoallergic contact dermatitis. Cutis 1968; 4:856. 129. Niinimaki A, Niinimaki M, Makinen-Kiljunen S, Hannuksela M. Contact urticaria from protein hydrolysates in hair conditioners. Allergy 1998; 53(11):1078–1082. 130. Pasche-Koo F, Claeys M, Hauser C. Contact urticaria with systemic symptoms caused by bovine collagen in a hair conditioner. Am J Contact Dermat 1996; 7(1):56–57. 131. Schalock PC, Storrs FJ, Morrison L. Contact urticaria from panthenol in hair conditioner. Contact Dermatitis 2000; 43(4):223. 132. Scheman A. New trends in hair care products: an update for dermatologists. Cosmetic Dermatology 1998; 11:17–21. 133. Nedorost ST. Facial erythema as a result of benzophenone allergy. J Am Acad Dermatol 2003; 49(5 Suppl):S259–S261. 134. Tosti A, Bardazzi F, De Padova MP, Caponeri GM, Melino M, Veronesi S. Contact dermatitis to minoxidil. Contact Dermatitis 1985; 13(4):275–276. 135. Friedman ES, Friedman PM, Cohen DE, Washenik K. Allergic contact dermatitis to topical minoxidil solution: etiology and treatment. J Am Acad Dermatol 2002; 46(2):309–312. 136. Whitmore SE. The importance of proper vehicle selection in the detection of minoxidil sensitivity. Arch Dermatol 1992; 128(5):653–656. 137. Suzuki K, Suzuki M, Akamatsu H, Matsungaga K. Allergic contact dermatitis from minoxidil: study of the cross-reaction to minoxidil. Am J Contact Dermat 2002; 13(1):45–46. 138. Roenigk HH, Jr., Pepper E, Kuruvilla S. Topical minoxidil therapy for hereditary male pattern alopecia. Cutis 1987; 39(4):337–342. 139. Alomar A, Smandia JA. Allergic contact dermatitis from minoxidil. Contact Dermatitis 1988; 18(1):51–52. 140. Wilson C, Walkden V, Powell S, Shaw S, Wilkinson J, Dawber R. Contact dermatitis in reaction to 2% topical minoxidil solution. J Am Acad Dermatol 1991; 24(4):661–662. 141. Fisher AA. Use of glycerin in topical minoxidil solutions for patients allergic to propylene glycol. Cutis 1990; 45(2):81–82. 142. Harry RG, Rieger MM. In: Harry’s Cosmeticology. 8th ed. New York: Chemical Pub. Co., 2000. 143. Scheman AJ, West DP, Hordinksy MK, Osburn AH, West LE. Alternative formulation for patients with contact reactions to topical 2% and 5% minoxidil vehicle ingredients. Contact Dermatitis 2000; 42(4):241. 144. Crichlow S, Warin AP. Allergic contact dermatitis from dyes in wigs following diphencyprone treatment. Contact Dermatitis 2004; 51(3):148–149. 145. Shehade SA, Beck MH. Contact dermatitis from disperse dyes in synthetic wigs. Contact Dermatitis 1990; 23(2):124–125. 146. Dwyer CM, Forsyth A. Allergic contact dermatitis from bindi. Contact Dermatitis 1994; 30(3):174. 147. Sommer S, Wilkinson SM. Allergic contact dermatitis caused by a nickel-containing headband. Contact Dermatitis 2001; 44(3):178. McMichael PTR 01/21/08 Chapter 17

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148. Baxter KF, Wilkinson SM. Contact dermatitis from a nickel-containing bindi. Contact Dermatitis 2002; 47(1):55. 149. Lembo G, Nappa P, Balato N, Ayala F. Hat band dermatitis. Contact Dermatitis 1985; 13(5):334. 150. Cohen DE, Brancaccio R, Andersen D, Belsito DV. Utility of a standard allergen series alone in the evaluation of allergic contact dermatitis: a retrospective study of 732 patients. J Am Acad Dermatol 1997; 36(6 Pt 1):914–918. 151. Larsen WG, Jackson EM, Barker MO, et al. A primer on cosmetics. AAD Advisory Board, CTFA Task Force on Cosmetics. J Am Acad Dermatol 1992; 27(3):469–484. 152. Groot ACd. In: Patch Testing: Test Concentrations and Vehicles for 3700 Chemicals. 2nd ed. Amsterdam, New York: Elsevier, 1994. 153. Warshaw E. Contact Dermatitis. In: Rakel R, ed. Conn’s Current Therapy. London, England.: W.B. Saunders; 2000:830–831. 154. Scheuer E, Warshaw E. Allergy to corticosteroids: update and review of epidemiology, clinical characteristics, and structural cross-reactivity. Am J Contact Dermat 2003; 14(4):179–187. 155. Amin S, Lahti A, Maibach HI. In: Contact Urticaria Syndrome. Boca Raton, Fla.: CRC Press, 1997. 156. Diagnostics. C. Chemotechnique Diagnostics Catalogue 2005: The complete range of products for patch testing. In; 2005. 157. Eskelinen A, Molitor C, Kanerva L. Allergic contact dermatitis from 2,7-dihydroxynaphthalene in hair dye. Contact Dermatitis 1997; 36(6):312–13. 158. Wedi B, Hoting E, Koerner M, Kapp A. Allergic contact dermatitis due to monovalent sensitization to the oxidation hair dye intermediate oxamitol (2-aminomethyl-p-aminophenol-2HCl) without cross-sensitivity to haptens of the para-group. Contact Dermatitis 2000; 42(2):104–105. 159. Hansson C, Thorneby-Andersson K. Allergic contact dermatitis from 2-chloro-p-phenylenediamine in a cream dye for eyelashes and eyebrows. Contact Dermatitis 2001; 45(4):235–236. 160. Krasteva M, Cristaudo A, Hall B, et al. Contact sensitivity to hair dyes can be detected by the consumer open test. Eur J Dermatol 2002; 12(4):322–326. 161. Guerra L, Bardazzi F, Tosti A. Contact dermatitis in hairdressers’ clients. Contact Dermatitis 1992; 26(2):108–111. 162. Le Coz CJ, Kuhne S, Engel F. Hair dye allergy due to 3-nitro-p-hydroxyethyl-aminophenol. Contact Dermatitis 2003; 49(2):103. 163. Blanco R, de la Hoz B, Sanchez-Fernandez C, Sanchez-Cano M. Allergy to 4-amino-3-nitrophenol in a hair dye. Contact Dermatitis 1998; 39(3):136. 164. de Groot AC, Weyland JW. Cosmetic allergy from the aminoketone colour basic blue 99 (CI 56059). Contact Dermatitis 1990; 23(1):56–57. 165. Wong GA, King CM. Immediate-type hypersensitivity and allergic contact dermatitis due to para- phenylenediamine in hair dye. Contact Dermatitis 2003; 48(3):166. 166. Andersen KE, Carlsen L. Pyrocatechol contact allergy from a permanent cream dye for eyelashes and eyebrows. Contact Dermatitis 1988; 18(5):306–307. 167. Gottlober P, Gall H, Bezold G, Peter RU. [Allergic contact dermatitis in beauty parlor clients]. Hautarzt 2001; 52(5):401–404. 168. Matsunaga K, Hosokawa K, Suzuki M, Arima Y, Hayakawa R. Occupational allergic contact dermatitis in beauticians. Contact Dermatitis 1988; 18(2):94–96. 169. Broeckx W, Blondeel A, Dooms-Goossens A, Achten G. Cosmetic intolerance. Contact Dermatitis 1987; 16(4):189–194. 170. Vilaplana J, Romaguera C, Grimalt F. Contact dermatitis from resorcinol in a hair dye. Contact Dermatitis 1991; 24(2):151–152. 171. Guarrera M, Saino M, Rivara G, Crovato F. Allergic contact dermatitis from brilliantine. Contact Dermatitis 1991; 25(2):130–131. 172. Sharvill D. Reaction to Chlorhexidine and Cetrimide. Lancet 1965; 17:771. 173. Horn HM, Murray C, Aldridge RD. Contact allergy to decyl glucoside. Contact Dermatitis 2005; 52(4):227. 174. Soga F, Izawa K, Inoue T, Katoh N, Kishimoto S. Contact dermatitis due to disodium ethylenediamine- tetraacetic acid in cosmetics and shampoo. Contact Dermatitis 2003; 49(2):105. 175. Ancona-Alayon A, Jimenez-Castilla JL, Gomez-Alvarez EM. Dermatitis from epoxy resin and formaldehyde in shampoo packers. Contact Dermatitis 1976; 2(6):356. 176. Bruynzeel DP, van Ketel WG, de Haan P. Formaldehyde contact sensitivity and the use of shampoos. Contact Dermatitis 1984; 10(3):179–180. 177. Verbov JL. Contact dermatitis from miranols. Trans St Johns Hosp Dermatol Soc 1969; 55(2):192–195. 178. Dooms-Goossens A, Debusschere K, Dupre K, Degreef H. Can eardrops induce a shampoo dermatitis? A case study. Contact Dermatitis 1988; 19(2):143–145. 179. Eisenberg BC. Contact dermatitis from selenium sulﬁ de shampoo. AMA Arch Derm 1955; 72(1):71–72. 180. Sylvest B, Hjorth N, Magnusson B. Lauryl ether sulphate dermatitis in Denmark. Contact Dermatitis 1975; 1(6):359–362. McMichael PTR 01/21/08 Chapter 17

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181. de Boer EM, van Ketel WG, Bruynzeel DP. Dermatoses in metal workers. (II). Allergic contact dermatitis. Contact Dermatitis 1989; 20(4):280–286. 182. Sasseville D, Moreau L. Allergic contact dermatitis from triethanolamine polypeptide oleate condensate in eardrops and shampoo. Contact Dermatitis 2005; 52(4):233. 183. Yates VM, Finn OA. Contact allergic sensitivity to zinc pyrithione followed by the photosensitivity dermatitis and actinic reticuloid syndrome. Contact Dermatitis 1980; 6(5):349–350. 184. Brandrup F, Menne T. Zinc pyrithione (Zinc Omadine) allergy. Contact Dermatitis 1985; 12(1):50. 185. Widstrom L. Allergic reactions to ammonium persulphate in hair bleach. Contact Dermatitis 1977; 3(6):343. 186. Downing JG. Dangers involved in dyes, cosmetics and permanent wave lotions applied to hair and scalp. AMA Arch Derm Syphilol 1951; 63(5):561–564. 187. White IR, Lovell CR, Cronin E. Antioxidants in cosmetics. Contact Dermatitis 1984; 11(5):265–267. 188. Assier-Bonnet H, Revuz J. Chloroacetamide as a cause of contact dermatitis in hairdressing. Contact Dermatitis 1999; 40(5):284–285. 189. Heine A, Laubstein B. Contact dermatitis from cyclohexanone-formaldehyde resin (L2 resin) in a hair lacquer spray. Contact Dermatitis 1990; 22(2):108. 190. Monk B. Allergic contact dermatitis to D & C yellow 11 in a hair cream. Contact Dermatitis 1987; 17(1):57–58. 191. van Ketel WG. Hair lotion dermatitis with sensitization to d-panthenyl ethyl ether. Contact Dermatitis 1984; 10(1):48. 192. Kantor GR, Taylor JS, Ratz JL, Evey PL. Acute allergic contact dermatitis from diazolidinyl urea (Germall II) in a hair gel. J Am Acad Dermatol 1985; 13(1):116–119. 193. Jaworsky C, Taylor JS, Evey P, Handel D. Allergic contact dermatitis to glutaraldehyde in a hair conditioner. Cleve Clin J Med 1987; 54(5):443–444. 194. Dooms-Goossens A, Vandaele M, Bedert R, Marien K. Hexamidine isethionate: a sensitizer in topical pharmaceutical products and cosmetics. Contact Dermatitis 1989; 21(4):270. 195. Fujita M, Aoki T. Allergic contact dermatitis to pyridoxine ester and hinokitiol. Contact Dermatitis 1983; 9(1):61–65. 196. Bruynzeel DP, de Groot AC, Weyland JW. Contact dermatitis to lauryl pyridinium chloride and benzoxonium chloride. Contact Dermatitis 1987; 17(1):41–42. 197. Calnan CD. Hair dye reaction. Contact Dermatitis Newsletter 1967; 1:208. 198. Goh CL, Lim KB. Allergic contact dermatitis to zinc pyrithione. Contact Dermatitis 1984; 11(2):120. 199. Dickel H, Taylor JS, Evey P, Merk HF. Comparison of patch test results with a standard series among white and black racial group. American Journal of Contact Dermatitis 2001; 12(2):77–82. 200. DeLeo VA, Taylor SC, Belsito DV et al., The effect of race and ethnicity on patch results. Journal of the American Academy of Dermatology 2002; 46(2S):S107–S112. McMichael PTR 01/21/08 Chapter 18

18 The Biopsychosocial Aspects of Hair Disease

Lucinda S. Buescher Department of Dermatology, Southern Illinois University School of Medicine, Springﬁ eld, Illinois, U.S.A. David Resch Division of Medicine/Psychiatry, Southern Illinois University School of Medicine, Springﬁ eld, Illinois, U.S.A.

Scalp hair is unique as a physical attribute in humans because it lends itself to nearly instanta- neous transformation. Cultural inﬂ uences and personal preferences dictate which particular hair characteristics, such as length, color and texture, are considered desirable and attractive. Various styles and adornments are used to convey health, status, intelligence and youthfulness. In a state of health, hair can be maintained with minimal effort and is often taken for granted. When unwanted changes in hair are perceived, especially thinning and loss, the impact on psychological and social well-being can be dramatic. This occurs even with gradual hair loss associated with senescence and in those with a predisposition to androgenetic alopecia (1). On the other hand, emotional and psychological disturbances can manifest as disorders of the skin and hair. This chapter reviews those disorders of the hair that demonstrate the complex interplay between physiology, psychology and social sequelae. Various types of factitial hair loss, most notably trichotillomania, are discussed with a mention of available data on ethnic differences and similarities. Delusions of parasitosis and body dysmorphic disorder occasionally present with a primary complaint related to the hair or scalp; these topics are also included in this chapter.

FACTITIAL HAIR LOSS The term trichotillomania (TTM) was proposed in 1889 by Hallopeau and is derived from its Greek roots: thrix (hair), tillein (pull), and mania (madness) (2). The perpetuation of “mania” is an unfortunate misnomer because, while individuals with this condition have an irresistible impulse to pull out their hair, very few patients have bipolar disorder. TTM has earned a place in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) with other disorders of impulse control, such as gambling (Table 1) (3). Hair pulling can be performed in a highly auto- matic fashion and is associated with impaired inhibition of motor responses (4). Although TTM shares with other impulse control disorders the qualities of tension before performing hair pulling and gratifi cation after, a new category for placement of this disorder is proposed under Anxiety Disorders in DSM-IV. TTM has many demographic and phenomenological similarities to other stereotypical self-injurious symptoms such as skin picking or nail biting (5,6). Estimates of TTM incidence vary from 0.6–3.4% of the American population affected up to a 10% lifetime risk (7). It is most likely underestimated because it is a secretive behavior and may go unnoticed except in the most severe cases. The mean age of onset is 9–13 years and occurs equally in boys and girls; but in adults it is more frequently reported in females (11). In studies of college students, 10–15% report “hair-pulling,” without the associated DSM-IV criteria of tension or noticeable hair loss (8–10). Little research has been done on rates of TTM in different ethnic populations. One Indian study of obsessive-compulsive patients found a 3% incidence of TTM in their patients which compares to a 4% rate in an inclusive study group of obsessive-compulsive patients in the United States (12,13). An African-American subset of college students was found to have a 10% rate of hair pulling and 2% met the criteria for TTM, but these rates were not signifi cantly different than the non–African-American students in this study (14). In 2006, a group of 252 college students (84.3% African American) was evaluated and 6% reported hair pulling, but none of these individuals met the criteria for TTM (15). The main clinical fi nding in patients with TTM is hair loss. The scalp is the most common site of involvement and the pattern of hair loss is characteristically irregular and angular in McMichael PTR 01/21/08 Chapter 18

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TABLE 1 Diagnositic Criteria for Trichotillomania 1. Recurrent pulling out of one’s hair resulting in noticeable hair loss. 2. An increasing sense of tension immediately before pulling out the hair or when attempting to resist the behavior. 3. Pleasure, gratifi cation or relief when pulling out the hair. 4. The disturbance is not better accounted for by another mental disorder and is not due to a general medical condition. 5. The disturbance causes clinically signifi cant distress or impairment in social, occupational, or other important area of functioning. Source: From Ref. 3. confi guration. The crown of the scalp is frequently affected and when signifi cant hair loss has occurred the pattern is called the “Friar Tuck” sign (Fig. 1) (19). Interestingly, the patches are rarely completely devoid of hair but, rather, show a decreased density of hairs that are short but of varying lengths. On close inspection, perifollicular erythema or hemorrhage may be observed. Frequently more than one site is involved, especially eyebrows and eyelashes, but any hair-bearing skin can be affected. Forty-three percent of patients will deny their alopecia is self-induced (20). The differential usually includes alopecia areata, tinea capitis, and secondary syphilis. Another unique feature of TTM is its characteristic pathology. Histologically, there are an increased number of hair follicles in catagen phase. Some follicles show follicular plugging with pigment casts. Trichomalacia is a histopathologic sign of trauma to the hair shaft. In this condition, the hair shaft within the follicle is small and wavy or spiral-shaped (21). The exact etiology of TTM is not known, but several authors have noted certain characteristics common to patients with this disorder. Children with TTM have a greater need for tactile stimulation and using their fi ngers to palpate various materials is soothing (22). A negative emotion or stressor may be the initial trigger for the desire to pull their hair and most patients report performing hair-pulling when they are alone and in quiet surroundings. One patient was observed pulling eyebrows only during stages 3 and 4 (non-REM) while sleeping (11). Patients, especially children, with TTM are also reported to have a tendency to strive for perfection. Some affected individuals also have body dysmorphic disorder, over half have major depression, and approximately half have a generalized anxiety disorder (11,24). Eight percent of patients with TTM have fi rst-degree relatives with hair pulling (23). Genetic studies have demonstrated some potential alterations in patients with TTM. Research- ers evaluating the 5HT-2A receptor abnormalities have identifi ed South-African Caucasians having a higher incidence of TTM and T102T genotype compared to control subjects or patients with obsessive-compulsive disorder (16). In addition, two mutations in the SLITRK1 gene were found among some individuals with TTM but not in their unaffected family members. The SLITRK1 gene is involved in neuronal dendritic outgrowth and interconnections of neurons. This mutation is estimated to affect 5% of patients with TTM (17). This genetic mutation is over- represented in Costa Ricans and Ashkenazi individuals, however no studies of TTM in these populations have been conducted (18). Some differences in effect and behaviors associated with hair pulling in African-Ameri- can college students were discussed in a recent study. This population had negative emotions related to the process of hair pulling but reported no distress or loss in productivity due to the behavior. Additionally, African-American hair pullers were less likely to seek help from mental health professionals for it (15).

FIGURE 1 (See color insert.) Friar Tuck sign of trichotillomania. McMichael PTR 01/21/08 Chapter 18

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Two other factitial diseases should be considered in unexplained cases of alopecia or hair breakage. Trichotemnomania was fi rst described in 1968 and has rarely appeared in the English literature. The defi nition stems from the Greek word temnein, “to cut.” This disorder manifests as an irresistible urge to cut or shave one’s hair. The presentation may be one of widespread, total loss of terminal hair or localized hair loss or shortened hairs (25). Areas of alopecia result from shaving, while hair of different lengths results from cutting. Biopsies taken from affected areas would show entirely normal hair structures without infl ammation. Recently, trichoteiromania (teiro, Greek for “I rub”) (26), or compulsive hair rubbing, has been described. Patients in the literature present with hairs of different lengths and patchy hair loss (27). Many of the hairs show brush-like distal tips secondary to repeated frictional trauma. One patient disclosed that she believed that rubbing her hair would make it grow (26). Too few cases of these factitial hair disorders have been reported to make signifi cant generalizations. Treatment for TTM has incorporated pharmacologic and nonpharmacologic options. Habit reversal therapy is the most thoroughly studied psychotherapy for habit disorders (28). Selective serotonin reuptake inhibitors (SSRIs), such as fl uoxetine, sertraline, paroxteine, fl uvox- amine, escitalopram and clomipramine, have been reported to be benefi cial in treating TTM, as is combined therapy with pimozide, olanzapine or risperidone (Table 2) (28–40). Greater benefi t is derived by combining SSRIs and cognitive behavioral therapy (28). Treatment response may be lost over time (41). A few placebo-controlled trials have failed to show effi cacy of SSRIs in TTM (36,42,43). When using pharmacotherapy for TTM, SSRIs are typically the fi rst class of antidepressants used due to their comparable effi cacy and better safety profi le. Typical initial and target doses are listed in Table 2. At least 4 weeks are necessary for antidepressant effects from these agents, and time to response for TTM is approximately the same. Patients should be advised of this delayed onset of response when medications are prescribed to avoid early discontinuation of treatment. Common side effects of these agents are nausea, vomiting, diarrhea, tremor, and anxiety/restlessness. Since 2004 these agents have carried a black box warning by the U.S. Food and Drug Administration. This warning addresses the potential increased risk of suicidal ide- ation in adolescents and young adults. The risk appears to be higher in patients with increased anxiety after starting the medication (44).

DELUSIONS OF PARASITOSIS (EKBOM’S SYNDROME) Occasionally, the scalp or hair may be the site of a delusional infestation. Delusions of parasitosis is a rare psychiatric disorder that is characterized by a solitary delusion, that of a parasitic infestation. By defi nition, the delusion is fi rmly believed and cannot be shaken by rationaliza- tion. Patients will commonly complain of a sensation of perceived parasites crawling upon or burrowing into the skin. One constant fi nding, though, is the lack of primary lesions. The patient has entirely normal skin fi ndings or only secondary lesions as a result of scratching or

TABLE 2 Antidepressants Used for Psychological Hair Disorders Relative histamine Relative alpha Usual daily Usual daily H1 receptor- Relative adrenergic starting dose dose range blocking anticholinergic receptor-blocking Generic name (mg) (mg) potency potency potency Selective serotonin reuptake inhibitors Fluoxetine (Prozac Sarafem®) 10–20 10–60 Low/absent Low/absent Low/absent Sertraline (Zoloft®) 25–50 50–200 Low/absent Low/absent Low/absent Paroxetine (Paxil®) 10–20 20–60 Low/absent Very mild Low/absent Fluvoxamine (Luvox®) 25–50 100–200 Low/absent Low/absent Low/absent Citalopram (Celexa®) 10–20 20–60 Low/absent Low/absent Low/absent Escitalopram (Lexapro®) 10 10–20 Low/absent Low/absent Low/absent Heterocyclic agents Clomipramine (Anafranil®) 25–50 100–225 Moderate High Moderate Doxepine (Sinequan, Adapin®) 25–50 100–200 High High Moderate/high Source: From Ref. 36. McMichael PTR 01/21/08 Chapter 18

270 Buescher and Resch picking. Individuals suffering from this condition may injure themselves in attempts to be rid of the “parasites” (45). They may exhibit signs secondary to remedies undertaken to eradicate the nonexistent parasites, such as asteatosis or irritant dermatitis (Fig. 2) (46). Patients who present with delusions of parasitosis are most often women in their fi fth decade or older. The mean duration of symptoms at the time of presentation was 3–4 years. Social isolation was a common premorbid feature (47,48). Approximately 8.4% to 25% of patients have a shared delusion with family member or friend (48). The diagnosis is one of exclusion and requires a detailed investigation into (i) a possible real infestation, (ii) potential causes of pruritus, and (iii) organic causes of adult onset psychiatric symptoms. This involves inspection of the notorious “baggie” containing what the patient believes to be the parasites or parts of parasites. On occasion, it may be helpful to send the contents to entomolo- gists working at local public health departments who are experts at examining such debris. Delusions of parasitosis belongs in a group of disorders called monosymptomatic hypochondriacal psychosis (3,49). The delusional disorder is truly isolated to the one concern, unlike schizophrenia, which involves multiple functional defi cits such as hallucinations, lack of social skills, and fl at affect in addition to the delusional symptoms (3). Other causes include narcotic usage, withdrawal from cocaine, amphetamines, or alcohol, vitamin B12 defi ciency, thiamine defi ciency, multiple sclerosis, cerebrovascular disease, Huntington’s disease, syphilis, HIV-1 infection, hyperthyroidism, diabetes mellitus, drug-induced psychosis, and psychotic depression (46,48,50–53). Patients typically are highly resistant to accepting a psychiatric diagnosis as the reason for their symptoms. Antipsychotics are the typical pharmacologic treatment of choice. The course of delusions of parasitosis is not as unfavorable as commonly thought for those patients who engage in treatment. Short preclinical courses may indicate a better outcome. The full resolution rate for patients before psychopharmacologic interventions was 33.9% compared to a rate of 51.9% after the use of medications (47). Antidepressants, such as SSRIs, may also be used with co-morbid depressive disorders. A common feature of antipsychotics is their ability to block central nervous system dopamine receptors (54). Extrapyramidal side effects, such as parkinsonism, are caused by the same dopaminergic- blocking effects of these agents. The agents have been divided into two major classes: typical and atypical. The primary difference between the two classes is the ratio of serotonin blockade compared to dopaminergic blockade. Table 3 lists the commonly used antipsychotic agents, and

FIGURE 2 Delusions of scalp parasites resulting in excessive use of home remedy to eradicate the parasites. McMichael PTR 01/21/08 Chapter 18

Biopsychosocial Aspects of Hair Disease 271

TABLE 3 Antipsychotic Medications Used in Psychological Hair Disorders Adult daily Relative Relative Relative risk of dose Relative anticholinergic extrapyramidal orthostatic Generic (trade) name range (mg) sedation effect risk hypotension Typical agents Haloperidol (Haldol®) 1–20 Low Low High Low Pimozide (Orap®) 1–10 Low Low High Low Atypical agents Olanzapine (Zyprexa®) 2.5–15 Moderate Low Low Low Risperidone (Risperdal®) 0.5–6 Low Low Moderate Low Quietiapine (Seroquel®) 25–300 High Low Low High Ziprasidone (Geodon®) 20–160 Moderate Low Low Low Aripiprazole (Abilify®) 5–30 Low Low Low Low Source: From Refs. 35, 36.

Tables 4 and 5 list the possible metabolic derangements that may occur and the parameters to be followed for patients taking atypical antipsychotics (55–61). In addition to metabolic derangements, antipsychotic drugs can cause prolongation of the QT interval, potential torsades de pointes, and sudden death. The largest change in the QT interval was seen with thioridazine (an increase in the QTc of 30.1 milliseconds), followed by ziprasidone (15.9 ms increase), haloperidol (7.1 ms increase), quetiapine (5.7 ms increase), risperidone (3.9 ms increase) and olanzapine (1.7 ms increase) (62,63). The association of sudden death and antipsychotic medications has been described since the 1960s (64–66). Recently, Danish researchers demonstrated that use of antipsychotics (even short term, <90 days) created a three-fold increase in the risk of sudden cardiac death (67). The specifi c duration of the QT interval that is most associated with an adverse cardiac event is not established (68). Nonetheless, current recommendations suggest obtaining a baseline ECG before starting antipsychotic medications and periodically thereafter (69). Prescribing antipsychotic medications should be risk-stratifi ed based on the corrected QT interval: short QTc (QTc < 0.41 sec), borderline QTc (QTC = 0.42–0.44 sec), and prolonged QTc (>0.45 sec) (70–72). Risk stratifi cation should also include consideration of other risk factors: congenitally prolonged QT interval, female gender, hypokalemia, hypomagnesemia, use of sympathomimetics, antiarrhythmics that block the potassium channel (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide), some macrolide and fl uoroquinolone antibiotics, tricyclic antidepressant drugs (amitriptyline, nortiptyline, imipramine, doxepin, clomipramine) and serotonin agonists of the triptan class (73–77).

BODY DYSMORPHIC DISORDER Most individuals with hair loss, even gradual loss as seen in those with a predisposition to androgenetic alopecia, will report some degree of distress related to the loss. A majority of these report feeling self-conscious and ridiculed and wishing they had more hair. Those with greater hair loss are more preoccupied about it and use more coping strategies to deal with it (78). Typical coping strategies include compensating for hair loss by improving other physical features such as improving their ﬁ tness and physique. Another way to cope is to camouﬂ age the hair loss by wearing caps or wigs or altering their hair style to conceal it (79). Those patients

TABLE 4 Metabolic Effects of Antipsychotics. Generic (trade) name Weight gain Risk for diabetes mellitus Worsening lipid proﬁ le Atypical agents Olanzapine (Zyprexa®) High Low Low Risperidone (Risperdal®) Moderate Moderate/low Moderate/low Quietiapine (Seroquel®) Moderate Low/moderate Low/moderate Ziprasidone (Geodon®) Low/absent Absent/low Absent/low Aripiprazole (Abilify®) Low/absent Absent/low Absent/low Source: From Ref. 34. McMichael PTR 01/21/08 Chapter 18

272 Buescher and Resch

TABLE 5 Metabolic Parameters to Monitor in Patients on Antipsychotics Recommended monitoring for patients on atypical antipsychotics Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Personal/family history of diabetes X X mellitus or hyperlipidemia Weight (BMI) X X X X X X Waist circumference X X X Blood pressure X X X Fasting plasma glucose X X X Fasting lipid proﬁ le X X X Source: From Ref. 34.

who seek treatment from a dermatologist have higher levels of distress and use more coping behaviors than individuals who do not seek medical care (80). Occasionally a patient may present who reports a distressing amount of hair loss that far surpasses that observed on physical examination. Alternatively, patients may complain that their hair “looks really weird” or just isn’t “right” (81). Some patients may focus on impercep- tible increases in hair on other areas of the body that are psychologically disturbing to them. Even if a slight aberration is noticeable on close inspection, a patient’s concern and preoccupation with it may seem excessive. If these concerns lead to impairment in their social or occupational functioning, they may suffer from body dysmorphic disorder. The primary criteria for patients with body dysmorphic disorder are a perceived fl aw in their appearance and a profound preoccupation with this (usually) imaginary defect. If a slight physical anomaly is present, the individual’s concern is extreme. Additionally, the distress must be signifi cant enough to impair important areas of life functioning, such as attending school, going to work or other social situations. Preoccupations with hair are second only to those of the skin in all groups studied to date including adolescents, adult men and women (82,83). Coping mechanisms utilized by psychologically healthy people become repetitive and compulsive in patients with body dysmorphic disorder. Mirror gazing is the most common of these behaviors with nearly 80% pathologically driven to stare at their refl ection, on average, four to fi ve times longer than controls (over 1–3 hours vs. 21–36 minutes per day, respectively) (84). Other pathologic behaviors include constantly comparing themselves to others (especially celebrities and media images of perfection) and continually seeking reassurance that their hair looks normal or is suffi ciently camoufl aged. Compulsive skin picking and TTM may occur in body dysmorphic patients (85). In fact, in one study, 26% of patients with TTM also had body dysmorphic disorder (86). Physicians should be aware that patients with body dysmorphic disorder often have psychiatric comorbidities. More than half will have concurrent clinical depression, which usually manifests after the onset of body dysmorphic disorder symptoms. One-third of patients will have social phobias, substance abuse or obsessive compulsive disorder and over half have avoidant personality disorder (87). Unfortunately in body dysmorphic disorder the degree of patient insight is variable and dynamic, with an estimated 40% who are actually delusional at some point during their illness (88,89). During times of stress, when insight may be low, patients may be reluctant to accept and initiate appropriate psychological interventions because of the stigma of mental illness. Fortunately, treatment often improves insight. SSRIs have been shown to be helpful in some cases of body dysmorphic disorder. The dosages of SSRIs required are typically greater than the dosage required for the treatment of depression (90). Most patients require combination treatment with cognitive behavioral therapy and medications. Antipsychotics can be helpful in some cases, but demographics to identify this subpopulation are uncertain.

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38. Reid TL. Treatment of resistant trichotillomania with paroxetine. Am J Psychiatry 1994; 151(2):290. 39. Stein DJ, Hollander E. Low-dose pimozide augmentation of serotonin reuptake blockers in the treatment of trichotillomania. J Clin Psychiatry 1992; 53(4):123–126. 40. Koran LM, Ringold A, Hewlett W. Fluoxetine for trichotillomania: an open clinical trial. Psychopharmacol Bull 1992; 28(2):145–149. 41. Walsh KH, McDougle CJ. Pharmacological strategies for trichotillomania. Expert Opin Pharmacother 2005; 6(6):975–984. 42. Christenson GA, et al. A placebo-controlled, double-blind crossover study of fl uoxetine in trichotillomania. Am J Psychiatry 1991; 148(11):1566–1571. 43. Swedo SE, Lenane MC, Leonard HL. Long-term treatment of trichotillomania (hair pulling). N Engl J Med 1993; 329(2):141–142. 44. Physician’s Desk Reference. 61st ed. Montvale, NJ: Medical Economics Data, 2007. 45. Marschall MA, et al. Chronic wounds and delusions of parasitosis in the drug abuser. Plast Reconstr Surg 1991; 88(2):328–330. 46. Koo J, Lee CS. Delusions of parasitosis. A dermatologist’s guide to diagnosis and treatment. Am J Clin Dermatol 2001; 2(5):285–290. 47. Trabert W. 100 years of delusional parasitosis. Meta-analysis of 1,223 case reports. Psychopathology 1995; 28(5):238–246. 48. Slaughter JR, et al. Psychogenic parasitosis. A case series and literature review. Psychosomatics 1998; 39(6):491–500. 49. Musalek M, et al. The position of delusional parasitosis in psychiatric nosology and classifi cation. Psychopathology 1990; 23(2):115–124. 50. Krishnan A, Koo J. Psyche, opioids, and itch: therapeutic consequences. Dermatol Ther 2005; 18(4):314–322. 51. Mitchell J, Vierkant AD. Delusions and hallucinations of cocaine abusers and paranoid schizophrenics: a comparative study. J Psychol 1991; 125(3):301–310. 52. Pope FM. Parasitophobia as the presenting symptom of vitamin B12 defi ciency. Practitioner 1970; 204(221):421–422. 53. de Ronchi D, et al. Development of acute psychotic disorders and HIV-1 infection. Int J Psychiatry Med 2000; 30(2):173–183. 54. Perry PJ, Alexander B, Liskow BI. Psychotropic Drug Handbook, 8th edition. Lippincott Williams Wilkins 2006; 726. 55. American Diabetes Association and American Psychiatric Association. Consensus Development Conference on Antipsychotics Drugs and Obesity and Diabetes. Diabetes Care 2004; 27(2):596–601. 56. Gupta M, Gupta A. The use of antidepressant drugs in dermatology. J Eur Acad Dermatol Venereol 2001; 15:512–518. 57. Zetin M. Psychopharmacohazardology: major hazards of the new generation of psychotherapeutic drugs. Int J Clin Pract 2004; 58(1):58–68. 58. Meehan WJ, Badreshia S, Mackley CL. Successful treatment of delusions of parasitosis with olanzapine. Arch Dermatol 2006; 142(3):352–355. 59. Mitchell C. Successful treatment of chronic delusional parasitosis. Br J Psychiatry 1989; 155:556–557. 60. Munro A. Monosymptomatic hypochondriacal psychosis manifesting as delusions of parasitosis. A description of four cases successfuly treated with pimozide. Arch Dermatol 1978; 114(6):940–943. 61. Wenning MT, et al. Atypical antipsychotics in the treatment of delusional parasitosis. Ann Clin Psychiatry 2003; 15(3–4):233–239. 62. Harrigan EP, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004; 24(1):62–69. 63. Chong SA, et al. Prolonged QTc intervals in medicated patients with schizophrenia. Hum Psychopharmacol 2003; 18(8):647–649. 64. Johnson FP, et al. Sudden death of a catatonic patient receiving phenothiazine. Am J Psychiatry 1964; 121:504–507. 65. Wilson IC, Reece JC. Simultaneous death in schizophrenic twins. Arch Gen Psychiatry 1964; 11:377– 384. 66. Hollister LE, Kosek JC. Sudden death during treatment with phenothiazine derivatives. Jama 1965; 192:1035–1038. 67. Straus SM, et al. Antipsychotics and the risk of sudden cardiac death. Arch Intern Med 2004; 164(12):1293–1297. 68. Welch R, Chue P. Antipsychotic agents and QT changes. J Psychiatry Neurosci 2000; 25(2):154–160. 69. Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161(8):1334–1349. 70. Zareba W, Lin DA. Antipsychotic drugs and QT interval prolongation. Psychiatr Q 2003; 74(3):291– 306. 71. Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003; 107(2):85–95. McMichael PTR 01/21/08 Chapter 18

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72. Blair J, Taggart B, Martin A. Electrocardiographic safety profi le and monitoring guidelines in pediatric psychopharmacology. J Neural Transm 2004; 111(7):791–815. 73. Cubeddu LX. QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Am J Ther 2003; 10(6):452–457. 74. Vieweg WV, Wood MA. Tricyclic antidepressants, QT interval prolongation, and torsade de pointes. Psychosomatics 2004; 45(5):371–377. 75. Justo D, et al. Torsade de pointes induced by psychotropic drugs and the prevalence of its risk factors. Acta Psychiatr Scand 2005; 111(3):171–176. 76. Stollberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol 2005; 20(5):243–251. 77. Letsas KP, et al. Drug-induced QT interval prolongation after ciprofl oxacin administration in a patient receiving olanzapine. Int J Cardiol 2006; 109(2):273–274. 78. Cash T. The psychological effects of androgenetic alopecia in men. J Am Acad Dermatol 1992; 29:926–931. 79. Cash T. The psychology of hair loss and its implications for patient care. Clin Dermatol 2001; 19:161–166. 80. Cash T, Price V, Savin R. Psychological effects of androgenetic alopecia on women: comparison with balding men and with female control subjects. J Am Acad Dermatol 1993; 29:568–575. 81. Pope H, Philllips K, Olivadia R. In: The Adonis Complex. New York: Simon and Schuster, Inc., 2000:192. 82. Phillips K, Didie E, Menard W. Clinical Features of body dysmorphic disorder in adolescents and adults. Psychiatry Res 2006; 141:305–314. 83. Phillips K, Menard W, Fay C. Gender similarities and differences in 200 individuals with body dysmorphic disorder. Compr Psychiatry 2006; 47:77–87. 84. Veale D, Riley S. Mirror, mirror on the wall, who is the ugliest of them all? The psychopathology of mirror gazing in body dysmorphic disorder. Behav Res Ther 2001; 39:1381–1393. 85. Phillips K, Taub S. Skin picking as a symptom of body dysmorphic disorder. Psychopharmacol Bull 1995; 31:279–288. 86. Phillips K. In: The Broken Mirror: Understanding and treating body dysmorphic disorder. New York: Oxford University Press, 1986:335. 87. Phillips K, Castle D. Body dysmorphic disorder. In: Castle D, Phillips K, eds. Disorders of Body Image. Petersfi eld (UK): Wrightson Biomedical Publishing, 2005:101–120. 88. Eisen J, Phillips K, Coles M. Insight in obsessive compulsive disease and body dysmorphic disorder. Compr Psychiatry 2004; 45:10–15. 89. Phillips K, McElroy S, Keck P Jr, Pope H J, Hndson J. Body dysmorphic disorder; thirty cases of imagined ugliness. Am J Psychiatry 1993; 150:150, 302–308. 90. Gupta MA, Gupta AK, Haberman HF. Dermatologic signs in anorexia nervosa and bulimia nervosa. Arch Dermatol 1987; 123(10):1386–90. McMichael PTR 01/21/08 Chapter 18 McMichael PTR 01/21/08 Chapter 19

19 Scalp Infections and Infestations

Bryan K. Chen and Sheila Fallon Friedlander Rady Children’s Hospital and Health Center, UC San Diego School of Medicine, San Diego, California, U.S.A.

SCALP INFECTIONS Tinea Capitis Historical Background The term tinea was introduced as early as AD 400 by the Romans who believed that the “moth- eaten” appearance of the scalps of individuals with dermatophyte infections represented the work of the tinea moth worm. The British introduced the misnomer “ringworm” in the 1500s, which persists as a common colloquial term today. Sabouraud established the current classifi - cation of dermatophytes into genera in his landmark work Les Teignes (1). It was not until the 1920s that Hopkins and Benham established medical mycology as a fi eld of scientifi c study. Numerous investigators have since made major contributions to the study of dermatophytes.

Epidemiology Tinea capitis is predominantly a disease of children between the ages of 4 and 7 years, and is the most common fungal infection in young children. In one representative North American city, the prevalence of symptomatic, culture-proven infection was 5%, while the asymptomatic carriage rate was 8% (2). The overall incidence of tinea capitis in the general population appears to be increasing, particularly among African-American children who account for more than 80% of reported cases (3). The causative organisms of tinea capitis belong only to two genera: Tricho- phyton and Microsporum. Currently in the United States, greater than 95% of tinea capitis cases are caused by the anthropophilic dermatophyte T. tonsurans, while the remainder of cases are largely due to the zoophilic organism M. canis. This epidemiology represents a signiﬁ cant shift from the early 1900s when M. audouinii was the predominant cause of tinea capitis in the United States. The organisms responsible for superﬁ cial scalp fungal infections also vary considerably with geography (Table 1). To diagnose and treat fungal infections of the scalp appropriately, one must be aware of their changing epidemiology.

Pathogenesis Dermatophytes cause superfi cial fungal infections of the keratinized tissues including the hair. Infection begins with the adherence of hyphae to the perifollicular stratum corneum. Dermatophytes produce keratinases that facilitate invasion into keratinized tissue. The hyphae intercalate between the wall of the follicle and the hair shaft until they reach the level of the mid-follicle. The organism subsequently penetrates the cortex of the hair and achieves a depth of invasion to the level of Adamson’s fringe, where the hair fi rst keratinizes. The hyphae proliferate and elaborate arthroconidia. A plucked diseased hair will break at its weakest point, just above the fringe. Microscopically, ectothrix arthroconidia can be observed in the surface of plucked hairs. The arthroconidia of endothrix dermatophytes, however, are localized within the hair shaft. These fragile hairs that are fi lled with arthroconidia have a tendency to break at the surface of the scalp to cause “black dot” tinea capitis.

Clinical Findings The pattern of clinical ﬁ ndings with tinea capitis infection depends on the causative organism and the host inﬂ ammatory response (Table 2). The most common presentation of tinea capitis exhibits patches of alopecia with superimposed scale. A single species of dermatophyte may McMichael PTR 01/21/08 Chapter 19

278 Chen and Friedlander

TABLE 1 Primary Causes of Tinea Capitis Based on Geography N. America S. America Europe Africa Asia Australia T. tonsurans M. canis M. canis T. violaceum M. audouinii M. canis M. canis T. violaceum T. verrucosum M. canis M. canis T. tonsurans T. rubrum T. tonsurans M. audouinii M. audouinii T. mentagrophytes T. mentagrophytes T. tonsurans T. soudanense T. tonsurans T. violaceum T. mentagrophytes T. verrucosum T. mentagrophytes T. yaoundei T. violaceum T. schoenleinii T. gourvilii T. schoenlinii cause a variety of clinical manifestations. Three patterns of dermatophyte invasion give rise to different clinical presentations.

Ectothrix infection occurs when hyphae that are on the surface of the hair shaft produce arthroconidia with subsequent destruction of the cuticle. Clinical fi ndings with this form of infection may range from pauci-infl ammatory patchy alopecia with or without scale (Fig. 1), to kerion formation. Such cases may be fl uorescent (Microsporum spp.) or non-fl uorescent (Trichophyton rubrum and some Microsporum spp.) with the Wood’s lamp. Endothrix infection is caused by anthropophilic organisms in the genus Trichophyton. Arthro- conidia are confi ned to the area within the hair shaft, and fl uorescence with Wood’s lamp is not seen. Clinical fi ndings range from the black dot and patchy alopecia to kerion formation. T. tonsurans and T. violaceum are the more common causes of endothrix infection. Favus is an unusual, but severe, infl ammatory form of tinea capitis most commonly caused by T. schoenleinii. Hyphae are arranged parallel to the hair and air spaces can be observed within the shaft. The infection begins with patchy perifollicular erythema and scale, progressing to the development of thick yellow crusts of hyphae and skin debris centered about single hairs known as scutula. A bluish fl uorescence is observed with Wood’s lamp examination. A musky odor and purulent discharge may accompany the infection. Chronic infections that expand peripherally typically leave central atrophic scarring.

Diagnosis Tinea capitis should be considered in any child with scalp scaling, erythema or patchy alopecia. The clinician should bear in mind, however, the more unusual presentations of tinea capitis including the “black dot” variant, the painful, boggy inﬂ ammatory lesion of a kerion (Fig. 2) as well as favus, characterized by crusting, atrophy and scarring. The dramatic shift over the last several decades in the predominant causative organism of tinea capitis infection in the United States from the ectothrix organism M. audouinii to the endothrix species T. tonsurans, has limited the clinical utility of the Wood’s lamp examination for the diagnosis of tinea capitis in this country. Unlike T. tonsurans, uncommon cases of M. canis or T. schoenleinii species that produce green ﬂ uorescent pteridines can be detected with the Wood’s lamp.

TABLE 2 Hair Invasion Patterns by Dermatophytes Wood’s lamp Invasion pattern Organism fl uorescence Clinical type Ectothrix M. canis Yes +/− Infl ammatory M. audouinii Yes +/− Infl ammatory M. ferrugineum Yes Noninfl ammatory M. distortum Yes +/− Infl ammatory M. gypseum No Infl ammatory or favus T. rubrum No +/− Infl ammatory Endothrix T. tonsurans No Black dot; +/− infl am T. violaceum No Black dot; favus T. soudanense No Noninfl ammatory T. rubrum No +/− Infl ammatory Favus T. schoenleinii Yes Favus McMichael PTR 01/21/08 Chapter 19

Scalp Infections and Infestations 279

FIGURE 1 Annular scaling plaque of pauci- inﬂ ammatory tinea capitis.

Children suspected of having tinea capitis should be examined for the presence of posterior cervical and occipital lymphadenopathy. The presence of occipital adenopathy in combination with alopecia or scaling in children suspected of having tinea capitis has been demonstrated to have a high predictive value for a positive fungal culture (4). The presence of pediatric scalp scaling with adenopathy in the general population, however, is not specifi c to the diagnosis of tinea capitis, as these clinical fi ndings are commonly associated with seborrheic dermatitis and atopic dermatitis in children (5). Due to the often subtle and nonspecifi c manifestations of tinea capitis, its clinical signs and symptoms alone are not suffi cient to diagnose this infection. A fungal culture is the gold standard for the diagnosis of tinea capitis and should be obtained whenever this entity is suspected. The authors prefer use of the cotton swab method to the brush culture technique, plucking of hairs, or a scalp scraping. A cotton swab is moistened with tap water, rolled and vigorously rubbed over the affected areas of the scalp and inoculated onto fungal culture such as Sab- ouraud’s agar containing cycloheximide and chloramphenicol or dermatophyte test medium (DTM). If the cultures must be sent to an outside lab, the cotton-tipped applicator should be used as above then inserted into a bacterial culture transport container. Not only is the cotton- swab method nonthreatening to the child, rapid and economical, but it has been shown to be as

FIGURE 2 (See color insert.) Kerion formation in tinea capitis. McMichael PTR 01/21/08 Chapter 19

280 Chen and Friedlander sensitive and specifi c as the brush culture technique, with 100% concordance between the two methods (6). Scalp dermatophyte infection can be more rapidly though less reliably diagnosed using a 10–30% potassium hydroxide preparation of hair on a glass slide with a cover-slip. DMSO (40% dimethyl sulfoxide) may be added for more rapid dissolution of the keratin. Hyphae and/or arthroconidia are noted within (endothrix) or around (ectothrix) the hair. In the case of favus, the presence of air spaces can be detected within the hair shaft. The detection of hyphae can be facilitated with special stains such as Chlorazo Black and Schwartz Lampkin or Calcofl uor White (0.1%) which requires a fl uorescence microscope to visualize. False negative results may occur and a fungal culture is still required for identifi cation of the specifi c pathogen involved. Sabouraud’s agar provides a reliable and selective medium for the detection of dermatophytes. Colonies begin to grow at approximately one week at room temperature. Dermatophyte growth on DTM is indicated by a red color change. This relatively inexpensive media, however, does carry a 10–15% false positive rate due to contamination with nondermatophyte fungi (7). Dermatophyte colonies in culture appear fl uffy, wooly, furry or powdery, in contrast to Candida yeast which grows as creamy, smooth colonies. The specifi c identities of dermatophytes are based on certain criteria including the macrosopic appearance of colonies (texture and pigmentation), the microscopic morphology of arthroconidia, nutritional requirements, temperature tolerance and urease susceptibility. More recently polymerase chain reaction assays have been employed in the identifi cation of dermatophytes and may be more commonly utilized in the future. If a culture grows a saprophyte in an immunocompetent host, the culture should be repeated as it is extremely rare to fi nd a persistent saprophytic culture in a normal host.

Differential Diagnosis Several conditions may be clinically indistinguishable from tinea capitis including seborrheic dermatitis, atopic dermatitis and psoriasis. Alopecia areata typically causes completely bare patches of scalp with variable regrowth and no scale. Trichotillomania presents with hairs of variable lengths and blunt ends, but usually no scale. With pustular or inﬂ ammatory lesions, bacterial and yeast folliculitis should be kept in mind. Traction folliculitis may also induce follicular papules, pustules, and alopecia, particularly in the fronto-temporal and occipital areas of the scalp. If scarring is present, discoid lupus or a primary scarring alopecia are further considerations.

Treatment If clinical ﬁ ndings are suggestive of tinea capitis infection, systemic antifungal therapy can be initiated while awaiting culture results. Topical antifungals alone are ineffective against tinea capitis infections because they are unable to penetrate into the hair shaft, the site of dermatophyte invasion. It is not known whether the addition of a topical antifungal to systemic therapy is of any beneﬁ t in active infection

Griseofulvin At the present time, oral griseofulvin remains the standard FDA-approved medication for the treatment of tinea capitis infections. It was isolated from the mold Penicillium griseofulvum in 1939. It has a narrow spectrum of action, specifi c to dermatophytes of the genera Trichophyton, Microsporum and Epidermophyton, with no activity against yeasts. Griseofulvin interferes with fungal cell wall, protein and nucleic acid synthesis. It also possesses anti-infl ammatory and immunomodulatory effects (8). While griseofulvin is fi rst-line treatment for tinea capitis in the U.S., alternatives include terbinafi ne , itraconazole, and fl uconazole. At the present time, these are all off-label utilizations of these drugs for this indication. The current recommended dose of griseofulvin is 20 to 25 milligrams per kilogram per day of the microsized formulation (Table 3). This dose represents a signifi cant increase over the last several decades and is a refl ection of the emergence of apparently “tolerant” organisms (9). Subtherapeutic doses and patient noncompliance with regard to duration and dose of treatment have also contributed to the McMichael PTR 01/21/08 Chapter 19

Scalp Infections and Infestations 281

TABLE 3 Dosing Recommendations for Systemic Therapies in the Treatment of Tinea Capitis Griseofulvin Terbinafi ne Itraconazole Fluconazole 20–25 mg/kg/day microsize 3–6 mg/kg/day Capsule dosing: 6 mg/kg/day or 10–15 mg/kg/day based on mass: 5 mg/kg/day Duration: 2–4 ultramicrosize 10–20 kg: 62.5 mg/day; Duration guided by clinical weeks, guided by Duration: 6–8 weeks; continue 20–40 kg: 125 mg/day; response: 2–4 weeks clinical response 2 weeks after resolution of >40 kg: 250 mg/day continuously or 2–4 one-week signs/symptoms Duration guided by clinical pulses, 2–3 weeks between response: 2–4 weeks pulses continuously or 2–4 Suspension not recommendeda one-week pulses, 3–4 weeks between pulses; M. canis may require longer course aItraconazole suspension has been known to cause pancreatic adenocarcinomas in rats at doses comparable to humans. need for increasing doses for the effective management of this infection. Studies have demonstrated an inverse correlation between dose and recurrence rate, with a higher risk of relapse in patients treated with 15 mg/kg/day microsize as compared to children treated with 25 mg/kg/day (10). Mycologic cure rates of 52% to 100% have been achieved with griseofulvin depending on the dose, pathologic organism and duration of therapy (11–16, 45). The required duration of therapy is typically 6–8 weeks, although treatment must be continued until clinical and mycological cure have been achieved, occasionally necessitating treatment for 12–16 weeks. The Committee on Infectious Diseases of the American Academy of Pediatrics recommends continuing treatment for 2 weeks after the clinical resolution of signs and symptoms (17). The ultramicrosized formulation is more rapidly absorbed and is administered at a dose of 10 to 15 mg/kg/day. The safety and effi cacy profi les of both formulations are similar, though the ultramicrosized formulation is not available in liquid form. Griseofulvin is poorly water- soluble and should be taken with a fatty meal or whole milk for improved absorption. The most common side effects are headache and gastrointestinal discomfort. Uncommonly, it may cause a rash and elevated liver enzymes. In an otherwise healthy patient, laboratory monitoring is not necessary for the usual 8 week course. If more prolonged therapy is required, many experts will obtain laboratory evaluations as a precaution. After the start of treatment, patients occasionally develop an eczematous id reaction. Topical steroids and oral antihistamines are usually effective and treatment should not be discontinued.

Terbinafi ne Terbinafi ne, a tertiary allylamine, is one of several newer antifungal agents including itraconazole and fl uconazole that feature more convenient, shorter dosing regimens owing to their longer half-lives and tendency to persist in the hair follicle long after discontinuation of therapy. Terbinafi ne has demonstrated effi cacy in the treatment of dermatophyte infections and possesses fungicidal activity in vitro. It inhibits squalene epoxidase, an enzyme involved in the synthesis of ergosterol, an essential component of fungal cell membranes. In addition, the resultant accumulation of squalene in the fungal cytoplasm damages cell membranes (18). The drug distributes extensively throughout the epidermis, dermis, adipose tissue, hair and nails. Its mean elimination half-life in the epidermis-dermis, hair and nails is approximately 28 days (19). The oral form was approved by the FDA in 1996 for the treatment of onychomycosis. In 2007, FDA approved terbinifi ne mini-tablets for the indication of tinea capitis following review of a large, a yet unpublished comparative trial documenting effi cacy with higher dosing (5–8 mg/kg/day). Previous studies have utilized the mass-determined dosing regimens of 62.5 mg/day if 10–20 kg, 125 mg/day if 20–40 kg, and 250 mg/day for children over 40 kg in body mass. Pulse therapy has demonstrated effi cacy in a small cohort, with week-long pulses of therapy separated by 2- then 3- week intervals (20). Moderate to severe disease may require 3 or more week-long treatment pulses. Evidence suggests there is a direct relationship between terbinafi ne dose and cure rate. Children receiving more than 4.5 mg/kg/day were more likely McMichael PTR 01/21/08 Chapter 19

282 Chen and Friedlander to be cured than those receiving lower doses, and studies are ongoing regarding the possible superiority of high-dose (6–8 mg/kg/day) therapy for young children, which may require such doses due to higher elimination rates than in adults (21). Previous studies involving terbinafi ne for the treatment of tinea capitis have most often involved doses of 3 to 6 mg/kg/day and have ranged in duration from 1–12 weeks, with a wide range of cure rates depending, in part on the causative organism (22–27). Comparative trials have suggested that treatment with terbinafi ne for 4 weeks is as effective as griseofulvin for 8 weeks. Studies seem to favor terbinafi ne over griseofulvin in the treatment of Trichophyton species for outcomes evaluated 12 weeks after treatment (28). In studies involving the treatment of patients infected with Trichophyton and Microsporum species, 2-week and 4-week courses of terbinafi ne resulted in mycological cure rates of 60–80% and 84–86%, respectively (29). Terbin- afi ne appears to be less effi cacious against M. canis than T. tonsurans, necessitating higher doses or longer courses of therapy to treat infections with the zoophilic organism (30). After a course of terbinafi ne has been completed, mycologic cure rate may continue to improve for a few weeks. The chemical can be detected in the hair for 50 days following the administration of terbinafi ne for 2 weeks (31). Gastric acidity and the presence of food do not signifi cantly impact the absorption of terbinafi ne, which carries a bioavailability of 70–80% (32). Common side effects include headache, gastrointestinal discomfort and rash. Transient elevations in liver transaminases occur in 3–7% of patients, though clinically signifi cant hepatotoxic effects are rare (33). Plasma concentrations of terbinafi ne are reduced by rifampin and increased by cimetidine. Some experts recommend baseline and repeat laboratory monitoring including complete blood count with differential and liver enzymes, while others obtain blood tests only if the patient becomes symptomatic. Dosage adjustments are required for patients with renal and/or hepatic disease.

Itraconazole Itraconazole, a triazole antifungal inhibits fungal lanosterol 14-α demethylase, the enzyme that converts lanosterol to ergosterol in the synthesis of the cell membrane. Itraconazole possesses fungistatic properties and a broad spectrum of activity against dermatophytes, dimorphic and dermatiaceous fungi, yeasts and some molds (34). Itraconazole distributes widely into lipophilic tissues, skin and adnexal structures. After the medication is discontinued, therapeutic drug levels persist at 6 months in the nails and up to 9 months in the hair (35). Itraconazole has been administered at a dose of 5 mg/kg/day, continuously for 2–4 weeks to treat tinea capitis infections with some variability in the response rate (36–38). Pulse dosing regimens of 3–5 mg/kg/day for 1 week, with each pulse separated by 2–3 week intervals, have also been used successfully (39,40). The number of pulses required, ranging from 1–5, are largely dependent upon the severity of disease. The oral solution is dosed at 3 mg/ kg/day for 4 weeks but a component of this oral solution, cyclodextrin has caused pancreatic adenocarcinomas in rats that have ingested amounts comparable to human-ingested doses. For this reason, we cannot recommend the suspension formulation. Infections due to M. canis may require longer courses of therapy. For maximal absorption, itraconazole capsules should be taken with food. Antacids, H2 blockers and proton pump inhibitors will decrease systemic absorption. The liquid formulation has a greater bioavailability but is also associated with a higher rate of gastrointestinal side effects and a theoretical risk of adenocarcinomas in humans. Common adverse effects are mild and include gastrointestinal symptoms, headache, rash and dysgeusia. Transient elevations in liver transaminases may occur, but clinically signiﬁ cant hepatic dysfunction is rare. Because it is a cytochrome P-450 inhibitor, concomitant use will raise levels of phenytoin, coumadin, nortriptyline, benzodiazepines and FK506. Dose adjustments are not needed for renal disease.

Fluconazole Fluconazole is also a fungistatic triazole with the same mechanism of action as itraconazole. Unlike the other azoles, ﬂ uconazole is not lipophilic. The oral bioavailability of the drug is greater than 90%, and absorption is not affected by gastric pH or the presence of food. After a 5-day course, ﬂ uconazole can be detected 4–5 months following discontinuation of the medication (41). McMichael PTR 01/21/08 Chapter 19

Scalp Infections and Infestations 283

The typical dose might be 6 mg/kg/day for approximately 3 weeks, with duration guided by the clinical response. The clinical cure rates obtained with fl uconazole have been highly variable. Mycological cure rates of 82–100% have been achieved with fl uconazole in several clinical trials with dosing of 5–8 mg/kg/day (42–44). However, a recent multicenter trial of over 800 patients with 3 treatment arms (fl uconazole 6 mg/kg/d for 3 weeks, fl uconazole 6 mg/kgd for 6 weeks, and griseofulvin 11 mg/kg/d for 6 weeks) documented suboptimal response rates with any of these regimens. Cure rates of 45%, 50%, and 52%, respectively, were noted. Some experts believe that stringent cure criteria and the disallowance of any concurrent topical therapy may have contributed to these relatively poor outcomes (45). Gastrointestinal symptoms and headache are the most common side effects. Transient elevations in liver enzymes may occur but are rarely associated with clinically signifi cant hepatotoxicity. The drug-interaction profi le for fl uconazole, another inhibitor of the P-450 system, is similar to that of itraconazole. Fluconazole is largely renally excreted and may require a dosage adjustment in patients with renal impairment.

Voriconazole Voriconazole, a newer triazole antifungal which carries a broad spectrum of activity, has been available in the United States since 2002. Its mechanism is the same as that of the other triazoles. Though clinical experience with voriconazole in the treatment of dermatophytes is lacking, in vitro susceptibilites of common isolates including T. tonsurans and M. canis to voriconazole compare favorably to those of ﬂ uconazole and griseofulvin (45a). Voriconazole is dosed at 6 mg/kg once every 12 hours x 1 day (loading dose), followed by 4 mg/kg every 12 hours (46). It is approved for use in children as young as 2 years of age. As the absorption of voriconazole is decreased 22% by administration with food, it should be taken 1 hour before or 2 hours after meals. More clinical data will be required to determine the appropriate role of voriconazole in our armamentarium for the treatment of tinea infections, and many experts believe this drug should be reserved for more serious fungal infections. Adverse effects of voriconazole include visual disturbance, rash, and increased liver function tests. Drug interactions are also possible; the Physicians Desk Reference should be consulted regarding a drug in question.

Adjunctive Therapies and Measures Ketoconazole 2% and zinc pyrithione 1% and 2% shampoos have been shown to decrease surface colony counts of dermatophytes (47). In one study, ketoconazole 2% shampoo as monotherapy for 8 weeks to treat Trichophyton tonsurans tinea capitis has achieved a 12-month mycological cure rate of 33% (48). It is not known, however, whether adjunctive treatment with these medicated shampoos reduces the risk of transmission of the disease to other individuals. For asymptomatic family members, use of these shampoos 2–3 times weekly may help prevent infection and decrease the asymptomatic dermatophyte carriage rate. Children with tinea capitis may return to school once appropriate treatment has been initiated. Items that may function as fomites such as hats, combs, brushes and hair accessories should be disinfected or preferably discarded. If a zoologic organism such as M. canis is isolated on fungal culture, a household pet should be suspected and taken to the veterinarian for evaluation. The utility of post-treatment cultures is controversial and most experts base duration of treatment on clinical response; if the patient does not improve, repeat culture should be obtained.

Kerion The use of systemic corticosteroids in the management of inﬂ ammatory tinea capitis is controversial. The results of a study comparing an 8-week course of griseofulvin plus a 3- to 4-week tapering course of prednisolone to 8 weeks of griseofulvin alone revealed 100% clinical and mycological cure rates in both groups at 12 weeks evaluation (49). Another study comparing griseofulvin alone to griseofulvin plus intralesional corticosteroid injections revealed no signiﬁ - cant differences in time to mycological cure or hair regrowth (50). McMichael PTR 01/21/08 Chapter 19

284 Chen and Friedlander

Without corticosteroids, appropriate antifungal therapy quickly decreases the inﬂ ammatory component of the kerion. For these reasons, the use of systemic or intralesional corticosteroids is usually not necessary. Some practitioners recommend initiating prednisone at a dose of 1–2 mg/kg/day for 10 to 14 days if no improvement is noted within 2 weeks of systemic antifungal therapy.

Piedra Piedra, also known as trichomycosis nodularis, is a superﬁ cial, asymptomatic fungal infection of the hair shaft. The agent causing black piedra is Piedraia hortae, while the causative organism in white piedra is Trichosporon beigelii.

Epidemiology Black piedra is most prevalent in hot and humid climates and is found in the tropics, worldwide. Infection is promoted in certain indigenous cultures for religious and aesthetic reasons. The scalp is the most commonly affected hair-bearing area. White piedra is most common in semi-tropical and temperate areas including South America and Asia. Generally, the scalp hair is less commonly affected than the genital, axillary and facial hair (51). The infection is sporadic in Europe and parts of the southern U.S. In Brazil, white piedra is most common on the scalp and appears to have a predilection for women and children age 2–6 years (52).

Clinical Findings Black piedra is characterized by hard, darkly pigmented nodules of variable size, ﬁ rmly attached to the hair shaft. The nodules have a predilection for the frontal scalp, may weaken the hair and produce hair breakage (53). White piedra presents as tan, elongated, cylindrical nodules located circumferentially around and loosely adherent to the hair shaft. White piedra less commonly induces hair fragility and breakage than black piedra. T. beigelii may also cause onychomycosis. When this oppor- tunistic pathogen disseminates in immunocompromised individuals, management is difﬁ cult and the mortality rate is high (54).

Diagnosis KOH examination of a nodule of black piedra will demonstrate a periphery of aligned pigmented hyphae and well-organized center of thick-walled cells closely packed together. Fungal spores can be identiﬁ ed in the densely packed extracellular material. P. hortae colonies are dark- brown to black and grow slowly on most laboratory media. Nodules of white piedra have a more disorganized appearance than those of black piedra. KOH examination reveals arthroconidia arranged in a tightly packed fashion around the hair, with hyphae arranged perpendicularly to the hair shaft. Spores may be surrounded by coexis- tent bacteria. In fact, there is evidence that suggests a synergistic relationship between T. beigelii and corynebacteriae (55,56). Colonies in culture are creamy white in appearance and may be mistaken for yeast.

Differential Diagnosis The differential diagnosis of scalp lesions of black and white piedra include pediculosis capitis (nits), hair casts, dandruff as well as hair shaft deformities such as monilethrix and trichorrhexis nodosa. These conditions can readily be distinguished from one another with gross and microscopic examination.

Treatment Although guidelines state that shaving the scalp hair is the most effective treatment for white and black piedra (57) a small study showed effective treatment of white predva with a combination of oral azoles and antifungal shampoo therapy (57a). Topical antifungals including the imidazoles and ciclopirox as well as 6% precipitated sulfur in petrolatum and 1–2.5% selenium sulﬁ de lotion may be effective. Black piedra may respond to oral griseofulvin therapy (58). Given the high rate McMichael PTR 01/21/08 Chapter 19

Scalp Infections and Infestations 285 of relapse and evidence of intra-follicular involvement with white piedra, some authorities recommend systemic antifungal therapy. Itraconazole may be effective in this setting (59).

SCALP INFESTATIONS Pediculosis Capitis Historical Background Pediculosis has been documented in the literature for thousands of years. The most frequently quoted early reference to lice is in Exodus 8:17 in which Aaron “stretched out his hand with his staff and struck the dust of the earth, and it became lice on man and on beast…” Although some 560 species of blood-sucking lice have been described, only one species of louse is responsible for nearly all cases of lice infestation of the scalp: Pediculus humanus capitis (Fig. 3). Head lice do not pose a signiﬁ cant public health risk, they are not vectors of disease and they are not a sign of uncleanliness. Although head lice infestation is associated with little morbidity, it accounts for many days lost from school, and creates a considerable amount of anxiety in the parents of school-aged children who themselves are often embarrassed by the social stigma of this diagnosis.

Epidemiology Pediculosis capitis is estimated to affect 9 million people per year, affecting individuals of all socioeconomic groups (60). The infestation most frequently occurs in children, especially girls 3 to 12 years of age (61). The overall prevalence is 1–3% in industrialized countries. Infestations in the United States are less common in the black population than other races perhaps because they have oval rather than round-shaped hair shafts in cross-section that are more difﬁ cult for the lice to grasp. There appears to be a seasonal trend, with infestations occurring more frequently during the warmer months (62). Hair length and the frequency of brushing and shampooing do not signiﬁ cantly affect the likelihood of an infestation with head lice. Transmission typically occurs by direct head-to- head contact with an infested individual. This transfer of lice is optimal when the unaffected hairs are in parallel with and slow-moving, relative to the affected hairs (63). Indirect spread of lice through contact with fomites that have come into contact with the hair and scalp, including brushes, combs and hats is possible, though less likely.

Louse Features The head louse measures 1–2 mm in length (Fig.4). They are unable to jump or ﬂ y, only crawl, though they are capable of traveling at a pace of over 20 cm/min. They possess three pairs of clawed legs designed to grasp hairs and narrow sucking mouth parts that inject saliva. Head lice generally remain close to the scalp. Males can easily be distinguished from females by visual inspection. Males have brown transverse bands on the abdomen, along the edge of the overlapping chitinous plates. Females are generally 20% larger than males and have a more

FIGURE 3 (See color insert.) Clinical appearance of louse scalp infestation. McMichael PTR 01/21/08 Chapter 19

286 Chen and Friedlander

FIGURE 4 Close view of adult louse. rounded and full appearance to the abdomen. Female lice live up to 4 weeks, laying approximately 10 eggs a day. Eggs enclosed in chitinous casings, also known as nits, are ﬁ rmly attached to the hair shaft by a glue-like adhesive and are difﬁ cult to remove. The eggs hatch nymphs in 10–14 days that then grow for 9–12 days and mate to produce more eggs to complete the 3- week life cycle. A louse living on the scalp feeds by piercing the skin with a tube-like structure equipped with a serrated end, called the haustellum, injecting small amounts of saliva in combination with anticoagulant and a vasodilator, and ingesting a tiny blood meal every 4 to 6 hours. Head lice usually cannot survive more than 1 day away from the scalp. It takes several weeks for the affected individual to develop a sensitivity to louse saliva which is largely responsible for causing itching and irritation (64).

Clinical Findings Pruritus is the primary symptom of pediculosis capitis and may be mild to severe depending in part on the stage in the evolution of immune sensitivity, though patients with head lice are not always symptomatic (65). Other common ﬁ ndings include inﬂ ammatory bite reactions, excoriations, cervical lymphadenopathy and conjunctivitis (66). A hypersensitivity eruption or id reaction may resemble a viral exanthema or eczema, and most commonly occurs around the occipital and temporal scalp and surrounding cutaneous areas. In certain severe and untreated cases, a secondary bacterial infection may occur.

Diagnosis The most sensitive means of diagnosing pediculosis capitis is the detection of a live louse on the head, which is often challenging. After the hair is brushed to untangle the hair, a fi ne-tooth comb with teeth positioned 0.2 to 0.3 mm apart should be placed near the crown until it touches the scalp, then drawn down with a fi rm motion. The scalp hair in its entirety should be combed thoroughly in this fashion, with examination of the comb for dislodged lice after each stroke. If no lice are found, this process should be repeated at least once. If an infestation is present, it typically takes approximately one minute to discover the fi rst louse (67). Wetting hair prior to combing may increase the sensitivity of louse detection (68). Head lice can be found by visual inspection of the scalp and hair alone, but may miss up to 75% of infestations detectable with a fi ne-tooth comb. The condition is frequently misdiagnosed when based on the fi nding of nits since they may be present months after successful treatment (69). According to the Centers for Disease Control and Prevention, the fi nding of many eggs within 6.5 millimeters of the scalp is diagnostic for head lice; however, over two-thirds of individuals with this fi nding do not go on to develop an active infestation (70). For these reasons, though the presence of nits close to the scalp is a suspicious fi nding, detection of a live louse is both suffi cient and optimal for the diagnosis of pediculosis capitis. McMichael PTR 01/21/08 Chapter 19

Scalp Infections and Infestations 287

Differential Diagnosis Hair casts (inner sheath keratin remnants) as well as white piedra caused by Trichosporon beigelii may resemble nits. Hair casts form when the soft inner root sheath keratin remains adherent to the hair shaft. Unlike nits, they are freely movable along the hair shaft. The white to tan nodules of white piedra are also loosely adherent to the hair shaft and completely encircle the hair shaft unlike nits which are ﬂ ask-shaped, discrete casings ﬁ rmly attached to one side of the hair shaft. Flakes of seborrheic dermatitis or scalp psoriasis may be mistaken for nits. Psocids are louselike insects that are rare causes of human scalp infestation. Upon close inspection, however, they can easily be distinguished from human lice by their more prominent mouth parts, larger heads and hind legs, and longer antennae (71).

TREATMENT The Problem of Resistance Over the last several years, we have witnessed the emergence of lice that are resistant to chemical pediculicides (72–77). There are various proposed mechanisms of lice resistance. Elevated glutathione-S-transferase activity is thought to cause resistance to organophosphates (malathion), while enhanced monooxygenase activity (increased drug metabolism) and knock-down resistance (nerve insensitivity) are believed to be responsible for pyrethroid resistance. Louse resistance in the United States has been reported with lindane and permethrin, pediculicidal agents currently approved by the FDA for the treatment of head lice. Lice resistant to both malathion and pyrethrin have been reported in England (78). Malathion had been off the market in the United States for many years, but was then reintroduced in 1999 for the treatment of head lice. A study in Florida examining in vitro pediculicidal activity of malathion indicated a lack of resistance to this agent (79). Since resistance patterns have historically followed patterns of medication use, resistance to Malathion is likely to emerge in the future.

Permethrin Permethrin 1% (Nix®), a synthetic pyrethroid, has been approved by the FDA for the treatment of pediculosis capitis since 1986 and is available without prescription (Table 4). Its mechanism of action is to interfere with sodium transport to cause nerve depolarization, resulting in respiratory paralysis (80). Permethrin 5% (Elimite® or Acticin®) cream is an FDA-approved treatment for scabies. Permethrin 1% is not 100% ovicidal, as 20–50% of viable eggs hatch after application. In 1987, a single 10-minute application of Nix affected a cure in greater than 99% of subjects (81). Since 1994, however, increasing resistance of lice to this agent has been observed in the United States, the United Kingdom, France, Argentina, the Czech republic and Israel (82–84). Permethrin is retained on the hair 2–3 weeks after application. This residual activity, however, is no longer lethal to newly hatched nymphs. Most experts therefore recommend repeating the application one week later. Though permethrin-resistant lice may be resistant over a broad range of concentrations, the 5% cream has also been used preemptively to counter the relative resistance of lice to permethrin 1% (85). Nix has a favorable safety proﬁ le. It has proven to be safe for an 8–14 hour application in infants as young as 1 month (86). Studies with systemic doses utilizing animal models found permethrin to be 3 times less toxic than the natural pyrethrins (87). Side effects are minor and include rash, pruritus, burning and rarely allergic reactions.

Pyrethrins Natural pyrethrins are a mixture of six extracts including pyrethrin I and II, jasmolin I and II and cinerin I and II, from the ﬂ ower heads of Chrysanthemum cinerariae folium, a relative of the ragweed (88). Pyrethrin shares the same mechanism as permethrin, inhibiting sodium channel repolarization of the arthropod neuron to cause respiratory paralysis and death. Unlike permethrins, however, they are unstable to heat and light and do not possess retained activity after washing. Since 1950, piperonyl butoxide (PBO) has been added to all McMichael PTR 01/21/08 Chapter 19

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TABLE 4 Comparison of the Pediculicides Pyrethrins (with Characteristic Permethrin piperonyl butoxide) Malathion Lindane Ivermectin Class Synthetic Chrysanthemum Organophosphate Organochlorine Avermectin pyrethroid extract derivative Trade names Nix cream rinse, RID, A-200, R&C, Ovide, Prioderm Kwell, Kwellada, Stromectol, Lyclear, generic Paratrol, Pronto, Gammexane, Zimectrin, Clear, other Gammexol, Ivomec, generics generic Heartguard, Cardomec Application time 10 minutes 10 minutes 8–12 hours 5–10 minutes N/A Residual activity Yes No Yes No No Adverse effects Erythema, edema, Possible allergic Skin irritation; CNS toxicity, Pruritus, rash, pruritus, dermatitis malodorous, seizures, rash, ﬂ ulike hypoesthesia ﬂ ammable. nausea, vomiting, symptoms, (rare) diarrhea ↑liver enzymes Documented Czech Republic, Czech Republic, UK, Egypt Netherlands, UK, None reported resistance Israel, UK, USA, Israel, UK, France, Panama, US, France, Argentina, Egypt, worldwide Argentina worldwide FDA pregnancy B C B B C category

manufactured natural pyrethrin products. PBO has insecticidal activity itself, it enhances the effect of the natural pyrethrins and it has been found to block the monooxygenase pathway of louse resistance (89). There are several name-brand formulations available including RID® mousse or shampoo, A-200® shampoo, R&C® shampoo, Paratrol®, Pronto®, Clear® shampoo as well as generic formulations. The different vehicles of these products account for their differences in efﬁ cacy. A-200 shampoo, for example, contains benzyl alcohol that enhances the pediculicidal activity of pyrethrin (90). None of these natural plant extracts in combination with PBO are totally ovicidal, with 20–30% of eggs remaining viable after a single treatment (91). A second treatment 7–10 days later is required to kill the nymphs that hatched from those eggs in the interim. Pyrethrin- resistant cases of pediculosis capitis have been reported in the United Kingdom (92). Although pyrethrin resistance has not been documented in the United States, there have been a greater number of treatment failures with the pyrethrins (93). In Panama in 2000, RID and A-2000 carried ovicidal activity of 69% and 83%, respectively. The safety proﬁ le of the pyrethrins is generally favorable. Although allergic contact dermatitis is rare with pyrethrins, they should not be used in patients with ragweed allergies. Ker- osene or petroleum distillates used to extract the natural pyrethrins may cause eye irritation.

Malathion Malathion is the most ovicidal and has the most rapid onset of action of all the pediculicides developed over the last several decades (94). Malathion has been removed from the U.S. market twice due to problems associated with prolonged application time, ﬂ ammability and odor. In 1999 it was re-introduced in the United States and marketed under the brand name Ovide®, a 0.5% formulation available by prescription. Malathion is an organophosphate and irreversible inhibitor of cholinesterase. It causes acetylcholine accumulation at the receptor site, causing respiratory paralysis of arthropods (95). Malathion binds to the sulfur atoms of the hair, which accounts for its residual activity against head lice. In spite of its quick action, the ofﬁ cially recommended application time of topical malathion as established by the original FDA studies is 8–12 hours. Evidence, however, suggests that McMichael PTR 01/21/08 Chapter 19

Scalp Infections and Infestations 289 a signifi cantly shorter exposure time may be suffi cient (79). In controlled in vitro susceptibility trials utilizing malathion 0.5% lotion, 98–100% of lice were dead 5 minutes after administration, with <5% of eggs hatching after a 10-minute exposure. After a 12-hour application time of malathion 0.5% to the scalp, 95% of patients are lice- free and 85.5% are nit-free one week after application (82). If lice remain, a second application 7 days after the fi rst is recommended. Data suggest, however, that a single application of 2 hours or less may be adequate (96). Malathion resistance, based on a modifi cation of acetylcholines- terase, has been reported in England, but not in the United States. In clinical trials, 10% of patients experience minor side effects including erythema of the conjunctiva and scalp, scalp tingling and dandruff (97). Long applications times of 8–12 hours may cause headaches due to inhalation of malathion fumes. This solution comprised of 78% isopropyl alcohol is fl ammable and electric appliances such as curling irons and hair dryers should not be used concurrently.

Lindane Lindane and malathion are the only prescription medications approved by the FDA for the treatment of pediculosis. It belongs to a class of chemical insecticides called organochlorides that also includes DDT. Absorption of lindane through the louse chitinous skeleton is more effi cient than through human skin. Lindane functions to inhibit γ-aminobutyric acid to cause excess stimulation of the louse CNS with resultant death (98). At one time, lindane 1% shampoo was the predominant treatment for pediculosis capitis. Compared to the other pediculicides, lindane has an inferior side-effect profi le. This chemical can accumulate in human adipose and nervous tissue, with the potential for CNS toxicity. Lindane should be kept out of the reach of children, patients should be warned against ingesting it, applications should not exceed the recommended time of 5–10 minutes, and repeated applications should be avoided. Lindane has been removed from the market in California in the wake of central nervous system toxicity reports (99,100). Despite its short application time, lindane is a slowly metabolized and slow-acting pediculicide in which the louse suffers a slow death in multiple stages over several hours including twitching, extrusion of the male sexual organs and convulsions that can be detected by the patient. Most patients prefer a more rapidly pediculicidal agent. Lindane also carries a signifi cant failure rate that can be partly attributed to resistant lice. Louse resistance to lindane has occurred in multiple countries worldwide including the UK, the Netherlands, Panama and the United States (101). Lindane has been compared to several pediculicides and was found to be the least ovicidal, with the slowest killing effect (79). In the United States, lindane resistance is apparent by the fi nding that only 17% of lice are dead after 3 hours of continuous exposure to undiluted lindane (102). In a recent Panama study, 1% lindane shampoo was found to be only 24% ovicidal (79). Minor side effects of lindane include pruritus, edema, burning and erythema. Lindane may cause anemia in addition to neurotoxicity and is contraindicated in patients with seizure histories or in individuals with concurrent conditions that lower the seizure threshold such as HIV disease. With widespread resistance to this insecticide and the availability of other effi cacious agents with safer side-effect profi les, lindane is seldom the pediculicide of choice.

Ivermectin The FDA has approved ivermectin for the treatment of onchocerciasis and strongyloides. Pedic- ulosis is not an approved indication. Ivermectin is a macrocyclic lactone with a structure similar to macrolide antibiotics. Ivermectin binds and activates glutamate-gated chloride channels of invertebrate muscle and nerve cells. The resulting hyperpolarization causes paralysis and eventual death (103). The off-label dose of ivermectin for pediculosis capitis is 200 µg/kg, followed by a second dose 1 week later (104,105). Ivermectin carries an excellent side-effect proﬁ le with no reports of serious effects. Resistance of head lice to this therapy also has not been reported. A topical formulation of this drug has been developed, but not yet widely tested or marketed. McMichael PTR 01/21/08 Chapter 19

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Other Agents Oral administration of trimethoprim-sulfamethoxazole (TMP-SMX) has been shown, off label, to be effective in several small studies for treating head lice. The combination of permethrin and TMP-SMX appears to be more effective than either agent alone (106). Its mechanism of action is thought to be eradication of the gut fl ora of the louse, with death caused by a defi ciency of B vitamins. The potential for serious adverse effects including Stevens-Johnson syndrome limits its use for this indication. Albendazole, a proven antihelminthic and antiprotazoal medication has demonstrated effi cacy against pediculosis capitis at a success rate of 61.5% (107). The primary mechanism of albendazole is thought to be inhibition of microtubule assembly via binding to beta-tubulin. The suggested dose is two 400 mg oral doses, administered one week apart. Carbaryl, available as a 0.5% lotion and shampoo is used in the United Kingdom for the treatment of pediculosis capitis. It is a cholinesterase inhibitor with an unpleasant odor. It is not available in the United States. The lotion requires a 24-hour treatment time, while the shampoo is applied for only 3–10 minutes but requires a second treatment. The lotion was shown to be more effective than the shampoo in clinical trials (108). Lice do not appear to have developed resistance to this product at this time. Crotamiton 10% lotion is available by prescription in the United States but not currently approved by the FDA for the indication of pediculosis capitis. The mechanism of action is not known. It appears to have excellent antipruritic activity (109). Evidence of its effi cacy in the eradication of head lice is limited, but reports suggest that a single night-time application may be effective (110). Safety of crotamiton for use in children has not been established. Hair Clean 1-2-3® (Quantum Health, Eugene, Oregon, U.S.A.) is available in some health stores. It contains anise, ylang-ylang, coconut oils and isopropyl alcohol. Its mechanism of action is not known. In one study, it was found to effect a greater cure rate than 1% permethrin (98% vs. 89%) (111). A recently described suffocation-based pediculicide in the form of a lotion (Nuvo®, Dale Pearlman MD, Menlo Park, California, U.S.A.) has demonstrated overall cure rates of 96% and 94% with and without physical removal of nits, respectively (112). The product includes stearyl alcohol, propylene glycol, sodium lauryl sulfate, cetyl alcohol, water, methyl-4-hydroxybenzoate, propyl p-hydroxybenzoate and butyl p-hydroxybenzoate, and is available in over-the counter form as Cetaphil® lotion. (The product has not been evaluated or approved by the FDA for this purpose.) The lotion is generously applied to the scalp and hair until the sites are wet, then blown dry with a hair dryer to form a “shrink-wrapped” adherent fi lm. This is usually left in place for 8–12 hours, but because it is not readily apparent, patients can presumably carry on daily activities if required during this time. Treatment is repeated once a week as necessary, with 3 weekly treatments a frequently used duration. The mechanism of killing is suffocation by the plugging of the louse’s respiratory spiracles. Components of this lotion are recognized as nontoxic by the FDA. Given the ease of application, reportedly high cure rates, and lack of signifi cant side effects, this treatment would appear to be a reasonable fi rst or second option for families. A variety of new agents are regularly introduced and touted as 100% effective, and a suffocation-based pedic- ulocide currently approved in Canada also holds promise but is not yet available in the U.S. Many experts believe that careful “nit-picking” with an appropriate comb following hair washing is a very reasonable and successful therapeutic intervention, without risk of adverse effects. However, the degree of obsessiveness required is sometimes lacking in caretakers, who prefer less time-consuming options. There are anecdotal reports of other non-chemical modalities such as the LiceGuard Robi-Comb® (Health Tech), a fi ne-toothed metal electric comb pow- ered by a single AA battery. This product kills lice by electrocution, requiring daily combing for 2 weeks (113). The safety and effi cacy of this device has not been adequately evaluated. Some have advocated the application of greasy products including petroleum jelly, may- onnaise, pomades and oils for the treatment of head lice. Viscous substances are thought to obstruct the respiratory spiracles of the adult louse, as well as the operculum of the eggs, to block air exchange. Though they are innocuous substances, the messy residue requires frequent shampooing for 7–10 days for complete removal. As the true pediculicidal activity of these occlusive agents is unknown, we cannot recommend their use as primary therapy for head lice. McMichael PTR 01/21/08 Chapter 19

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TREATMENT FAILURES When a scalp louse infestation persists, the provider must consider and address possible explanations including misdiagnosis, noncompliance, reinfestation and resistance of lice to the pediculicide used. In such cases, the clinician may try to combine mechanical removal with the application of a pediculicidal agent. Chemical agents should be chosen based on the patterns of local resistance. If louse resistance is suspected, agents can be used sequentially. Cetaphil lotion applied weekly for 3 weeks is a benign option. If permethrin 1% is ineffective, a trial with the 5% formulation may be effective. A louse infestation resistant to 5% permethrin may respond to malathion. When the FDA-approved agents as monotherapy have failed, alternative agents, adjunctive measures and physical removal should be considered.

SCREENING The eradication of pediculosis capitis is best viewed as a community-wide endeavor. Par- ents must cooperate with educational administrators to address this problem in grade- schools. Screening in the school community even for live lice has not been proven to have any effect on the incidence of head lice over time; neither has it been shown to be cost- effective (114). In a study of 1729 school children screened for head lice, less than one-third of the 91 children with nits had concomitant lice, while only 18% of those with nits alone converted to an active infestation over 2 weeks of observation (115). Descriptive studies suggest that the education of parents in the proper diagnosis and treatment of head lice may be beneﬁ cial (116–118). Cursory school screenings are no substitute for a careful check for live lice by a trained parent, guardian or school personnel. These checks should be directed by the presence of symptoms (scalp pruritus). The “no nit” policy adopted by some schools which prohibits children from returning to school until all nits and live head lice are eradicated results in the exclusion of many students without active infection from the classroom. If a child has been diagnosed with pediculosis capitis with the ﬁ nding of live lice, he or she should be allowed to return to school after the appropriate treatment. Careful checks for lice on the heads of other children who may have had head-to-head contact with the affected child would be prudent. A “no live lice,” evidenced-based policy for classroom attendance would seem more reasonable and result in fewer missed school days.

ADJUNCTIVE CONTROL MEASURES Additional environmental control measures include the isolation of potential fomites in plastic bags for 2 weeks and the washing or vacuuming of personal items such as brushes, hats, combs, linens and stuffed animals. Though these actions appear to be reasonable, they have no proven beneﬁ t in effecting a cure (119). Fumigation of households and the spraying of potential fomites with insecticides are not necessary. Empiric treatment of contacts or family members also is not required. In certain Afghan refugee populations, the use of mosquito netting imbued with permethrin not only decreased the spread of malaria but reduced the incidence of head lice. In clinical practice, the appropriate use of an effective pediculicidal agent is still needed to eradicate a louse infestation.

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J Eur Acad Dermatol Venereol 2002; 16:257–259. 63. Canyon DV, Speare R, Muller R. Spatial and kinetic factors for the transfer of head lice (Pediculus capitis) between hairs. J Invest Dermatol 2002; 119:629–631. 64. Frankowski BL, Weiner LB. Head lice. Pediatrics 2002; 110(3):638–643. McMichael PTR 01/21/08 Chapter 19

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65. Mumcuoglu KY, Klaus S, Kafka D, et al. Clinical observations related to head lice infestation. J Am Acad Dermatol 1991; 25:248–251. 66. Bloomfi eld D, Adam HM. Head lice. Pediatr Rev 2002; 23:34–35. 67. Mumcuoglu KY, Friger M, Ioffe-Upensky I, et al. Louse comb versus direct visual examination for the diagnosis of head louse infestations. Pediatr Dermatol 2001; 18:9–12. 68. De Maeseneer J, Blokland I, Willems S, et al. Wet combing versus traditional scalp inspection to detect head lice in schoolchildren: observational study. BMJ 2000; 321:1187–1188. 69. Roberts RJ. Head Lice. N Engl J Med 2002; 346(21):1645–1650. 70. Williams LK, Reichert A, MacKenzie WR. Lice, nits, and school policy. Pediatrics 2001; 107:1011–1015. 71. Elston DM. What’s eating you? Psocoptera (book lice, psocids). Cutis 1999; 64:307–308. 72. Yoon KS, Gao JR, Lee SH. Permethrin-resistant human head lice, Pediculus capitis, and their treatment. Arch Dermatol 2003; 139(8):994–1000. 73. Burkhart CG, Burkhart CN. Clinical evidence of lice resistance to over-the-counter products. J Cutan Med Surg 2000; 4:199–201. 74. DeBerker D, Sinclair R. Getting ahead of head lice. Australas J Dermatol 2000; 41:209–212. 75. Downs AM, Stafford KA, Hunt LP, et al. Widespread insecticide resistance in head lice to the over- the-counter pediculocides in England, and the emergence of carbaryl resistance. Br J Dermatol 2002; 146:88–93. 76. Picollo MI, Vassena CV, Mougabure Cueto GA, et al. Resistance to insecticides and effect of synergists on permethrin toxicity in Pediculus capitis (Anoplura: Pediculidae) from Buenos Aires. J Med Entomol 2000; 37:721–725. 77. Burkhart CG. Relationship of treatment-resistant head lice to the safety and effi cacy of pediculicides. Mayo Clin Proc 2004; 79(5):661–666. Review. 78. Downs AM, Stafford KA, Harvey I, Coles GC. Evidence for double resistance to permethrin and malathion in head lice. Br J Dermatol 1999; 141:508–511. 79. Meinking TL, Serrano L, Hard B, et al. Comparative in vitro pediculicidal effi cacy of treatments in a resistant head lice population in the United States. Arch Dermatol 2002; 138:220–224. 80. Permethrin. In: Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 2000:497, 767, 3167. 81. Meinking TL, Taplin D. Advances in pediculosis, scabies and other mite infestations. Adv Dermatol 1990; 5:131–150. 82. Burgess IF, Peock S, Brown CM, et al. Head lice resistant to pyrethroid insecticides in Britain. BMJ 1995; 311:752. 83. Picollo MI, Vassena CV, Mougabure Cueto GA, et al. Resistance to insecticides and effects of synergists on permethrin toxicity in Pediculus capitis (Anoplura: Pediculidae) from Buenos Aires. J Med Entomol 2000; 37:721–725. 84. Mumcuoglu KY, Miller J, Gofi n R, et al. Epidemiological studies on head lice infestations in Israel. I. Parasitological examinations of children. Int J Dermatol 1990; 29:502–506. 85. Jones KN, English JC. Review of Common Therapeutic Options in the United States for the Treatment of Pediculosis Capitis. Clin Infect Dis 2003; 36:1355–1361. 86. Quarterman M, Lescher J. Neonatal scabies treated with permethrin 5% cream. Pediatr Dermatol 1994; 11:264–266. 87. Meinking T. Infestations. Curr Probl Dermatol 1999; 11:73–120. 88. Craig W, Chesney P, Cobbs C, et al. Pyrethrins and piperonyl butoxide. In: Allen L, Ambrosio T, Amerson A, Amidon G, eds. Drug information for the health care professional. Rockville, MD: United States Pharmacopeial Convention, 1998:2458–2550. 89. Hemingway J, Miller J, Mumcuoglu K. Pyrethroid resistance mechanisms in the head louse Pediculus capitis from Israel: implications for control. Med Vet Entomol 1999; 13:89–96. 90. Picollo MI, Vassena CV, Casadio AA, et al. Laboratory studies of susceptibility and resistance to insecticides in Pediculus capitis (Anoplura; Pediculidae). J Med Entomol 1998; 35:814–817. 91. Meinking TL, Entzel P, Villar ME, et al. Comparative effi cacy of treatments for pediculosis capitis infestations. Update 2000. Arch Dermatol 2001; 137:287–292. 92. Burgess I, Peock S, Brown C, Kauffman J. Head lice resistant to pyrethroid insecticides in Britain [letter]. Br Med J 1995; 311:752. 93. Meinking TL, Taplin D. Infestations. In: Schachner LA, Hansen RC, eds. Pediatric Dermatology. 3rd ed. Philadelphia: Elsevier Limited, 2003. 94. Taplin D, Castillero PM, Spiegel J, et al. Malathion for treatment of Pediculus humanus var capitis infestation. JAMA 1982; 247:3103–3105. 95. Malathion. In: Physicians’ desk reference. Montvale, NJ: Medical Economics, 2003: 1925–1926. 96. Abramowicz M. Malathion for treatment of head lice. Med Lett Drugs Ther 1999; 41:73–74. 97. Dodd C. Interventiosn for treating head lice (Cochrane Review). Cochrane Database Syst Rev 2001:(3) CD 001165 fl ip. 98. Lindane. In: Physicians’ desk reference. Montvale, NJ: Medical Economics, 2000:504–505. 99. Meinking TL, Taplin D. Safety of permethrin vs. lindane for the treatment of scabies. Arch Dermatol 1996; 132:959–962. McMichael PTR 01/21/08 Chapter 19

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100. Franz TJ, Lehman PA, Franz SF, Guin JD. Comparative percutaneous absorption of lindane and permethrin. Arch Dermatol 1996; 132:901–905. 101. Maunder JW. Resistance to organochlorine insecticides in head lice and trials using alternative compounds. Community Medicine 1979: 125 (2):27–29. 102. Meinking TL, Serrano L, Hard B, et al. Comparative in vitro pediculicidal efﬁ cacy of treatments in a resistant head lice population in the United States. Arch Dermatol 2002; 138(2):220–224. 103. Ivermectin. In: Physicians’ desk reference. Montvale, NJ: Medical Economics, 2000:1886. 104. Burkhart CN, Burkhart CG. Another look at ivermectin in the treatment of scabies and head lice. Int J Dermatol 1999; 38(3):235. 105. Glaziou P, Nguyen L, Moulia-Pelat J, et al. Efﬁ cacy of ivermectin for the treatment of head lice (pediculosis capitis). Trop Med Parasitol 1994; 45:253–254. 106. Hipolito RB, Mallorca FG, Zuniga-Macaraig ZO, et al. Head lice infestation: single drug versus combination therapy with one percent permethrin and trimethoprim-sulfamethoxazole. Pediatrics 2001; 107:E30. 107. Akisu C, Delibas SB, Aksoy U. Albendazole: single or combination therapy with permethrin against pediculosis capitis. Pediatr Dermatol 2006; 23(2):179–182. 108. Maunder JW. Clinical and laboratory trials employing carbaryl against the human head louse, Pediculus humanus capitis (De Geer). Clin Exp Dermatol 1981; 6:605–612. 109. Burkhart C, Burkhart C, Burkhart K. An assessment of topical and oral prescriptions and over-the- counter treatments for head lice. J Am Acad Dermatol 1998; 6:979–982. 110. Karacic I, Yawalker SJ. A single application of crotamiton lotion in the treatment of patients with pediculosis capitis. Int J Dermatol 1982; 21:611–613. 111. Meinking T. Infestations. Curr Probl Dermatol 1999; 11:73–120. 112. Pearlman DL. A simple treatment for head lice: dry-on, suffocation-based pediculicide. Pediatrics 2004; 114(3):e275–e279. 113. Resnik KS. A non-chemical therapeutic modality for head lice. J Am Acad Dermatol. 2005; 52(2):374. 114. Hansen RC, Working Group on the Treatment of Resistant Pediculosis. Guidelines for the treatment of resistant pediculosis. Contemp Pediatr 2000; 17(Suppl):1–10. 115. Williams LK, Rechert A, MacKenzie WR, et al. Lice, nits, and school policy. Pediatrics. 2001; 107:1011–1015. 116. Mathias RG, Wallace JF. Control of head lice: using parent volunteers. Can J Public Health 1989; 89:461–463. 117. Clore ER, Longyear LA. Comprehensive pediculosis screening programs for elementary schools. J Sch Health 1990; 60:212–214. 118. Donnelly E, Lipkin J, Clore ER, Altschler DZ. Pediculosis prevention and control strategies of community health and school nurses: a descriptive study. J Community Health Nurs 1991; 8:85–95. 119. Elston DM. Controversies concerning the treatment of lice and scabies. J Am Acad Dermatol 2002; 46:794–796. McMichael PTR 01/21/08 Chapter 19 McMichael PTR 01/21/08 Chapter 20

20 Sources of Alopecia Information for Physicians and Patients

Jennifer Conde Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Amy J. McMichael Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

INTRODUCTION Managing and treating alopecia can be challenging and frustrating for the patient, the patient’s family, and the physician. This frustration is often heightened by the lack of available information regarding diagnosis and treatment of the hair or scalp condition. While many patients can simply turn to the Internet for information, there is relatively little that is guaranteed to be truthful and helpful from a simple search of a medical topic. Dermatologists are one of the best resources that patients have for ﬁ nding the most current and scientiﬁ cally correct information on the topic, while still within reach of the lay person’s understanding of disease. In order to best manage a patient with alopecia, one has to become familiar with the resources available to physicians, patients, and the general public regarding hair loss. Knowing how to access these resources as well as being familiar with what various sources and organizations offer allows more successful patient care. In this chapter, alopecia resources are discussed including disease state resoures, scalp prostheses, and research organizations (Table 1).

DISEASE STATE RESOURCES Disease state resources include the American Academy of Dermatology, the National Alopecia Areata Foundation, various research organizations, and alopecia patient support groups.

The American Academy of Dermatology The American Academy of Dermatology (AAD) (http://www.aad.org) is a tremendous source of information for physicians as well as patients. The AAD, with a membership of more than 15,000 physicians worldwide, is committed to advancing the diagnosis and medical, surgical, and cosmetic treatment of the skin, hair, and nails as well as supporting and enhancing patient care for a lifetime of healthier skin, hair, and nails. The AAD publishes brochures on hair loss as well as alopecia areata that are available to physicians and patients, and offers access to articles that are related to hair loss. The AAD staff are able to make appropriate referrals to physicians and patients requiring guidance. Possible referrals for those with hair loss may include: the International Society of Hair Reconstruction Surgery (ISHRS) or AgingSkinNet, a comprehensive online service sponsored by the AAD that focuses speciﬁ cally on the concerns that people encounter as their skin and hair age.

National Alopecia Areata Foundation The National Alopecia Areata Foundation (NAAF) ([email protected] or www.naaf.org) offers a multitude of services for both the patient and the physician. Founded in 1981 under the guidance of Dr. Vera Price, this non-proﬁ t organization has been in existence for twenty-ﬁ ve years. Its mission is to fund research to better understand the diagnosis and treatment of alopecia areata, to provide support for patients and families of persons with alopecia areata, to inform the public about alopecia areata, to advocate the concerns of persons with alopecia areata, and McMichael PTR 01/21/08 Chapter 20

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TABLE 1 Summary of Resources North American Hair Research Society http://www.nahrsmembers.org/home/ European Hair Research Society http://www.ehrs.org/ Australasian Hair and Wool Research Society http://www.ahwrs.org.au/ Locks of Love http://www.locksoﬂ ove.org/ 2925 10th Avenue North, Suite 102, Lake Worth, Florida, U.S.A. 1-888-896-1588 Cicatricial Alopecia Research Foundation http://www.carﬁ ntl.org/ PO Box 64158, Los Angeles, California, U.S.A. National Alopecia Areata Foundation http://www.naaf.org 14 Mitchell Boulevard, San Rafael, California, U.S.A. American Academy of Dermatology http://www.aad.org/ Member Resource Center PO Box 4014, Schaumburg, Illinois, U.S.A. 1-866-503-7546 to publish and distribute educational materials to patients and physicians so the condition is more recognized and understood. The multiplicity of services that this organization offers for both physicians and patients is noteworthy. Handouts and brochures are available for physicians, mental health providers, and patients—adults and children alike. Children’s videos or DVDs are helpful resources not only for physicians, but also for parents, teachers, and guidance counselors. The NAAF Annual Report is available to for those who wish to become familiar with the annual accomplishments of NAAF. NAAF publishes a quarterly newsletter with updates on the current accomplishments of the foundation, information on upcoming events, a directory of support coordinators in each state, as well as information on vendors for different items such as hair prostheses, scarves, and hats. NAAF also hosts a two-day international convention for affected individuals and their families each summer which is an invaluable way to meet support contacts from all over the world. Pen pal buddies for affected children and message boards that only NAAF members can access are also offered as a service by NAAF.

Patient Support Groups/Foundations The two best known and most active foundations for alopecia are the Cicatricial Alopecia Research Foundation (CARF) and the already-discussed National Alopecia Areata Founda- tion (NAAF). The Cicatricial Alopecia Research Foundation offers support for those suffering from scarring hair disorders. CARF’s mission includes raising funds to assist research for treatments, increasing education and advocacy, and raising public awareness. CARF began holding an international patient conference in 2005 that meets annually. This conference is a time for patients and their caregivers to come together and share their experiences as well as discuss the latest research. The Web site offers news, updates, and links to pertinent research articles. The Web site for this organization is info@carﬁ ntl.org

SCALP PROSTHESES For many patients with hair disorders, wigs are important to help the patient feel that they are not physically different from others. Many patients will strive to match their original hairstyle and color while others choose to be more adventurous and go to a totally different style from their native hair. In choosing any wig, most patients strive for a realistic, comfortable wig or hairpiece that ﬁ ts into their budgetary constraints. There are several companies and organizations that make and either sell or distribute wigs for those with signiﬁ cant hair loss. Locks of Love and the National Alopecia Areata Foundation are the two most recognized organizations providing scalp prostheses to children.

Locks of Love Locks of Love (http://www.locksoﬂ ove.org) is one of several public nonproﬁ t organizations that offers hairpieces for persons under the age of 18 suffering from a chronic hair disorder for McMichael PTR 01/21/08 Chapter 20

Sources of Alopecia Information for Physicians and Patients 299 a discounted price or free of charge depending on the circumstance. The hair prosthetics come from persons who donate their hair to this noteworthy organization. The hair prostheses are of highest quality as the hair is from human donors. Most of the recipients of these “locks of love” are children suffering from alopecia areata. By restoring the child’s physical appearance, the child’s self-esteem is oftentimes also restored. Locks of Love was established in 1997 and since that time the organization has grown to help over two thousand children each year from across the United States and Canada. Instructions and guidelines for donating hair can be found on the Locks of Love Web site. Hair donated must be dry, in a ponytail or braid, and must measure ten inches from tip to tip. Donations are equally needed from persons of all races, ages, and hair types. The headquarters for Locks of Love is in Palm Beach County, Florida and there are many opportunities to volun- teer services for this charitable organization. It is important to note that Locks of Love does not donate all their wigs. The program caters to children up to age 18 with free prostheses or using a sliding scale payment program based on need. The Web site of Locks of Love volunteers that they do sell hair that cannot be used to offset their manufacturing costs.

The National Alopecia Areata Foundation The National Alopecia Areata Foundation (NAAF), also offers wigs free to those with alopecia areata. NAAF also has a section of their Web site specifi cally designated as a marketplace for persons wishing to purchase garments to camoufl age areas of hair loss. The NAAF Web site lists reputable companies who donate a portion of their proceeds to the organization. The marketplace section of the Web site contains information on wigs, scarves, turbans, caps, and numerous additional products. The marketplace section of the Web site can be found at www. naaf.org/marketplace/marketplace.asp. Countless wig retailers can be found by searching the Internet, but caution must be used when retailers are not associated with a known organization. In order to minimize cost infl ation of wigs or unethical business practices, a patient must research diligently before consenting to any payment.

RESEARCH ORGANIZATIONS There are several well-established research societies that can serve as a resource for physicians and patients. The North American Hair Research Society (NAHRS) was established in 1990 by a group of dermatologists who wanted to further research related to hair disorders. The Web site for this research organization is www.nahrsmembers.org This nonproﬁ t organization brings together clinicians and basic scientists to form collaborative efforts to further understand hair disorders. The NAHRS Web site has links to news events and recent publications that are related to the latest advancements in hair research. Men- torship programs are offered for young fellows or clinicians interested in hair disorders. The NAHRS offers research grants each year to facilitate with the expenses of research and trials. Meetings are held twice annually at the American Academy of Dermatology and the Soci- ety for Investigative Dermatology. The NAHRS also joins with its corresponding international groups convening in an international meeting once every three years to discuss advancements on an international level. The international meeting is a conglomeration of the North American, the European, and the Australian Hair Research Societies as well as the Hair Research Society in Japan. This meeting is the largest meeting in the hair research community and research presented at this meeting is subsequently published in peer-reviewed journals. The meetings of the International Conference of Hair Research are hosted in rotation between Asia, North America, and Australia.

Clinical Trials Both local and national clinical trials are often offered to patients with hair loss. While patient participation in such research trials is never required, it can beneﬁ t the patient in treatment response or in increasing the knowledge of hair and scalp disorders in humans. Trials may be found by contacting university programs with signiﬁ cant dermatology research activity in McMichael PTR 01/21/08 Chapter 20

300 Conde and McMichael alopecia. The long established NAAF also sponsors research that furthers the mission of understanding hair and scalp disorders. ClinicalTrials.gov also provides regularly updated information about federally and privately supported clinical research in human volunteers. Clinical- Trials.gov provides information about a trial’s purpose, who may participate, locations, and phone numbers for more details. It is recommended that the information provided on this site be used in conjunction with advice from a physician. McMichael PTR 01/21/08 Chapter 21

21 Approach to the Patient with Alopecia

Lynne J. Goldberg Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, U.S.A.

INTRODUCTION A 32-year-old woman sits in your offi ce waiting room with her 9-month-old child in a stroller. She made an appointment several months ago to see you, as she has had dramatic hair loss for the past 6 months. Her hair has always been the pride of her appearance, and she is in a panic that she will lose it all. She is in otherwise excellent health, and no one in her family has hair loss. Her primary care physician tried to reassure her, but did not seem very impressed with her hair loss and looked at her scalp only briefl y. Her hairdresser sold her an expensive shampoo, which did not help. The one good thing is that she had to take the day off from work for the appointment and she is looking forward to spending the day with her baby. By the time they get to your waiting room, many patients with alopecia have already dealt with many obstacles. They have likely already seen at least one physician, who may or may not have known how to help them. They have polled their friends and family for advice. They may have had blood tests, which led them no closer to an answer as to why they were losing their hair. They have spoken to or traded calls with several of your offi ce staff, have obtained referrals and directions, have arranged time off from work, and may have had to deal with traffi c, parking, or public transportation. Some are calmer than others, yet each is very concerned, and no two scenarios are the same. With this in mind, the approach to each patient must be highly individualized and tailored to his or her specifi c needs. This chapter provides a framework for accomplishing this with information on how to obtain patient history to fi gure out why the patient has come and what they are seeking from the visit, standardized examination procedures, such as when to consider laboratory testing and when to consider a biopsy, and an approach to the differential diagnosis followed by a discussion on how to effectively communicate this information to the patient.

THE PATIENT HISTORY Patients with alopecia share a common complaint: they are losing their hair. Some will describe this phenomenon in incredible detail. One essential fact to obtain is whether or not the patient is actively losing hair. Some patients can pinpoint the exact day that they noticed there was increased hair in the shower drain. Others will not have noticed any shedding, but feel that their hair is thinning and that more scalp is showing. If they are shedding, it is important to ask if it is constant, increasing, decreasing, or variable (i.e., seasonal), and did it follow a precipitating event? Often patients will provide the number of hairs being shed, or bring in shed hair for examination. While it is useful for some patients to keep track of their loss, for others this task becomes time-consuming and stressful, and can ultimately be counter-productive. For those patients who seem unduly focused on this, it is advisable to downplay its usefulness. The hair sample should be taken, but any elective hair-shaft examination should be postponed.

Scalp Symptoms It is important to obtain from the patient a good description of his or her scalp symptoms. The most common symptom is pruritus followed by pain and burning. Try to elucidate how severe the symptoms are, how often they occur, and how long they last. Are there any precipitants? Rarely, a patient’s symptoms will be severe and signiﬁ cantly out of proportion to ﬁ ndings on their exam. It is important to recognize these patients. There is an entity described by Hoss and Segal called scalp dysesthesia syndrome (1). These patients have severe scalp itching and McMichael PTR 01/21/08 Chapter 21

302 Goldberg

burning, but no signifi cant fi ndings on examination of scalp biopsy specimens. The role of neu- rogenic infl ammation in such patients is currently being studied. Treatment with antidepressants may be benefi cial.

Hair Care Another key portion of the history is how the patient cares for their hair. This is especially important for African-American patients, who often permanently straighten their hair on a regular basis. Frequency of shampooing, interval between styling practices, products used, and styling techniques should all be investigated. Because these details are often left out of a routine history, it is helpful to use a questionnaire. All new hair-loss patients can be given this form in the waiting room, and then it is reviewed with the patient at the time of the visit. This helps to obtain detailed hair care information, and also serves the important function of sending a message to the patient that their hair-loss complaint is being taken seriously.

Past Medical History Certain aspects of the past medical history need to be specifi cally asked and included with the history of present illness. These include the menstrual history (if applicable), history of illnesses known to be associated with alopecia, recent hospitalizations or other stressful events that could precipitate an acute telogen effl uvium, and medication use (including use of oral contraceptives if applicable). Female patients need to be asked if they have gone through meno- pause, and when. Premenopausal women need to be asked if their periods occur monthly, are regular, or are particularly long or heavy. A history of irregular menses should prompt questions about hirsutism and acne, as alopecia, especially when combined with oligomenorrhea and hirsutism, can be a presenting sign of polycystic ovarian syndrome (2). A history of anemia should be sought for those whose periods are irregular, as iron defi ciency has been linked to hair loss (3). All patients should be asked specifi cally about a history of thyroid disease and lupus erythematosus.

Medication History When inquiring about medication use, remember in women to specify use of oral contraceptives, and to ask both men and women about vitamin and hormone supplementation. Certain oral contraceptives contain androgenic progestagens such as levonorgestrel that may contribute to hair loss. In these patients, simply changing their contraceptive pill can improve their hair loss and alleviate their concerns. Newer oral contraceptive pills are formulated with progestagens that actually have anti-androgenic activity (4,5). There are many medications that can cause hair loss (6); common medications associated with hair loss include anticoagulants, beta-blockers, lithium, interferon, and retinoids. A word of caution about medication-induced hair loss: many patients will ask whether or not their medication is causing their hair loss. This information is hard to obtain, and while alopecia is listed as a side effect of many medications, it is usually a rare or infrequent complication. It is best to search for and eliminate all other potential causes of hair loss before discussing a medication change with a primary care provider. It is as important to ask about discontinuation of medications as it is to ask which medications are being taken. This is especially true for oral contraceptives, as stopping a birth control pill can cause an acute telogen efﬂ uvium. Other causes of acute telogen efﬂ uvium include high fever, post-partum hair loss, and severe protein-calorie restriction (7).

Stress When inquiring about stressful events that could cause a telogen efﬂ uvium, one cannot ask the simple question “Are you under stress?” It is the rare person who lives a stress-free life. It is often more helpful to ask if there was a recent, extremely stressful event that was different than the day-to-day or baseline stressors. Many people ask about whether their hair loss is due to stress. The answer is that stress does not cause hair loss; if it did, most of the population would be bald. The association between stress and telogen efﬂ uvium is poorly documented (7). A McMichael PTR 01/21/08 Chapter 21

Approach to the Patient with Alopecia 303 study looking critically at the role of stress in skin disease did indicate a role of stress in alopecia areata (8). The association of stress and hair loss continues to be an active area of research in the ﬁ eld of psychoneuroimmunology.

Family History Another aspect of the history that is more diffi cult than meets the eye is the family history. Many patients will indicate on the questionnaire that they have no family history of hair loss. However, it sometimes becomes apparent on further questioning that they do not actually know about some of their family members, so the history is actually unknown rather than negative. Also, sometimes patients do not consider a receding hairline or a bald spot to be synonymous with baldness, and asking about a family history of baldness will elicit a false negative response. It should be explained to patients that a positive family history includes family members who were going bald and that they will not necessarily have gotten all the way there. Once patient history has been completed, practitioners should have a sense of what the patient is expecting from the visit. This is very important, as expectations vary widely, and are closely linked to patient satisfaction. It is most benefi cial when a patient leaves the offi ce feeling like they have learned or accomplished something. The patient who gives innumerable details about his or her hair care may feel that their complaints have not been taken seriously in the past, and will be grateful for being given the opportunity to investigate their concerns. Some patients just want to make sure that their hair loss does not indicate that they have cancer or some other systemic disease, and are easily reassured. However, some patients are more diffi cult to satisfy. These patients do not necessarily have the most severe hair loss; in fact the opposite is often true. Identifying this type of patient at the start of the examination will help to focus on their complaints and make certain that time is taken to educate them thoroughly and set realistic expectations.

THE HAIR LOSS EXAMINATION It is counterintuitive, but the best setting for a scalp examination is not necessarily the examination table. If the patient is sitting on a chair, it is easier to stand and look down at their scalp. Good lighting is essential. The fi rst thing to notice is whether the alopecia is “diffuse” or “patchy.” Consider hair loss in which no discrete areas of loss are identifi able as diffuse alopecia, and loss with defi ned bare areas as patchy. There is some overlap, and for practical purposes patients with diffuse loss limited to the crown, as seen in female pattern hair loss, are included in the diffuse category.

Diffuse Alopecia For diffuse alopecia, which is more common, the examination is performed in the same order, starting behind the patient with a part-width assessment. This is a very easy test, although it requires a little practice before one gets completely comfortable with it. Note that this is very difﬁ cult to perform if the patient has very short hair.

Part-Width Assessment To perform a part-width assessment, start by standing behind the patient. First part the patient’s hair in the midline occipital scalp, noting the width of the part. Is the part a straight line, or a jagged one? Is the width thin or thick? Then, part the patient’s hair in the midline of the crown. Asking the patient to look up will allow comparison of the occipital part with the crown part. Is the part wider on the crown, or is it equal (or narrower)? If the patient’s part is wider on the crown, then they likely have female pattern hair loss (9). In these patients, the crown part width can also be graded or quantiﬁ ed for purposes of assessing response to treatment. Some physicians will visually score the width of the part, noting it in the chart. Others prefer to actually measure the part width. Still others routinely use photography to follow their patients. Sometimes in a part-width assessment the hair loss is so diffuse that the part is widened equally on both the occiput and the crown, and no pattern is discernable. Sometimes the part McMichael PTR 01/21/08 Chapter 21

304 Goldberg is thin throughout, and there is no objective hair loss. This often occurs when the patient has a baseline of thick, dense hair. It is important to realize that this does not mean these patients have not lost hair. It will take more hair loss to cause objective ﬁ ndings of loss in a patient with thick hair as opposed to someone with thinner hair. Also, caution is required in the interpretation of a part width in patients that color their gray hair. As the hair lengthens, new growth will be gray. Gray roots simulate the patient’s part, leading to a falsely widened part width assessment.

The Hair-Pull Test After the part-width assessment a hair-pull test is performed. This is another simple procedure that requires some practice to master. Basically a small amount of hair is grasped between two fi ngers close to the scalp, and gently pulled along the entire length of the hair. Under normal circumstances few hairs are shed. Although the ideal number of hairs to pull varies in the literature (7,10), the most important thing is to try to keep the pull standardized by pulling the same amount each time. A positive pull is one in which many hairs are easily epilated. If this occurs, it is then imperative to look at the proximal ends of the hair shafts to see if they are telogen (club shaped) or anagen (more cylindrical). A positive pull of telogen hair shafts occurs early in telogen effl uvium, in some cases of female pattern hair loss, and in acute, active alopecia areata. In some cases of alopecia areata the pull will be positive with hair shafts that have a tapered, rather than club shaped proximal end. A positive pull of anagen hair shafts occurs in active scarring alopecia, anagen effl uvium and loose anagen syndrome. When done as a routine part of an initial examination in a patient with diffuse alopecia, a hair pull should be done at several random locations on the scalp. A hair-pull test is also very valuable in assessing response to therapy. Patients with active scarring alopecia and a positive pull test are at risk of signifi cant hair loss and need to be treated aggressively. The goal is to decrease infl ammation around the hair follicle, thus decreasing symptoms, improving erythema and scale, and halting follicular destruction, resulting in a negative hair pull. Patients with active alopecia sometimes have a positive hair pull at the periphery of their lesions, indicating that the lesions are in the process of enlarging. Successful treatment will decrease disease activity and lead to a negative pull, good news for the patient even before the hair has regrown. It is important to be aware that occasionally a patient will be very alarmed that their hair is being pulled out. They feel that they have lost enough already, and need everything that they have. In very anxious patients it is a good idea to fi rst explain what is about to be done and the information that it will provide. If the patient remains opposed, the physician should remain fl exible. Valuable trust can be gained by respecting the patient’s wishes. After the part-width assessment and hair-pull test, the examination continues by noting the hairline, especially checking to see whether or not there is bifronto-temporal recession. This is a common fi nding, and often there are short tapered hairs present. In some patients it is helpful to measure these hairs to use as a baseline to see if they are shortening or lengthening. Lengthening of frontal hairs is a good sign, either of spontaneous regrowth of a telogen effl uvium or lengthening of anagen in response to treatment in a patient with female pattern hair loss. Keep in mind that not all short hairs in this area are tapered; broken hairs can also be present, and raise the possibility of traction alopecia. After noting the hairline the exam progresses to the scalp, looking for erythema, scale, pustules, excoriations, or any other fi ndings.

Patchy Hair Loss The examination of someone with patchy hair loss is a little different. It is important to quantify the number and size of lesions, and estimate the overall degree of scalp involvement, either by dividing the scalp into quadrants or using other techniques (11). The scalp surface should be checked for loss of follicular oriﬁ ces and atrophy, both signs of scarring. An examination of the periphery of the bald areas is essential, looking for subtle perifollicular erythema and scale, a sign of lichen planopilaris, or exclamation point hairs, seen in alopecia areata. Exclamation point hairs are broken hairs that are thicker distally than at the scalp surface. Any regrowth, broken hairs, or sparing of hairs within the bald area should be noted. McMichael PTR 01/21/08 Chapter 21

Approach to the Patient with Alopecia 305

A template should be designed where ﬁ ndings can be efﬁ ciently recorded. Once the scalp examination is complete, an examination of the nails, teeth and oral mucosa, and general body hair can be helpful. If time permits, a full skin examination is a good idea for those patients not already followed by a dermatologist.

THE DIAGNOSIS By the time the examination is complete, one usually has some idea of the diagnosis, or at least the differential diagnosis. It is helpful to fi rst decide if the hair loss is diffuse or patchy, then non-scarring or scarring. A list of common causes of alopecia, in order of decreasing frequency, is listed in Table 1. Note that hair breakage is included in this list. While technically not alopecia, patients often perceive breakage of hair as hair loss. It is imperative to realize that certain “non-scarring” alopecias can result in irreversible hair loss (such as late male- and female-pattern hair loss), and sometimes the presence of scarring is not easily detected clinically, as the scalp can have a deceptively normal surface despite the loss of hair follicles in the dermis and subcutis below. The most common type of non-scarring alopecia is male- (MPHL) and female- pattern hair loss (FPHL). The diagnosis of MPHL is usually straightforward, with the major differential diagnosis, telogen effl uvium, being much less common. In women, FPHL can be very diffi cult to distinguish from telogen effl uvium, especially the chronic form described by Whiting (12). If there is loss on the crown, one can be relatively confi dent of FPHL. However, both can cause bifronto-temporal hair loss, and in the absence of a typical history for a telogen effl uvium, this pattern should be considered nondiagnostic. Patchy hair loss is most often due to alopecia areata, although one has to consider the other causes listed in Table 1. If there is sparing of gray hairs or exclamation point hairs, one can be confi dent of this diagnosis. One must be careful not to mislabel scarring alopecia as alopecia areata. Burned-out lichen planopilaris, or pseudopelade, can mimic alopecia areata, but careful exam will reveal a smooth scalp surface with loss of follicular orifi ces. Severe traction alopecia can mimic the ophiatic pattern of alopecia areata, but often with traction the hairline is retained, with broken hairs at the periphery. In addition to a smooth scalp surface, other clinical features suggestive of a scarring alopecia include the presence of pustules, crusting or marked erythema, perifollicular scale and erythema, atrophy, dyspigmentation, and tufting of hairs at the scalp surface. Because scarring alopecia by defi nition leads to permanent hair loss, it is important to maintain a high degree of suspicion for scarring, making the diagnosis early and limiting irreversible alopecia.

THE SCALP BIOPSY There are many things that need to be considered in deciding whether or not to do a scalp biopsy, including the suspected diagnosis, the certainty of the clinical diagnosis, the information to be gained, and the patient’s comfort level with the procedure. Historically, it was felt that all suspected scarring alopecias should be biopsied, and many clinicians still teach this. Biopsies of non-scarring alopecia have become more popular since Headington introduced

TABLE 1 Common Causes of Alopecia in a Dermatology Practice Diffuse Male- and female-pattern hair loss Telogen efﬂ uvium Hair breakage Patchy Alopecia areata Central centrifugal cicatricial alopecia Traction alopecia Lichen plano-pilaris Folliculitis decalvans Discoid lupus erythematosus Note: Scarring entities are in bold type. McMichael PTR 01/21/08 Chapter 21

306 Goldberg the histologic technique of transverse sections in interpreting scalp biopsies for alopecia (13). Because interpretation of scalp biopsies is diffi cult, it is important not only to consult a dermatopathologist with an interest in alopecia, but to exhibit good communication in describing the pattern of hair loss, its duration, and the differential diagnosis. The decision to biopsy should be based mainly on whether or not a treatment plan can be generated based on the clinical fi ndings. If diagnosis is uncertain, but the differential has similar treatment options (such as FPHL and telogen effl uvium), empiric treatment without a biopsy should be considered. If a patient has failed or is intolerant of initial treatment, or is very anxious, suggest a biopsy. Not all patients with classic central centrifugal cicatricial alopecia should be biopsied, though many dermatology hair disorder specialists feel biopsy of all scarring forms of hair loss should be done. Central centrifugal cicatricial alopecia is a common scarring alopecia and often the pattern is so typical that there is little in the differential diagnosis. Biopsy is not completely necessary for all patients with folliculitis decalvans or acne keloidalis nuchae. Patients in whom the diagnosis is uncertain, or those not responding to therapy, should be considered for biopsy. Biopsies should also be performed for patients with suspected lichen planopilaris and chronic cutaneous lupus, because these diseases exhibit a wide variety of clinical fi ndings that can overlap signifi cantly.

THE LABORATORY WORKUP There is no standardization as to whether or not to order laboratory tests on a patient with hair loss, and which tests to order. Some clinicians will routinely test for thyroid function and iron stores in all patients, while others will limit these tests to those patients whose history and examination suggests a systemic process contributing to their hair loss. There are certain situations where lab tests should be ordered routinely, such as androgen levels in patients with FPHL who have symptoms and fi ndings suggestive of androgen excess, or patients with chronic cutaneous (discoid) lupus erythematosus who require serologic studies to exclude systemic disease. Part of the reason that there are no accepted routine lab studies to order in alopecia is that the literature is controversial, especially on the subject of iron defi ciency. Rushton (3,14) has published several manuscripts on the importance of iron stores in proper hair growth. He feels that low ferritin is common in women with chronic telogen effl uvium, and a decrease in telogen hair follicles was found in women treated with iron and L-lysine (14). However, this is contradicted by the fi ndings of Sinclair (15) indicating that iron replacement did not improve patients with telogen effl uvium. See Chapter 9 for further discussion on this topic. In patients with female pattern hair loss, check androgen levels (total/free testosterone, dihydroepiandosterone sulfate) in those with very young onset of disease, severe or rapidly progressive disease, or signs of androgen excess. Some suggest TSH and serum ferritin be checked in all patients with female pattern hair loss as well (16), but this can be reserved for unexplained diffuse alopecia where there is no history to suggest an acute telogen effl uvium. In alopecia areata, it is wise to check thyroid function. It has been suggested that thyroid function in alopecia areata be checked when there are signs or symptoms of a thyroid abnormality, or if there is a strong family history of thyroid disease (17). Patients with discoid lupus require serol- ogy to exclude systemic lupus, and some patients will require laboratory studies for monitoring purposes if systemic medications are being used.

EDUCATING THE PATIENT Patient counseling is one of the most important aspects of the visit. Patients frequently feel their physician is not taking their hair loss complaint seriously, with good reason. Assessment of hair loss is very diffi cult, as symptoms and fi ndings overlap to a great degree, suitable scalp biopsies can be diffi cult to obtain and even more diffi cult to interpret, and treatment options are limited. It is a common belief among patients that once their hair falls out, it is lost forever. Patients often share their fear that if their hair continues to fall they will soon be bald. Many patients are put at ease simply by a discussion of the hair cycle; the knowledge that shed hair grows back is very reassuring. Many will ask how they will know if their hair is regrowing. It is crucial to McMichael PTR 01/21/08 Chapter 21

Approach to the Patient with Alopecia 307 explain that the shedding portion of the hair cycle lasts at least 4 months and that the new hairs grow over many years and are diffi cult to see on an individual basis. Another concept that should be explained is the difference between scarring and non- scarring alopecia. As already discussed, this distinction is sometimes not very simple. If the diagnosis is straightforward discussion should be tailored accordingly, allowing a reasonable amount of time for questions. Dermatology appointments can be lengthy and fi lled with emotion. For those patients who need repeated explanations or for those who have a long list of questions, the physician’s phone number should be provided for further discussion at a later date. This serves two purposes. It allows the practitioner to end the visit without the patient feeling short-changed, and it gives the patient some time to consider what has been discussed before asking further questions. Back to our patient. Her examination reveals shoulder-length blond hair, parted on the side. There is mild thinning of her bitemporal scalp. Her hair is healthy, without breakage. Her hairline is normal. Her scalp is normal without erythema or scale. There is no focal hair loss. A part-width assessment is near equal on her crown and occiput. A hair-pull test is negative. Based on her history, a clinical diagnosis of telogen effl uvium is made, likely resolving. There is no evidence of underlying female pattern hair loss. No biopsy is indicated. A test of her serum iron and iron stores is ordered, as she is postpartum and has resumed her menstrual periods. I explain to her that this type of hair loss occurs from the root, is temporary, and is not affected by her shampoo or styling technique. However, some patients with acute telogen effl uvium go on to develop female pattern hair loss, so if her shedding persists, she is to return in 6 months. I answer most of her questions, but the baby begins to get irri- table, so I provide her with my phone number in case she has any more. She is extremely grateful for my time and the explanation rendered, and happily leaves to take the baby to the zoo.

REFERENCES 1. Hoss D, Segal S. Scalp dysethesia. Arch Derm 1998; 134:327–330. 2. Lowenstein EJ. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatologic Therapy 2006; 19(4):210–223. 3. Rushton DH. Nutritional factors and hair loss. Clin Exp Dermatol 2002; 27:396–404. 4. Jones EE. Androgenic effects of oral contraceptives: Implications for patient compliance. Am J Med 1995; 98(1A):116S–119S. 5. Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update 2006; 12(2):169–178. 6. Tosti A, Misciali C, Piraccini BM, Peluso AM, Bardazzi F. Drug-induced hair loss and hair growth. Drug Safety 1994; 10(4):310–317. 7. Headington JT. Telogen efﬂ uvium. Arch Derm 1993; 129:356–363. 8. Picardi A, Abeni D. Stressful life events and skin diseases: disentangling evidence from myth. Psychother Psychosom 2001; (70):118–136. 9. Miller JJ. Medical pearl: comparing crown part width to occipital part width to diagnose female pattern hair loss. J Am Acad Dermatol 2005; 53(2):331–332. 10. Shapiro J, Wisemen M, Lui H. Practical management of hair loss. Can Fam Physician 2000; 46:1469– 1477. 11. Olsen E, Hordinsky M, McDonald-Hull S, et. al. Alopecia areata investigational assessment guidelines. J Am Acad Dermatol 1999; 40(2 Pt 1):242–246. 12. Whiting DA. Chronic telogen efﬂ uvium: increased scalp shedding in middle-aged women. J Am Acad Dermatol 1996; 35(6):899–906. 13. Headington JT. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol 1984; 120(4):449–456. 14. Rushton DH. Decreased serum ferritin and alopecia in women. J Invest Dermatol 2003; 121(5):17–18. 15. Sinclair R. There is no clear association between low serum ferritin and chronic diffuse telogen hair loss. Br J Dermatol 2002; 147(5):982–984. 16. Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol 2005; 53:301–311. 17. Chartier, MB, Hoss DM, Grant-Kels JM. Approach to the adult female patient with diffuse non- scarring alopecia. J Am Acad Dermatol 2002; 47:809–818. McMichael PTR 01/21/08 Chapter 21 McMichael R2 01/02/08 Chapter 21

Index

A [Alopecia information] AA. See Alopecia areata (AA) summary of resources, 298 AAD. See The American Academy of Dermatology 5-alpha-reductase inhibitors, 131 (AAD) Alternative treatments for hair loss, 197–208 Acid perm waves, 253 devices, 206 Acitretin, 145 dietary supplements, 203–206 Acquired immunodefi ciency syndrome (AIDS), 158 herbal remedies, 197–203 ACS. See Allergic contact dermatitis (ACS) mind-altering approaches, 206–207 Acticin®, 287 shampoos, 206 Acyclovir, 232 American Academy of Dermatology (AAD), 297 Adherent scalp fl aking, 79 Aminolevulinic acid (ALA), 231 Adjunctive therapies and measures, 283 Ammonium thioglycolate, 253 Adlendronate sodium, 99 Amphoteric detergents, 60 Adrenal suppression, 220 Anagen hair bulb, 139 AFM. See Atomic force microscopy (AFM) keratinocytes, 96 African phenotypes, 6 Anagen–telogen ratio, 122, 123 African scalp hairs, 157 Androgen-dependent hair, 212 AIDS. See Acquired immunodefi ciency syndrome Androgen production, 214 (AIDS) Androgen levels ALA. See Aminolevulinic acid (ALA) circulating, 214 Albendazole, 290 Androgenetic alopecia (AGA), 107–116, 124 Allergen(s) clinical features, 107 avoidance of, 259–260 counseling, 111 detection, 259 diagnosis, 110–111 Allergic contact dermatitis (ACD), 237–260 etiology, 108–109 contact allergens, 240–241 female, 107 diagnosis/management, 259–260 male, 107 epidemiology, 237–238 management, 110–16 hair dyes, 241–246 pathology, 108 management of, 259–260 treatment 111–116 types of contact reactions, 238–240 Androgens, 108, 124 Alopecia areata (AA), 91–103, 280 Androgen-secreting tumors, 108, 214 approach to the patient with, 301–307 Animal models, 137 biologics, 100 Anovulation, 214 clinical features, 91–94 Anthralin, 99 common causes of, 305 Antiandrogens, 114, 129–130, 220 episode of, 93 Antibiotics, 145 extensive patchy, 92 Antidandruff shampoos, 129, 255–256 light therapy, 99–100 Antidepressants, 270 long-standing extensive, 94 used for psychological hair disorders, 269 ophiasis pattern, 93 Anti-infl ammatory agents, 83 pathophysiology, 96–97 calcineurin inhibitors, 83 process, 91 topical corticosteroids, 83 registry, 101 Anti-Malassezia agents, 80–83 scalp, 92 ciclopirox, 82 scope of the problem, 94–96 coal tar, 80–81 tapered fi bers in patient with, 93 dispelling shampoo myths, 82–83 treatments, 97–100 gels, lotions, creams, 82 Alopecia areata registry, 101–102 ketoconazole, 81–82 participation, 102 selenium sulfi de, 81 Alopecia information shampoo comparison studies, 82 clinical trials, 299–300 zinc pyrithione, 81 for physicians and patients, 297–300 Anti-Malassezia effect, 82 research organizations, 299 Anti-Malassezia shampoo, 83 sources of, 297–300 Antipruritics, 80 McMichael PTR 01/21/08 Index

310 Index

Antipsychotic medications, 271 Cicatricial alopecia (CAs), 137–147 Antipsychotics, 270 animal models and the sebotrophic hypothesis, 137 metabolic parameters in patients on, 272 classifi cation, 144 Anti-seborrheic dermatitis products, 79 clinical presentation, 138–142 Anti-seborrheic shampoos, 102 epidemiology, 138 APS-1. See Autoimmune polyglandular syndrome histopathology, 137, 142–143 (APS-1) lymphocytic, 139 Aripiprazole (Abilify®), 271 mechanisms, 137–138 A-200® shampoo, 288 mixed, 142 Asian follicle, 5 neutrophilic, 141 Asian hair, 9–10 peroxisomes and lipid metabolism, 138 Asian hair shaft, 42 stem cells and immunology, 138 Asymptomatic fungal infection, 284 transplanting, 191–192 Asynchronous cycling, 44 treatment, 143–147 Atomic force microscopy (AFM), 32 treatment regimens for neutrophilic, 146 Australian Hair Research Societies, 299 Cicatricial Alopecia Research Foundation (CARF), 298 Autoimmune polyglandular syndrome (APS-1), 94 Ciclopirox, 82 Avodart®, 181 CIR. See Cosmetic Ingredient Review Citalopram (Celexa®), 269 B Citrullinemia, 153 Balding, 109 Clear® shampoo, 288 Basaloid cell islands, 57 Clomipramine (Anafranil®), 269 Basex syndrome, 153 Coal tar shampoos, 81 Beards and mustaches, 189 Cocamidopropyl betaine (CAPB), 254–255 Beau’s lines, 123 Cold waves, 253 Benzyl alcohol, 252 Combination therapy BHT. See Butylated hydroxytoluene for alopecia areata, 100–102 Biotin defi ciency, 127 for dandruff and seborrheic dermatitis, 83–84 Bird’s-nest hair, 26 Compulsive skin picking, 272 and dreadlocks, 161 Concomitant treatments, 129–131 Bjornstad’s syndrome, 153 Conditioner formulation, 62 Black dot tinea capitis, 277 Conditioning agents, 16–17 Black henna tattoos, 246 Conditioning shampoos, 60, 256 Bleaches, 252 Conradi-Hunermann syndrome, 153 Body dysmorphic disorder, 271–272 Contact allergens, 240–241 Botanical nutrients, 130–131 emulsifi ers, 240 Botanicals with DHT inhibition, 130 fragrances, 240 Botanicals, 247 hair bleaching agents, 240 2-Bromo-2-nitropropane-1,3-diol, 250 hair dyes, 240 Bronopol (2-Bromo-2-nitropropane-1,3-diol), 250 permanent waves, Bubble hair, 26, 160 preservatives, 240 Butylated hydroxytoluene (BHT), 252 Contact reactions diagnosis, 238 C mechanism, 238 Calcineurin inhibitors, 83 photoallergic, 240 CAPB. See Cocamidopropyl betaine types, 238–240 Captan, 256 Contact urticaria, 239–240 Carbaryl, 290 haircare products known to induce, 240 CARF. See Cicatricial Alopecia Research localized reactions, 239 Foundation unknown mechanism, 239–240 CAs. See Cicatricial alopecia Cooling of the epidermis Catagen, 55 methods of cooling, 230 Caucasian follicles, 6 post-cooling, 230 Caucasian hair, 23 pre-cooling, 230 CCCA. See Central centrifugal CA timing of cooling, 230 CCLE. See Chronic cutaneous lupus erythematosus Coping mechanisms, 272 Cedarwood (Juniperus virginiana), 208 Corkscrew hair, 152 Central centrifugal cicatricial alopecia (CCCA), 140, Cosmesis, 113 142, 191, 193 Cosmetic Ingredient Review (CIR), 252 Cetaphil® lotion, 290 Cosmetic screening series, 241 CHC. See Cysteamine hydrochloride Cosmetic treatments, 22–25 Chemical depilatory agents, 218 changes in hair properties caused by, 25 Christmas-tree pattern of loss, 186 Cradle cap, 73 Chronic cutaneous lupus erythematosus Crackling scale, 75 (CCLE), 139 Crandall’s syndrome, 153 Chronic defi ciencies, 127 Crotamiton, 290 Chronic infl ammation, 232 Curl relaxation, 67 Chrysanthemum cinerariae folium, 287 Cushing’s syndrome, 214, 215, 220 McMichael PTR 01/21/08 Index

Index 311

Custom soft mesh wig, 166 DMAPA. See Dimethylaminopropylamine human hair, 167 DMDM hydantoin. See Dimethyloldimethyl Cuticle, 1 hydantoin Cyclosporine, 145 Dominique-Jean Larrey, 110 Cyproterone, 219–220 Dopaminergic blockade, 270 Cyproterone acetate, 114 Dopaminergic blocking effects, 270 Cysteamine hydrochloride (CHC), 254 Doxepine (Sinequan, Adapin®), 269 Cysteine, 1 Drugs and botanical supplements, 128–129 Cytotoxic free oxygen radicals, 232 DSG4. See Desmoglein 4 DSM-IV. See Diagnostic and statistical manual of D mental disorders Dandruff DTM. See Dermatophyte test medium anthropology, 76 Dutasteride, 113, 130, 180 clinical presentation, 73–74 Dystrophic hair fi bers, 95 defi nitions, 73 differential diagnosis, 75–76 E effi cacy testing methods, 79 Ectothrix infection, 278, 280 etiology, 76 Efl ornithine cream, 219 FDA monograph, 80 Ekbom’s syndrome, 269–271 history, 79 Elderberry (Sambucus nigra), 203 prevalence, 75 Electromagnetic radiation (EMR), 226 treatment, 79–84 Elimite®, 287 Dandruff and seborrheic dermatitis ELM. See Epiluminescence microscopy clinical presentation, 73–74 EMR. See Electromagnetic radiation treatment, 79–84 Emulsifi ers, 352–253 use of medicated shampoos, 73–85 Endothrix, 280 Dandruff scalp fl akes, 77 Eosin, 49 Deep conditioners, 64 Epidermis Dehydroepiandrosterne sulfate (DHEAS), 124, 216 cooling of, 229–230 Depigmentation, 234 Epidermophyton, 280 Dermatophytes, 277 Epiluminescence microscopy (ELM), 39 colonies, 280 Epinephrine, 44 hair invasion patterns by, 279 Erosive pustular dermatosis, 142 Dermatophyte test medium (DTM), 279, 280 Escitalopram (Lexapro®), 269 Dermoscopy, 123 Estrogen, 130 Desmoglein 4 (DSG4), 152 Etiology of dandruff, 76–79 DHEAS. See Dehydroepiandrosterne sulfate hyperproliferation, 78 DHT. See Dihydrotestosterone infl ammation, 77–78 Diagnostic and statistical manual of mental disorders malassezia, 76–77 (DSM-IV), 267 nature of fl aking, 79 Diazolidinyl urea, 250 Eumelanin, 2 Dietary supplements, 203–207 Euxyl K400, 249–250 biotin, 204 Eyebrow repair, 187 copper, 204–205 Eyebrows, 186–188 devices, 206 chronic plucking, 187 iron, 203–204 long-term plucking, 186 L-lysine, 204 Eyelashes, 188–189 pantothenic acid, 204 shampoos, 206 F soy, 205–206 Factitial hair loss, 267–271 vitamin B6, 204 Female androgenetic alopecia, 107 zinc, 205 Female-pattern alopecia (FPA), 185 Diffuse alopecia, 303–304 Female-pattern hair loss (FPHL), 107, 108, 119, 124, hair-pull test, 304 194, 305, 306 part-width assessment, 303–304 Ferriman-Gallwey scoring system, 211–213 Dihydrotestosterone (DHT), 108, 124, 130, 175, 214 Ferriman-Gallwey tool, 215 Dimethylaminopropylamine (DMAPA), 255 Fiber-to-fi ber interactions, 26 Dimethyloldimethyl hydantoin (DMDM hydantoin), Film-forming conditioners, 62 251 Finasteride, 112–113, 130, 180, 220 Diphencyprone, 98 versus minoxidil, 113 treatment, 258 First National Health and Nutrition Examination Discoid lupus, 140 Survey, 94 Disease state resources, 297–298 Flaking, 73 National Alopecia Areata Foundation, 297–298 nature, 79 Patient Support Groups/Foundations, 298 Fluconazole, 282–283 The American Academy of Dermatology, 297 Fluorescent light transmitted microscopy, 29 Dispelling shampoo myths, 82–83 Fluoxetine (Prozac Sarafem®), 269 Dissecting cellulites, 143 Flutamide, 220 McMichael PTR 01/21/08 Index

312 Index

Fluvoxamine (Luvox®), 269 [Hair abnormalities (structural)] Follicle-stimulating hormone (FSH), 216 uncombable hair syndrome, 157 Follicular morphogenesis, 42–43 woolly hair and woolly hair naevus, 155–157 Follicular occlusion triad, 141 Hair bleaching, 21, 67 Follicular stelae, 41 Hair bulb, 48–50 Follicular unit transplantation (FUT), 177–178, 188 Hair care, 15–17, 302 Follicular units, 53, 177–178, 184 Haircare products, 16, 240 Folliculitis decalvans, 142 substances found to induce contact urticaria, Folliculo-isthmic cyst, 48 240 Formaldehyde and formaldehyde releasers, 250 hair color, 226 Fosamax®, 99 Hair coloring, 21, 64–67 FPA. See Female-pattern alopecia gradual dyes, 65 FPHL. See Female-pattern hair loss permanent, 22–24 Fragrance screening series, 247 permanent dyes, 66–67 Frontal fi brosing alopecia, 141 semipermanent dyes, 66 FSH. See Follicle-stimulating hormone temporary dyes, 65–66 Fungistatic triazole, 282 Hair conditioners, 61–64 FUT. See Follicular unit transplantation categories, 62 deep conditioners, 64 G diversity, 63–64 Galvanic electrolysis, 218 fi lm-forming conditioners, 62 Gasdermin 3-a transcription factor, 137 formulation, 62–63 Gastrointestinal symptoms, 283 hair rinses, 64 Gels, lotions, creams, 82 instant conditioners, 63–64 Genetics, 109 leave-in conditioners, 64 Germaben, 251 product type, 63 Germall 115, 251 protein-containing conditioners, 62–63 Germall II, 250–251 quaternary conditioners, 62 Ginkgo biloba, 199–200 role, 61 Glutathione-S-transferase activity, 287 silicone conditioners, 63 Glyceryl monothiogylocolate, 253–254 Hair cosmetics, 172–173 Glydant, 251 eyebrow and eyelash loss, 172–173 Gonadotropin-releasing hormone (GnRH), 219–220 Hair counts, 46 Graft preparation, 182 Hair curling Graham Little syndrome, 140 permanent, 67–68 Graham Little-Piccardi variant, 140 Hair cuticle Griseofulvin, 280–281, 283 atomic force image of, 32 Guidelines for laser hair removal, 233–234 SEM picture, 27–28 choice of settings, 232 Hair cycle, 225 fl uence, 232 Hair disease indications, 232 biopsychosocial aspects, 267–272 patient selection, 232 body dysmorphic disorder, 271–272 post-treatment care, 233 delusions of parasitosis, 269–271 pretreatment care, 232 factitial hair loss, 267–269 pulse width, 233 Hair disorders spot size, 232 psychological, 269 treatment endpoints, 233 Hair dye allergy, 242 Hair dyes, 241–246 H types, 65 HAART. See Highly active antiretroviral therapy Hair extensions, 170–172 Hair abnormalities (structural), 149–161 braids, 171, 172 bird’s-nest hair and dreadlocks, 161 methods of attachment, 170–171 bubble hair, 160 potential benefi ts, 171 loose anagen syndrome, 158–159 problems associated with, 171 monilethrix, 151–152 Hair follicle, 214–215 netherton’s syndrome (trichorrhexis invaginata), biology, 225–226 153–154 depth, 226 peripilar casts, 159 Hair follicle pigment system, 91, 214 pili annulati, 155 Hair gross structure, 41–42 pili multigemini, 159–160 Hair growth cycle pili torti, 152–153 normal, 43–44 pohl-pinkus lines, 159 Hair growth cycle and shedding, 120 proximal trichorrhexis nodosa, 150–151 Hair follicular cycling, 44 pseudomonilethrix, 152 Hair follicle anatomy straight hair naevus, 157–158 in human scalp biopsies, 41–57 trichonodosis, 160 Hair follicle growth and infl uence, 121 trichostasis spinulosa, 160–161 Hair follicle microscopic anatomy, trichothiodystrophy, 154–155 46–56 McMichael PTR 01/21/08 Index

Index 313

Hair fracture strength, 62 Hair transplantation, 175–195 Hair in time and space, 19–22 basic principles of, 178 Hair keratins, 1 creating recipient sites, 182–183 Hairlines, 186 donor harvesting, 181–182 Hair loss, 26 eyebrows transplantation, 186 alternative treatments for, 197–208 eyelash transplantation, 188–189 body, 97 graft preparation, 182 disorders, 120 history and evolution of, 175–178 factitial, 267–271 in Asian population, 194–195 photographic imaging, 35–39 into cicatricial alopeicia, 191–192 progression, 180 into scar tissue caused by physical trauma, radiation-induced, 191 189–190 scalp, 97 issue of naturalness, 178 social impact of, 175 mustache and beard transplant, 189 Hair loss examination, 303–305 patients of african descent, 192 diffuse alopecia, 303–304 placing, 183 patchy hair loss, 304–305 postoperative course, 183 Hair-loss patients, 302 practical applications of, 184–195 Hair matrix cells, 48, 49 the issue of density, 179–183 Hair measurements Hair types, 163–164, 225–226 computer-assisted, 38–39 human hair, 163–164 Hair morphology synthetic hair, 164 adaptive changes, 6–7 Haloperidol (Haldol®), 271 follicular units, 53 Hematoxylin, 49 hair shaft, 51–52 Head louse, 285 infundibulum, 47 Heat diffusion inner root sheath, 50–51 from chromophore, 228 isthmus, 47–48 Henle’s layer, 51 outer root sheath, 50 keratinization, 51 studies, 4–6 Henna hair dye, 245 terminal anagen hair, 53–55 Herbal remedies, 197–203 terminal catagen hair, 55–56 cedarwood (Juniperus virginiana), 208 terminal telogen hair, 56–57 elderberry (Sambucus nigra), 203 Hairpieces, 167–169 ginkgo biloba, 199–200 options for children, 170 He Shou Wu (Polygonum multifl orum), 200, 201 options for men, 169–170 horsetail (Equisetum arvense), 200, 202 Hair preparations lavender (Lavandula angustifolia), 208 reported to allergens found, 257 prickly ash bark (Zanthoxylum clava-herculis), 200, Hair pulling, 267 202 Hair-pull test, 304 pygeum (Prunus africana), 197–198 Hair relaxing steps, 70 rosemary (Rosemarinus offi cinalis), 200, 201 Hair removal saw palmetto (Serenoa repens), 197 gloves/pumice stones, 217 shea butter, 203 LASER method, 218–219 stinging nettle root, 198 light-assisted, 225–234 thyme (Thymus vulgaris), 207 mechanisms, 216 He Shou Wu (Polygonum multifl orum), 200, 201 Hair-removal light sources, 230–232 Heterocyclic agents, 269 intense pulsed light, 231 Highly active antiretroviral therapy (HAART), 75 LASERS, 230–231 Hirsutism, 211–221 photodynamic therapy, 231–232 adrenal suppression, 220 Hair removers, 254 androgen-dependent, 212 Hair restorers, 245 antiandrogens, 220 Hair rinses, 64 bleaching, 217 Hair shaft, 51–52 blend method, cuticle, 52 causes of, 215 examination of, 149 chemical depilatory agents, 218 Hair-shaft disorders cutting or shaving, 217 classifi cation of, 149–150 efl ornithine cream, 219 Hair shampoo diversity, 60 epidemiology, 211–212 Hair shape etiology, 212–215 permanent changes, 24 evaluation, 215–216 Hair shedding, 107 Ferriman-Gallwey scoring system for, 211–213 Hairspray, foams, and gels, 256 galvanic electrolysis, Hair straighteners, 254 hair-removing gloves/pumice stones, 217 Hair straightening, 21 idiopathic, 216 chemicals, 70 in adult hirsute women, 215 permanent, 69–70 management, 216–221 rationale for, 69 Mongoloid populations, 212 McMichael PTR 01/21/08 Index

314 Index

[Hirsutism] Hypertrichosis, 211–223, 232 ovarian suppression, 219 clinical features, 222–223 physical/cosmetic treatments, 217 causes and syndromes associated with, 222 plucking, 217 etiology, 221–222 sugaring, 217 generalized, 222 systemic therapies, 219–221 localized acquired, 222–223 thermolysis, localized congenital, 222–223 threading, 217 management, 223 waxing, 217 Hypertrichosis cubiti, 222 Hirsutism and hypertrichosis, 211–223 Hispanic hair, 41 I HLA. See Human leukocyte antigen ICD. See Irritant contact dermatitis HMPPC. See Hydroxymethyl pentylcyclohexene Ichthyosis linearis circumfl exa (ILC), 153 carboxaldehyde ICU. See Immunologic contact urticaria Hormones, 125 ILC. See Ichthyosis linearis circumfl exa Horsetail (Equisetum arvense), 200, 202 Imidazolidinyl urea, 251 Human hair, 1–17, 163–164 Immunologic contact urticaria (ICU), 239 amino acid analysis, 30–31 Immunology, 96 analytical chemistry, 32 Indo-European follicle, 5 attractiveness, 8–17 Infl ammation, 77–78 color, 2–3 Information Network of Departments of crimping the fi ber, 27 Dermatology (IVDK), 237, 240, 241, 246, cultural attitudes, 11–17 248, 249, 252, 253, 255 effect cosmetic practices, 22–24 study results, 243 evaluation techniques, 19–33 Infundibulum, 47 fi ber structure, function, and appearance, Inner root sheath, 50–51 22–24 Instant conditioners, 63–64 function, 7 IntelliStudioTM, 37 morphology, 3–7 Intense pulsed light (IPL), 218, 225, 231 record, 3 handpiece, 231 root damage on extraction, 27 International Society of Hair Restoration Surgery stretching the fi ber, 27 (ISHRS), 175, 297 structure, 1–3 Investigative techniques surface analysis, 32–33 for clinician, 27–33 tensile strength, 30 Iodopropynyl butylcarbamate (IPBC), 251 Human hair and attractiveness, 8–17 IPL. See Intense pulsed light cosmetic treatments, 8 Irritant contact dermatitis (ICD), 238 hair forms, styles, and fashions, 8–11 Irritant dermatitis, 75 hair, shine, and attraction, 8 ISHRS. See International Society of Hair Restoration Human hair follicle, 1 Surgery Human hair shaft, 1 Isthmus, 47–49 cross-sectional shape, 5 Itraconazole, 282, 285 identifying cosmetic damage, 24–27 IVDK. See Information Network of Departments of multiple, 2 Dermatology records, 3 Ivermectin, 289 Human keratinocytes, 78 Human leukocyte antigen (HLA), 96 K Human scalp Kenalog®, 102 biopsy, 44 Keratinization, 51–52 hair count in, 46 Keratolytics, 80 horizontal versus vertical sections, Keratosis follicularis spinulosa decalvans 44–46 (KFSD), 141 Human scalp biopsies Kerion, 283–284 hair follicle anatomy, 41–57 formation in tinea capitis, 279 Humoral immunity, 77 Ketoconazole, 81, 220 Huntington’s disease, 270 KFSD. See Keratosis follicularis spinulosa decalvans Huxley’s layer Kwashiorkor disease, 127 keratinization, 52 Hydrolyzed animal protein, 60 L Hydroxychloroquine, 145 Lanthionization, 69 21α-hydroxylase defi ciency, 214 Lanugo hair, 42 11β-hydroxylase defi ciency, 214 LAS. See Loose anagen syndrome Hydroxymethyl pentylcyclohexene carboxaldehyde LASER, 225, 230–231 (HMPPC), 246 LASER hair removal, 218–219, 225–234 2-Hydroxy-1,4-napthoquinone, 245 complications, 233–234 Hyperpigmentation, 234 guidelines for, 232–233 Hyperproliferation, 78 target of, 226–227 Hypersensitivity eruption, 286 wavelengths of, 231 McMichael PTR 01/21/08 Index

Index 315

Laser terms MIC. See Minimum inhibitory concentrations in dermatology, 227 Midisthmus, 48 Lasonia inermis, 245 Mini-micro grafting, 176–177 Lavender (Lavandula angustifolia), 208 Minimum inhibitory concentrations (MIC), 80 Lawsonia alba, 66 Minoxidil, 99, 111, 112, 114, 129, 180, 256–258 Leave-in conditioners, 64, 254 ACD, 258 LH. See Luteinizing hormone allergic contact dermatitis to, 258 Lichen planopilaris (LPP), 137, 139, 140, 145, 192, 305 versus fi nasteride, 113 burned-out, 305 Moisturizing shampoos, 16 Graham Little-Piccardi variant of, 140 Mongoloid, 4 Lidocaine, 44 Monilethrix, 151–152 Light and laser energy MPB. See Male-pattern baldness characterization, 227–229 MPHL. See Male-pattern hair loss fl uence, 229 Myeloid differentiation factor 88 (Myd88), 78 pulse width, 229 Mycological cure rates, 283 spot size, 229 Mycophenolate mofetil, 145 wavelength, 228 Myroxylon pereirae, 246 Light-assisted hair removal, 225–234 complications, 233–234 N Light therapy, 99–100 NAAF. See National Alopecia Areata Lindane, 289 Foundation absorption of, 289 NACDG. See North American Contact Dermatitis functions, 289 Group Lipase activity, 78 NAHRS. See North American Hair Research Lipid metabolism, 138 Society Lipotoxicity, 138 Nail abnormalities, 91 Locks of Love, 298–299 Nail biting, 267 Long hair, 14 Nail pitting, 91 Loose anagen syndrome (LAS), 158–159 National Alopecia Areata Foundation (NAAF), 99, Louse scalp infestation 297–300 clinical appearance of, 285 National Skin Center, 95 LPP. See Lichen planopilaris Neodymium:YAG (Nd:YAG), 218, 231 Luteinizing hormone (LH), 216 Netherton’s syndrome (trichorrhexis invaginata), Lye chemical relaxers, 69 153–154 Lymphocytic CAs NICU. See Nonimmunologic contact urticaria treatment algorithm, 145 No-lye chemical hair straighteners, 69 No-lye relaxers, 69 M Nonimmunologic contact urticaria (NICU), 239 Major histocompatiblity complex class I chain-related Nonmedicated grooming products and beauty treat- gene A (MICA), 97 ments, 59–70 Major histocompatibility complex (MHC), 138 Non-scarring hair loss, 91 Malassezia, 76–78, 80, 81 Normal skin barrier Malassezia furfur, 76, 77 restoration of, 260 Malathion, 287, 288–289 North American Contact Dermatitis Group Male androgenetic alopecia, 107 (NACDG), 237, 242, 246, 249, 258 Male-pattern baldness (MPB), 175, 184–185, 194 North American Hair Research Society Male-pattern distribution, 221 (NAHRS), 137 Male-pattern hair loss (MPHL), 119, 124, 305, 306 N-trichloromethylthio-4-cyclohexene-1,2-dicarboxi- Marasmus disease, 127 mide, 256 Marie Unna hypotrichosis, 157 Nuvo®, 290 Matting, 26 Medical history, 302 O Melanin Olanzapine (Zyprexa®), 271 absorption spectrum, 228 3β-ol-dehydrogenase defi ciency, 214 Melanin pigmentation, 42 Onychomycosis, 281 Melanocortin-1 receptor, 3 Oral contraceptives, 219, 220, 221 Melanocytes, 2 Outer root sheath (ORS), 6, 50 Melanosomes, 3 Ovarian neoplasms, 214 Menke’s kinky-hair syndrome, 152 Ovarian suppression, 219 Metallic dyes, 245 Ovide®, 288 Methyldibromoglutaronitrile/phenoxyethanol Oxidation dyeing process, 66 (MDGN+PE, Euxyl K400), 249–250 Methylisothiazolinone and methylchlorothiazolinone P (MI/MCI; Kathon CG), 250 Para-aminobenzoic acid (PABA), 251 MHC. See Major histocompatibility complex Parabens, 251 MICA. See Major histocompatiblity complex class I Paradoxical hypertrichosis, 234 chain-related gene A Para-phenylenediamine (PPD), 242–244, 246 Microsporum, 277, 280 sensitization, 246 McMichael PTR 01/21/08 Index

316 Index

Parasitosis Pili annulati, 155 delusions of, 269 syndromes associated with, 156 Paratrol®, 288 Pili multigemini, 159–160 Parkinson’s disease, 75 Pili torti, 152–153 Paroxetine (Paxil®), 269 ectodermal dysplasias associated with, 154 PARSOL 1789, 256 syndromes associated with, 153 Part-width assessment, 303–304 Pimecrolimus cream, 83 PAS. See Periodic acid-Schiff Pimozide (Orap®), 271 Patch testing, 245, 259 Piperonyl butoxide (PBO), 287–288 Patchy hair loss, 304–305 Pityriasis amiantacea, 76 Pathogenesis, 277 Pityrosporum ovale, 76, 77 Pathophysiology of alopecia areata Plucking, 217 genetics, 96–97 Pohl-pinkus lines, 159 histology, 96 Polarized light microscopy, 28–29 immunology, 96–97 Polycystic ovarian syndrome (PCOS), 212, 214, 215, nerves, 97 216, 219–221 Patient Support Groups/Foundations, 298 Polyvinylpyrrolidone (PVP), 62 Patients with alopecia, 301–307 Post-pubertal recession, 107 diagnosis, 305 Post-traumatic keloid formation, 194 educating the patient, 306–307 Prednisone, 145 hair loss examination, 303–305 Preservative screening series, 249 laboratory workup, 306 Preservative-free hair products, 251 patient history, 301–303 Preservatives, 248 scalp biopsy, 305–306 Prickly ash bark (Zanthoxylum clava-herculis), 200, 202 PBO. See Piperonyl butoxide Pronto®, 288 PCOS. See Polycystic ovarian syndrome Propecia®, 180 PPD. See Para-phenylenediamine Propionibacterium acnes, 77 PPD-sensitive patients, 244 Propylene glycol, 251 PDT. See Photodynamic therapy Protein-containing conditioners, 62–63 Pediculicides, 287 Proximal trichorrhexis nodosa, 150–151 comparison of, 288 Pruritus Pediculosis capitis, 285–287 alleviation of, 260 clinical fi ndings, 286 Pseudohermaphroditism, 108 diagnosis, 286 Pseudomonas aeruginosa, 250 differential diagnosis, 287 Pseudomonilethrix, 152 epidemiology, 285 Pseudopelade, 141 historical background, 285 Pseudo-TTD, 154 louse features, 285–286 Pseudovaginal perineoscrotal hypospadias, 108 Pediculus humanus capitis, 285 Psocids, 287 Penicillium griseofulvum, 280 Psoralen-ultraviolet A (PUVA), 99 Perifollicular edema, 233 Psoriasis, 75 Perifollicular erythema, 268 Psychological hair disorders Periodic acid-Schiff (PAS), 76 antidepressants used for, 269–271 Peripilar casts, 159 Pulse width, 229, 233 Permanent adverse effects, 234 PUVA. See Psoralen-ultraviolet A Permanent dyes, 66–67, 242–244 PVP. See Polyvinylpyrrolidone Permanent waves, 24, 253 Pygeum (Prunus africana), 197–198 Permethrin, 287 Pyrethrins, 287–288 Peroxisomes and lipid metabolism, 138 Pyrithione zinc (PZT), 81 Pheomelanin, 2 Photoallergic contact reactions, 240 Q Photodynamic therapy (PDT), 231, 232 Quaternary conditioners, 62 Photoepilation, 232 Quaternium-15, 250 Photographic imaging of hair loss, 35–39 Quietiapine (Seroquel®), 271 camera and lighting control, 36–37 camera-to-patient registration, 37–38 R computer-assisted hair measurements, 38–39 Race and hair form, 4 global photography, 35 Radioallergosorbent testing (RAST), 239 Piedra, 284 Rate-limiting enzyme, 219 black, 284 Receptor agonist, 131 clinical fi ndings, 284 Recipient sites, 182–183 diagnosis, 284 Refl ected light microscopy, 29 differential diagnosis, 284 Repeat open application testing (ROAT), 251 epidemiology, 284 Risperidone (Risperdal®), 271 KOH examination, 284 ROAT. See Repeat open application testing treatment, 284–285 Reticulate erythema, 234 white, 284 Rogaine®, 103, 129, 180 Pigmentary alterations, 234 Rosemary (Rosemarinus offi cinalis), 200, 201 McMichael PTR 01/21/08 Index

Index 317

S Silicone conditioners, 63 Sabouraud’s agar, 280 Silver scalp, 76 SAHA. See Seborrhea, acne, hirsutism, and alopecia Skin picking, 267 Salicylic acid, 80 SLR body, 36 Salti-Salem syndrome, 153 SLR sensor, 36 Saw palmetto (Serenoa repens), 197 Small angle X-ray scattering (SAXS), 6 SAXS. See Small angle X-ray scattering patterns, 6 Scalp biopsy, 42, 305–306 Soft-base vacuum custom wig, 166 horizontal, 42 Spironolactone, 220 Scalpdex, 74 Spot size, 229 Scalp examination, 123 Squaric acid dibutylester, 98 Scalp hair, 267 SSRIs. See Selective serotonin reuptake inhibitors Scalp infections, 277–285 Standard punch grafting, 176–177 adjunctive therapies and measures, 283 Standard punch-graft technique, 177 fl uconazole, 282–283 Stearyl-coenzyme A desaturase gene, 137 griseofulvin, 280–281 Stem cells and immunology, 138 itraconazole, 282 Stereotactic head device, 37 kerion, 283–284 Steroids, 98–99 piedra, 284 Stevens-Johnson syndrome, 290 terbinafi ne, 281–282 Stinging nettle root, 198 tinea capitis, 277–280 Straightening or relaxing techniques, 24 voriconazole, 283 Straight hair naevus, 157–158 Scalp infections and infestations, 277–291 Stress, 302 treatment, 287–291 Sudden onset hair loss, 26 Scalp infestations, 285–287 Sugaring, 217 pediculosis capitis, 285–287 Sulfi te waves, 254 Scalp infl ammation, 129 Sunscreens, 256 Scalp prostheses, 163–173, 298–299 Synthetic hair, 164 hair cosmetics, 172–173 Syphilis, 270 hair extensions, 170–172 Systemic therapy, 145 hairpieces, 167–169 hair types, 163–164 T locks of love, 298–299 Tangling. See Matting options for children, 170 T-cell immunity, 96 options for men, 169–170 TDT. See Thermal damage time The National Alopecia Areata Foundation, 299 Telogen club hairs, 57 wigs, 164–167 Telogen effl uvium (TE), 119–131, 186 Scalp reduction, 113, 178 anemia and, 126 Scalp symptoms, 301–302 biotin, defi ciency and, 127 Scanning electron microscopy (SEM), 30–31 camoufl age and cosmetic aids, 131 SCID. See Severe sombined immunodefi cent concomitant treatments, 129–131 Seborrhea, acne, hirsutism, and alopecia (SAHA), 124 diagnosis, 119–123 Seborrheic dermatitis, 73–85 diagnostic techniques, 123 involving alar crease, 74 drug for treatment of, 128 worsening, 75 drugs and-botanical supplements, 128–129 Sebotrophic hypothesis, 137 future, 131 Sebotrophic mechanism, 137 hair follicle growth and infl uence, 121 Selective photothermolysis hormones and, 125 extended theory, 227 laboratory evaluation, 124 theory, 226–227 nutritional infl uences, 125 Selective serotonin reuptake inhibitors (SSRIs), 269 protein and restricted calories and, 127 Selenium sulfi de, 81 scalp examination, 123 Semi-custom soft mesh cap, 165 scalp infl ammation and, 129 Semipermanent and temporary dyes, 244–245 screening laboratory tests, 124 Semipermanent dyes, 66, 244–245 senescent alopecia, 125 SEM. See Scanning electron microscopy shedding in, 121 Senescent alopecia, 125 shedding patterns and triggers, 122 Sertraline (Zoloft®), 269 surgery and, 128 Serum 3α-androstanediol glucuronide, 212 systemic disorders and, 128 Severe sombined immunodefi cent (SCID), 96 thyroid and, 125 Sex hormone-binding globulin (SHBG), 214, 219 triggers, 124–127 Shampoo comparison studies, 82 vitamin A defi ciency and, 126 Shampoos, 16, 59–60, 254 vitamin D and, 127 2-in-1 shampoo, 60 zinc defi ciency and, 126 diversity, 60 Telogen germinal unit, 57 formulation, 59–60 Telogen shed reported allergens to, 255 removing triggers, 123 SHBG. See Sex hormone-binding globulin Temporary dyes, 65–66, 244–245 McMichael PTR 01/21/08 Index

318 Index

Temporary henna tattoos, 246 [Treatment of dandruff and seborrheic dermatitis] TEM. See Transmission electron microscopy combination therapy, 83–84 Terbinafi ne, 281–282 effi cacy testing methods, 79–80 Terminal anagen hair, 47, 53–55 FDA monograph, 80 Terminal catagen hair, 55–56 history, 79 Terminal hairs, 41 keratolytics, 80 Terminal hair shaft follicle, 53 Trichomycosis nodularis, 284 Terminal telogen hair, 56–57 Trichophyton, 277, 280, 282 TE. See Telogen effl uvium Trichophyton rubrum, 278 Testosterone, 214 Trichophyton tonsurans infection, 75 Thermal damage time (TDT), 227 Trichosporon beigelii, 284 Thermal relaxation time (TRT), 226, 227, 229 Trichotillomania (TTM), 267–269, 280 Thermolysis, 218 children with, 268 Thyme (Thymus vulgaris), 207 diagnositic criteria for, 268 Thyroid, 125 Friar Tuck sign of, 268 Tinea capitis, 75, 277–280 Trimethoprim-sulfamethoxazole (TMP-SMX), 290 annular scaling plaque of, 278 TRT. See Thermal relaxation time clinical fi ndings, 277–278 Toll-like receptor (TLR) activation, 78 diagnosis, 278–280 Topical sensitizers, 98–99 differential diagnosis, 280 minoxidil, 99 epidemiology, 277 steroids, 98–99 historical background, 277 Transmitted light microscopy, 28 kerion formation in, 279 Trental®, 190 pathogenesis, 277 Trichilemmal cells, 55 pauciinfl ammatory, 278 Trichilemmal keratin, 47 primary causes based on geography, 278 Trichonodosis, 160 systemic therapies in, 281 Trichorrhexis invaginata, 153–154 treatment, 280 Trichorrhexis nodosa, 7, 25–26, 31, 150 Tissue expanders, 178 SEM of, 31 TLR. See Toll-like receptor Trichostasis spinulosa, 160–161 T lymphocytes, 96 Trichothiodystrophy (TTD), 153, 154–155 TMP-SMX. See Trimethoprim-sulfamethoxazole syndromes associated with, 154 Topical/intralesional therapy, 144 Trichothiodystrophy, 29 Traction alopecia, 195 Transient adverse effects, 233–234 U Transmission electron microscopy (TEM), 31–32 Uncombable hair syndrome, 157 Treatment for scalp infections and infestations, 287–291 adjunctive control measures, 291 V failures, 291 Vanicide 89 RE, 256 ivermectin, 289 Vancide ZP, 255–256 lindane, 289 Vegetable hair dyes, 245 malathion, 288–289 Vellus hairs, 41, 43, 212 other agents, 290 Verhoeff-Van Gieson (VVG), 143 permethrin, 287 Virilization, 211 problem of resistance, 287 Vitamin A defi ciency, 126–127 pyrethrins, 287–288 Vitamin D defi ciency, 127 screening, 291 Vitamin D3 supplements, 127 Treatment of alopecia areata, 97–100, 102–103 Voriconazole, 283 alopecia areata registry, 101 VVG. See Verhoeff-Van Gieson anthralin, 99 biologics, 100 W combination therapies, 100–102 Waving, 67 extensive disease, 102–103 Waving lotion ingredients, 67 light therapy, 99–100 permanent, 67 patchy disease, 103 Wave neutralizer ingredients, 68 potential future medical treatments, 101 permanent, 68 topical sensitizers, 98–99 Waves (permanent) Treatment of androgenetic alopecia, 111–116 types of, 68 for men, 111–113 Waxing, 217 for women 114–115 Weathered hair, 151 for non-caucasians, 115–116 Weathering, 7, 61, 149 Treatment of cicatricial alopecia (CAs), 143–147 severe, 7 medical, 144–146 Wigs, 164–167 surgical, 146–147 attachment, 167 Treatment of dandruff and seborrheic dermatitis, 79–84 cast of patient scalp, 168 anti-infl ammatory agents, 83 construction, 165 anti-malassezia agents, 80–83 custom hard-based human hair, 169 antipruritics, 80 double-sided tape, 167 McMichael PTR 01/21/08 Index

Index 319

[Wigs] Z hard-based vacuum custom, 168 Zimmer system, 230 mold of scalp, 168 Zinc deﬁ ciency, 126 trial vacuum base, 168 Zincon, 255–256 Wigs and accessories, 258–259 Zinc pyrithione (ZPT), 81, 255–256 Woolly hair and woolly hair naevus, 155–157 Ziprasidone (Geodon®), 271 Wooly hair syndrome, 6–7 ZPT. See Zinc pyrithione McMichael PTR 01/21/08 Index Template_7x10_Walsworth.indd

Dermatology Hair and Scalp Diseases:

+_d836551_cva.indd 1 nC nM nY nK 2/5/2008 11:04:12 AM McMichael_978-1574448221.indd 1 1/25/08 11:10:52 AM