Hair Loss: Principles of Diagnosis and Management of Alopecia

Hair Loss: Principles of Diagnosis and Management of Alopecia

Hair Loss: Principles of Diagnosis and Management of Alopecia Jerry Shapiro, FRCPC Clinical Professor and Director of the UBC Hair Research and Treatment Centre Division of Dermatology University of British Columbia Vancouver Canada

Martin Dunitz

© 2002 Martin Dunitz Ltd, a member of the Taylor & Francis group First published in the United Kingdom in 2002 by Martin Dunitz Ltd, The Livery House, 7–9 Pratt Street, London NW1 0AE Tel: +44 (0) 20 7482 2202 Fax: +44 (0) 20 7267 0159 E-mail: [email protected] Website: http://www.dunitz.co.uk This edition published in the Taylor & Francis e-Library, 2004. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London, W1P 0LP. A CIP record for this book is available from the British Library. ISBN 0-203-42852-8 Master e-book ISBN

ISBN 0-203-44903-7 (Adobe eReader Format) ISBN 1-85317-876-4 (Print Edition) Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Distributed in the USA by Fulfilment Center Taylor & Francis 7625 Empire Drive Florence, KY 41042, USA Toll Free Tel.: +1 800 634 7064 E-mail: cserve@routledge_ny.com Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel.: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by ITPS Limited Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424 E-mail: [email protected] Composition by Scribe Design, Gillingham, Kent

Contents

Foreword Acknowledgements 1

2

3

Assessment of the patient with alopecia Alopecia areata: Pathogenesis, clinical features, diagnosis and practical management Androgenetic alopecia: Pathogenesis, clinical features and practical medical treatment

vii

4

Surgical management of androgenetic alopecia

121

5

Drug-induced alopecia

135

6

Telogen effluvium: acute and chronic

147

Cicatricial (scarring) alopecia

155

ix

1

7 19

Index

83

175

Foreword

Jerry Shapiro is a dedicated clinician/scientist who has devoted himself to all aspects pertaining to the hair follicle. He has written a unique text that will be invaluable for clinicians, researchers, and students of the hair follicle. This is an organized and rational guide for assessing and managing hair loss, which is set apart from others by the blending of rich clinical detail with the latest investigative research and theories of pathogenesis, all extensively referenced. It is a practical and personal approach that reflects Dr Shapiro’s long experience with hair problems both in the clinic and in the laboratory. His explicit recommendations about management are given, and where appropriate, he also includes the treatment

preferences of other hair experts. Complex issues are presented, such as immunological factors in alopecia areata, in clear terms for all readers. The illustrations are extensive, a collection of unique photographs and photomicrographs from his own collection. The text is exceptionally readable and complements the book’s systematic and inviting organization. Jerry Shapiro has accomplished an amazing single-authored, comprehensive text about hair that enriches the reader from bench to bedside. Vera H Price MD, FRCPC Professor of Clinical Dermatology School of Medicine University of California, San Francisco

Acknowledgements

There are certainly many individuals to thank in the making of this book. First and foremost, I am most indebted to my hair loss patients who have trusted me and given me the privilege of taking care of their hair. It continues to be an honor for me and I thank them for this. Next, I would like to thank certain individuals who have played an important part in my career. Dr Harvey Lui, who has, and continues to guide and nurture me in the field of dermatology. Dr William Stewart, who was the first individual to encourage me to take on the field of hair. Dr David McLean, whose advice, support and encouragement helped the University of British Columbia Hair Research and Treatment Centre flourish. Dr Vera Price, who has been my ‘’hair’’ mentor for over 15 years and has been an inspiration and role model. Dr Wilma Bergfeld, who allowed me to learn from her in Cleveland and from whom I continue to learn. My Hair Fellows: Dr Chantal Bolduc, Dr Shabnam Madani and Dr Olga Bernardo, who took time out of their busy lives to commit a year to studying hair with me. Each fellow has questioned, challenged and inspired me to learn so much more; they truly are very special people. My research associate, Dr Liren Tang, who continues to teach me the molecu-

lar biology and basic science of hair. Drs Magda Martinka and David Shum, who continue to enlighten me regarding the histopathology of the hair follicle. Nina MacDonald, my first Hair Clinic nurse, who was dedicated and helped shape the University of British Columbia Hair Clinic during its early years. Lucianna Zanet, my Hair Transplant nurse, who has guided me for the last 10 years with all her great surgical skills and great common sense approach to patients. I thank my editors, Charlotte Mossop and Robert Peden, whose time and efforts were absolutely essential in making this book possible. I would like to thank the University of British Columbia’s Division of Dermatology and the Vancouver General Hospital Skin Care Centre for providing the environment for me to work in the field of hair. I also would like to especially thank my family and friends who stood back and allowed me to take the weekends and evenings to finally accomplish this endeavor. Jerry Shapiro University of British Columbia Hair Research and Treatment Centre

1 Assessment of the patient with alopecia

Hair loss (alopecia) is a very common patient problem and often a significant source of patient distress. An accurate diagnosis can frequently be difficult. A rational, organized approach is crucial, as therapy is dictated by the appropriate diagnosis.1 The first task of the physician is to address the patients’ concerns fully, exploring the impact of alopecia on psychosocial well-being. Next, an organized diagnostic approach can assist the physician in the recognition of the characteristic differential features of each disorder and help to identify the cause of alopecia and guide therapeutic direction. Ancillary laboratory evaluation may sometimes be necessary to help confirm a diagnosis. Patients are most appreciative of a supportive diagnostic approach.

The hair follicle is divided into 4 parts: (Figures 1.1 and 1.2) 1. Bulb: consisting of dermal papilla and matrix intermixed with melanocytes (Figure 1.3) 2. Suprabulbar area from matrix to insertion of arrector pili muscle 3. Isthmus extending from insertion of arrector pili muscle to sebaceous gland 4. Infundibulum extending from sebaceous gland to the follicular orifice.

Basic trichologic anatomy and physiology In order to appreciate an organized diagnostic protocol for alopecia, it is important to review the basics of hair anatomy and physiology of the scalp. Knowledge of the hair cycle is essential in understanding the patho-physiology of hair diseases and the mechanism of action of the present therapeutic agents used to modulate hair growth.

Figure 1.1 Diagrammatic representation of hair anatomy: The hair follicle is divided into 4 parts: bulb, suprabulbar area, isthmus, and infundibulum.

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Hair Loss: principles of diagnosis and management of alopecia

Figure 1.2 (a) Histology of the hair follicle on longitudinal section showing dermal papilla (DP), matrix (M), inner root sheath (IRS), outer root sheath (ORS) and fibrous root sheath (FRS). (b) Two anagen follicles side by side at the level of fat. Note the melanocytes within the matrix providing pigment to the hair. (Courtesy of Dr Magdalena Martinka and Dr David Shum.)

The lower portion of the hair follicle consists of five major portions (1) dermal papilla; (2) matrix; (3) the hair shaft, consisting from inward to outward of medulla, cortex, and cuticle; (4) inner root sheath, consisting of inner root sheath cuticle, Huxley’s layer on the inside and Henle’s layer on the outside; and (5) the outer root sheath.

The base of the follicle is invaginated by the dermal papilla, which contains highly vascularized connective tissue (Figure 1.4). Dermal papilla fibroblasts are inherently different from non-follicular dermal fibroblasts. There is a large amount of acid-mucopolysaccharides within the dermal papilla, staining positively for Alcian blue and metachromatically for

Assessment of the patient with alopecia

3

Figure 1.3 (a) Close-up of longitudinal section of dermal papilla (DP), which is an invagination of the dermis into the matrix (M). The DP allows capillaries to gain entrance to the cells of the matrix. It is the signal transduction and communication between the DP and the matrix that determines how long a hair will grow and how thick a shaft will be produced. Melanocytes fill the matrix and produce the pigment of the hair. (b) Cross-section of the follicle at the level of the dermal papilla. (Courtesy of Dr Magdalena Martinka.)

toluidine blue. The ground substance consists of not only non-sulfated polysaccharides such as hyaluronic acid, but also sulfated mucopolysaccharides such as chondroitin sulfate. Alkaline phosphatase activity is also increased in the anagen phase. In persons with dark hair large amounts of melanin can be seen in the dermal hair papilla. The hair matrix has large vesicular nuclei and deeply basophilic cytoplasm. Dopa-positive melanocytes are interspersed between the basal cells of the matrix lying on top of the dermal papilla (Figures 1.2 and 1.3). Melanin, varying in quantity in accordance with the color of the hair, is produced in these melanocytes and incorporated into the future cells of the hair through phagocytosis of the distal portion of the dendritic melanocyte. Cells of the hair matrix differentiate into six different types of cells, each of which

Figure 1.4 The different layers of the hair follicle

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Hair Loss: principles of diagnosis and management of alopecia

Figure 1.5 (a) Cross-section and (b) longtitudinal sections of the follicle at the suprabulbar level. In the central portion of the follicle the matrix (M) is forming cortex, which is surrounded by the cuticle. This is subsequently invested by the cuticle of the inner root sheath (IRS), Huxley’s layer with trichohyaline granules, and the already keratinized Henle’s layer.The outer root sheath (ORS), hyaline membrance and fibrous root sheath (FRS) surround the whole structure. (courtesy of Dr David Shum.) keratinizes at a different level. The outer layer of the inner root sheath (IRS), Henle’s layer, keratinizes first, establishing a firm coat around the soft central portions of the follicle. The two apposed cuticles covering the inside portion of the IRS and the outside of the hair keratinize next, followed by Huxley’s layer. The hair cortex then follows, and the medulla is last (Figure 1.4). The hair medulla appears amorphous because of its only partial keratinization. It may not always be present. The hair cortex cells during upward growth from the matrix cells keratinize gradually by losing their nuclei and become filled with keratin fibrils. No keratohyaline granules (as in keratinizing epidermis) or trichohyaline granules (as in inner root sheath) are formed

during keratinization. Keratin of the cortex is hard keratin, in contrast to the inner root sheath or epidermis, which is soft keratin. The hair cuticle located peripheral to the hair cortex consists of overlapping cells arranged like shingles and pointing upward with their peripheral portions. The cells of the hair cuticle are tightly interlocked with the cells of the inner root sheath cuticle, resulting in the firm attachment of the hair to its inner root sheath. The hair and the inner root sheath move in unison upward. The inner root sheath is composed of three layers (Figures 1.4 and 1.5). None of these layers contain melanin, and all keratinize with trichohyalin granule formation. These granules stain eosinophilic, in contrast to the basophilic keratohyalin granules of the epidermis. The cuticle of the IRS consists of one layer of flattened overlapping cells that

Assessment of the patient with alopecia

point downward in the direction of the hair bulb. Since the cells of the hair cuticle point upward, these two types of cells interlock tightly. Trichohyalin granules are few in the IRS cuticle. Huxley’s layer is two cell layers thick and develops numerous trichohyalin granules (Figure 1.5). Henle’s layer, only one cell layer thick, already shows numerous trichohyalin granules as it emerges from the matrix. Just before the isthmus the IRS becomes fully keratinized (Figure 1.6). However, at the level of the isthmus the IRS disintegrates. The cells of the IRS do not contribute to the emerging hair, but serve as a hard molding scaffold up to the arrector pili muscle. The outer root sheath (ORS) extends from the matrix cells to the entrance of the sebaceous duct, where it changes into surface epidermis. The ORS is thinnest at the level of the hair bulb, gradually increases in thickness, and is thickest in the middle portion of the hair follicle, the isthmus. In its lower portion, below the isthmus, it is covered by IRS and does not undergo keratinization. The ORS has plentiful vacuolated cytoplasm owing to its plentiful glycogen. The point of insertion of the arrector pili muscle is referred to as the bulge area, and is the likely location of the first primordial cells (stem cells) of the hair follicle.2–7 Stem cells from the bulge area likely migrate to other portions of the hair follicle and differentiate into its differing layers. The isthmus is the segment that extends from the arrector pili muscle to the sebaceous gland duct entrance. There is no inner root sheath here. The ORS undergoes trichilemmal keratinization, producing large homogeneous keratinized cells without the formation of keratohyaline granules. The upper portion of the follicle above the entrance of the sebaceous duct is the infundibulum. It is lined by surface epidermis

5

Figure 1.6 Cross-section of the follicle just beneath the isthmus showing the eosinophilic completely keratinized inner root sheath (IRS) enclosing the hair shaft (HS). All of this is surrounded by outer root sheath, hyaline membrane and fibrous root sheath. Only anagen hairs have inner root sheaths. (Courtesy of Dr David Shum.)

undergoing keratinization with the formation of keratohyaline granules. The glassy or vitreous layer, which forms a homogeneous eosinophilic zone peripheral to the outer root sheath, is periodic acid Schiff-positive and diastase-resistant. It differs from usual basement membrane zone by being thicker. It is thickest around the lower third of the hair follicle. Peripheral to this vitreous layer lies the fibrous root sheath, which is composed of thick collagen bundles. This connective tissue sheath may contain considerable reproductive potential, as was recently shown by Reynolds et al.8 Melanosomes of the hair cortex are larger than those of the epidermis. They lie singly or within groups not within lysosomes. They are located usually in the interfibrillary matrix,

6

Hair Loss: principles of diagnosis and management of alopecia

within the cells, and only rarely in the intercellular space (Figure 1.7). Two types of melanin are present in mammalian hair, the black brown pigment eumelanin and the yellow red pheomelanin. Both are synthesized from tyrosine, which is converted to dopaquinone which can then undergo oxidative reactions to form either eumelanin or pheomelanin. In the eumelanin containing follicle, melanocytes contain ellipsoidal melanosomes with a lamellar internal structure (eumelanosomes) Pheomelanogenesis is associated with melanocyte-containing spherical melanosomes which have a less well defined internal structure containing granules or vesicles. In fire-red hair there are high levels of pheomelanosomes. In other hair colors, melanocytes have higher amounts of eumelanosomes. Dark hair contains more eumelanin and blond hair more pheomelanin. In white hair, melanocytes at the basal layer of the hair matrix are usually reduced in number or are absent. Melanocytes show degenerative changes, especially of melanosomes. The hair shafts only contain the detritus of melanin or no melanin at all. Unlike animals, where hair cycling is synchronous, on the human scalp there is an asynchronous mixture of hairs actively growing and resting. During the hair cycle, the middle and upper portions of the hair follicle are the permanent segment of the hair follicle, while the lower portion is non-permanent. (Figure 1.8). The growing or anagen hairs are anchored deeply within the subcutaneous fat (Figure 1.8) and cannot be pulled out easily. Hair fiber is produced during anagen at a rate of approximately 1 cm/month or 0.35 mm/day. The telogen hairs are located higher up in the dermis (Figures 1.8 and 1.10) and can be pulled out relatively easily. The normal scalp contains 100,000 hairs. Blonds

Figure 1.7 Melanosomes, either eumelanin or pheomelanin, during anagen are transferred from melanocytes to matrical cortex cells via dendritic ends.

tend to have more, at 120,000, and redheads less, at 80,000. The average number of hairs for a normal scalp is 250 per square cm or 1100 per square inch. There is ethnic variation, with fewer hairs per square cm in Blacks and Orientals. The scalp consists of almost 90% of hairs in anagen, 1% in catagen and 10% in telogen. Anagen may last up to 2–6 years, telogen 3 months, and catagen 3 weeks. This ratio is usually uniformly distributed over the entire scalp. In certain individuals, there is periodicity in the number of telogen hairs, with a maximal number in late summer. Increased hair shedding is usually noted in autumn. Decreased telogen hairs occur in December, January or February. Physiologic hair shedding of 100 hairs per day is usual on the average, with fluctuations over the year. The sizes of the hair shafts are important in determining a diagnosis. Vellus hairs or miniaturized vellus-like hairs of androgenetic alopecia (AGA) have a shaft diameter of less than

Assessment of the patient with alopecia

7

Figure 1.8 During the hair cycle, the middle and upper portions of the hair follicle are the permanent segments of the hair follicle, while the lower portion is non-permanent. (a) The growing or anagen hairs are anchored deeply within the subcutaneous fat and cannot be pulled out easily. The telogen hairs are located higher up in the dermis and can be pulled out relatively easily. The scalp consists of almost 90% hairs in anagen, 1% in catagen and 10% in telogen. Anagen may last up to 2–6 years, telogen 3 months, and catagen 3 weeks. This ratio is usually uniformly distributed over the entire scalp. The dermal papilla (DP) is pulled upward with each cycle, and during telogen is closely associated with the stem cells of the bulge area. Communication signals between dp and stem cells of the bulge probably determine the length of anagen and the matrix girth of the next hair cycle. (b) The newly formed anagen hair pushes out the previous telogen hair.

Figure 1.9 Vellus-like hairs are less than 0.03 mm in diameter and rarely grow more than 1–2 mm. Terminal hairs are coarse over 0.06 mm in diameter and can grow up to 3 feet. A true vellus hair does not have an attached arrector pili muscle. Only miniaturized vellus-like hairs of androgenetic alopecia have arrector pili muscle.

8

Hair Loss: principles of diagnosis and management of alopecia

0.03 mm (Figures 1.9 and 1.11). Terminal hairs have a shaft diameter greater than 0.06 mm. One can induce hair growth promotion by increasing the number of anagen hairs per unit area and by increasing the duration of the anagen phase.

Patient approach Figure 1.10 Cross-section of telogen hair. A central starshaped area of trichilemmal keratin can be noted, surrounded by outer root sheath, hyaline membrane and fibrous root sheath. The lower portion of terminal telogen hairs is found higher up in the dermis, unlike terminal anagen hairs, whose bulbs are found in the area of subcutaneous fat. (Courtesy of Dr David Shum.)

There are many etiologic factors that cause clinical hair loss, or alopecia, including endocrine abnormalities, genetic predisposition, systemic illness, drugs, psychological abnormalities, diet, trauma, infections, autoimmunity, and structural hair defects. Because of the multiplicity of disorders that can result in hair loss, a thorough history and physical examination are important, and ancillary laboratory work-up may be necessary.

Figure 1.11 Small vellus-like hairs (V) in androgenetic alopecia, (a) Hair shafts are small (<.03 mm). (b) The small size of the hairs make the sebaceous glands look more hyperplastic. (Courtesy of Dr David Shum and Dr Magdalena Martinka.)

Assessment of the patient with alopecia

History The history is of critical importance in developing the initial differential diagnosis (Table 1.1). The age of the patient is very important. Certain conditions are more common in childhood compared to the adult. The two most common forms of hair loss in children are tinea capitis and alopecia areata. The duration and pattern (i.e. diffuse versus focal) of hair loss is very important to determine. A full list of current and past medication should be obtained (see Chapter 5), since many medications can induce hair loss. Patients should be asked questions regarding hair shedding (alopecia areata or telogen effluvium) versus simple hair thinning without shedding (androgenetic alopecia). Key questions implicating a telogen effluvium are: Any pregnancy, high fever, operations/general anesthesia, crash diets, or weight loss in the preceding 6 months? A positive family history of alopecia areata or androgenetic alopecia may point to a genetic predisposition for hair loss. In addition, the presence or absence of coincidental acne and

Table 1.1 Hair loss history questionnaire

9

abnormal menstrual cycles may indicate an androgen excess causing androgenetic alopecia. Thyroid screening questions may point to hyper- or hypothyroidism, and a strict vegetarian diet can implicate iron deficiency anemia. Some hair care practices (e.g. bleaching, back brushing, permanent waving) may result in hair breakage. It is important to establish whether the hair falls out from the roots or breaks off along the shafts, since there are completely different causes for each of these situations (Table 1.2). It is also important to question about the loss of axillary and pubic hair, eyelashes, eyebrows, and body hairs, since any hair-bearing area may be affected by alopecia areata or trichotillomania. The patient’s concerns and expectations should be acknowledged and fully explored. Many patients with hair disorders become frustrated when their worries about hair loss are either ignored or dismissed as insignificant. Explanation and discussion may resolve the problem without specific intervention. Occasionally an underlying depression or dysmorphophobia (pathologically focused

Table 1.2 Differential diagnosis

10

Hair Loss: principles of diagnosis and management of alopecia

Figure 1.12 Presence or absence of follicular ostia is crucial in the differential diagnosis. Note: (a) Follicular ostia in a non-scarring alopecia, such as alopecia areata. (b) Absence of follicular ostia in a scarring alopecia. fixation on body image) may be present. It is important that these psychiatric conditions be recognized and managed before any further treatment is initiated.

Clinical examination Clinical examination should be performed in three stages. On the scalp, first inspect for inflammation, scale, and erythema. It is important to determine if the hair loss is associated with scalp scarring (Table 1.3), as this introduces an entirely different differential diagnosis. Non-cicatricial alopecias demonstrate visible follicular units, while cicatricial alopecias are devoid of follicular units (Figure 1.12). Second, examine the pattern of density and distribution of hair. Certain characteristic patterns of hair loss are more common for certain diseases. Random patterns are more common for alopecia areata. Finally, study the quality of the hair shaft in terms of caliber, fragility, length and shape. It is useful to take a

contrast paper and place the hairs against it to examine the sizes of hairs (Figure 1.13). Pull test: To determine the ongoing activity of hair loss, a useful ancillary test, the ‘pull test’, should be conducted. Approximately 60 hairs are grasped between the thumb, index and middle fingers from the base of the hairs near the scalp, and firmly, but not forcefully, tugged away from the scalp (Figure 1.14). If

Table 1.3 Causes of alopecia

Assessment of the patient with alopecia

11

Figure 1.13 A contrast paper positioned at an involved area of the scalp will help determine the length, size and overall caliber of the hair shafts. This alopecia areata patient showed one month of spontaneous regrowth in a bald patch without any treatment.

Figure 1.14 Pull test: (a) Approximately sixty hairs are grasped from the proximal portion of the hairs shafts at the level of the scalp. (b) The hairs are then tugged from proximal to distal end. (c) The number of hairs extracted is counted. It is normal to pull up to 6/60 (< 10%) hairs. More than 6/60 hairs is a positive pull test and implies pathology. This is a 57year-old female with diffuse alopecia areata displaying a very positive pull test.

12

Hair Loss: principles of diagnosis and management of alopecia

more than 10% or 6 hairs are pulled away from the scalp, this constitutes a positive pull test and implies active hair shedding. If less than 6 hairs can be easily pulled away from the scalp, this is considered normal physiologic shedding. The patient must not shampoo for at least one day prior to the pull test. The pull test helps to assess the severity and location of hair loss. Trichogram/pluck test: The trichogram/ pluck test is another method of assessing hair loss. On the fifth day after the last shampoo, hairs are taken from specified sites9. The surrounding hair is fixed with clips and 60–80 hairs are grasped with a hemostat covered with rubber and are plucked, twisting and lifting the hair shafts rapidly in the direction of emergence from the scalp (Figure 1.15). Hair shafts are then cut off 1 cm above the root sheaths and roots are arranged side

by side on a slide. Anagen hairs are distinguished from telogen hairs and anagen to telogen ratios are calculated. Counts of dystrophic hairs are unreliable, since much of the observed hair dystrophy is artefactual, owing to hair damage caused by the plucking procedure. For noncicatrizing alopecias this anagen/telogen ratio has diagnostic significance. Because a scalp biopsy can give the physician the same information plus more regarding inflammation and the size of hairs, the trichogram has not become routine. The unit area trichogram, popularized by Rushton,10 is more accurate than the regular trichogram, as it takes into account not only anagen/telogen ratios but also hair density and size. With this technique, a fixed area is marked on the scalp through a template and all the hairs in that area are individually epilated with tweezers and mounted on a

Figure 1.15 Trichogram/Pluck test: The trichogram/pluck test is another method of assessing hair loss. On the fifth day after the last shampoo, hairs are taken from specified sites. (a) The surrounding hair is fixed with clips and 60–80 hairs are grasped with a hemostat covered with rubber and are plucked, twisting and lifting the hair shafts rapidly in the direction of emergence from the scalp. (b) Anagen hairs are distinguished from telogen hairs and anagen to telogen ratios are calculated.

Assessment of the patient with alopecia

slide for counting. This meticulous technique can be quite laborious and requires very special skill. Hair counts: Daily scalp counts can be useful to the physician to help quantify how much the patient is losing and make sure this is not more than physiologic hair loss. It is normal to lose 100–150 hairs per day. Patients are asked to collect all the hairs shed in one day, count them and place them in plastic sandwich bags. All hairs shed in the shower, or sink or on the brush, counter or pillow are collected. Shampoo days are labeled separately, as it is expected that there will be more shedding on those days. Patients are instructed to do this

13

daily for 7 days. If the patient is losing less than 100 hairs per day, then there is currently no active shedding, but only physiologic hair loss. Performing a hair count is tedious and timeconsuming for the patient. But it is something that patients can do on their own to follow their progress.11

Light-microscopic examination Hairs extracted by slow pull can be examined under the light microscope (Figure 1.16). Hair shafts are mounted in parallel

Figure 1.16 Light microscopic examination of hairs: (a) telogen hair with characteristic club; (b) anagen hair with inner root sheath; (c) hair shaft abnormality: trichorrhexis nodosa secondary to trauma. (Courtesy of Dr David Shum.)

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Hair Loss: principles of diagnosis and management of alopecia

Figure 1.17 How to do a scalp biopsy: (a) In order to obtain sufficient histopathologic information, the scalp biopsy should be taken from an active inflammatory area containing hair follicles or active hair destruction. In noninflammatory conditions a biopsy in a representative area is sufficient. If possible the biopsy should be taken from a cosmetically less apparent area of the scalp. Staying away from hair parts or the frontal portion of the scalp is recommended. The area to be biopsied is marked with a red china marker. For local anesthesia, lidocaine 1 % with epinephrine in a concentration of 1:100,000 is injected with a 30 gauge needle into the scalp. Epinephrine causes vasoconstriction, which has a hemostatic effect in a highly vascular site such as the scalp. In addition, a mandatory waiting period of at least 10 minutes is suggested following the anesthetic injection. This allows the vasoconstrictive effect of epinephrine to take effect and hence maximize the hemostasis. (b) A 4.0 mm punch biopsy is placed parallel to follow the direction of the hair. In patients who have curly hair as above, insert the punch perpendicular to the scalp. (c) Direct vertical pressure is applied along with the rotation of the punch. Penetration of the punch to a depth of approximately 3.5–4.0 mm is sufficient to obtain a full scalp thickness. The typical punch should be pushed right through to the hub.

Assessment of the patient with alopecia

15

(d) The same needle for the anesthesia can be used to hook the tissue beneath the hair bulbs. (e) Aluminum chloride 20% solution on a Qtip can be used for hemostasis after the biopsy has been removed. (f) The biopsy defect is closed with a bluecolored monofilament suture, which helps to identify the suture on the hairy scalp, particularly with pigmented hairs. The suture needle is passed through the upper dermis, preventing damage to the hair bulbs located in the deep dermis. Wound dressings are not necessary for scalp biopsies.

between two glass slides taped together. A drop of cyanoacrylic glue placed on the slide will give greater contrast under the microscope compared to a dry mount. Roots should be examined to determine the stage of the hair cycle and for the presence of dystrophy. Hair shaft abnormalities (which can increase hair fragility and cause hair loss) can be diagnosed with this method. The hair shafts need to be examined to detect fractures, irregularities, coiling and twisting and

extraneous matter. The free ends of the hair should be checked to see whether they are tapered, cut, fractured or weathered. For the most part, most hair shaft abnormalities are quite rare, and the hair mount is not used routinely at the University of British Columbia (UBC) Hair Clinic unless indicated. If fungal diseases are suspected, hairs should be placed on a glass slide with 20% potassium hydroxide added in order to demonstrate fungal spores and hyphae.

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Hair Loss: principles of diagnosis and management of alopecia

The scalp biopsy: Scalp biopsies are indicated in all cases of cicatrizing alopecias and in all cases of unexplained non-cicatrizing alopecias12. At the UBC Hair Clinic all biopsies for non-cicatrizing alopecias are performed with transverse/horizontal sectioning rather than longitudinal/vertical sectioning. This allows a greater number of follicles to be examined. The biopsy must be deep and include the entire follicular unit, including some subcutaneous fat (Figure 1.17). Usually this involves a depth of 4 mm. The technique of vertical sectioning was popularized by Headington13 and subsequently by Whiting14 and Sperling.15 At the UBC Hair Clinic a 4 mm punch biopsy is trisected at two levels and subsequently horizontal sections are read from the base of the follicle to the papillary dermis. Normally a scalp biopsy has 35–40 hairs at the upper levels in papillary dermis. At the level of reticular dermis near the base of the infundibulum, the number is reduced to 35; at the deeper levels near the subcutaneous fat, the numbers are even less, at around 30. The upper levels contain telogen and anagen hairs, as well as terminal and vellus and vellus-like miniaturized hairs. The mid-levels consist of anagen and telogen hairs with terminal hairs only. The deeper levels contain anagen terminal hairs. The difference between the upper levels and mid levels is usually the number of vellus or vellus-like hairs. The difference between the mid levels and the lower levels is the number of terminal telogen hairs. Anagen/telogen ratios as well as terminal/vellus ratios can easily be calculated on the basis of the above and the morphology of the follicles. Peri-, intra- and interfollicular inflammation, if present, will be very prominent at all levels of the biopsy. For cicatrizing alopecias, two biopsies are taken. The first 4 mm punch biopsy is taken for transverse sectioning. Another 4 mm bi-

opsy is bisected longitudinally. One half is sent for direct immuno-fluorescence and the other half for longitudinal sectioning. Not only are the various scarring alopecias difficult to differentiate from each other clinically, but occasionally they may also be difficult to distinguish clinically from non-scarring alopecias. For those difficult cases, it is obligatory to perform a 4 mm scalp biopsy. The characteristic histologic features of the most common non-cicatrizing and cicatrizing alopecias are discussed in subsequent chapters. Laboratory tests: Lab tests may be helpful in establishing a diagnosis. Evaluation of serum ferritin may be necessary to exclude iron deficiency anemia, particularly in women with diffuse alopecia. If thyroid dysfunction is suspected, a thyroid-stimulating hormone level should be investigated. In women with androgenetic alopecia and virilizing signs such as hirsutism, acne, or irregular menses, an endocrinologic work-up consisting of free testosterone, and dehydroepiandrosterone sulfate (DHEAS) is advised to rule out hyperandrogenemic states. In cases of confirmed scarring alopecia due to discoid lupus erythematosus, an antinuclear antibodies (ANA) examination should be performed.

Non-cicatricial alopecias In the non-cicatricial alopecias, there is preservation of follicles on clinical and histologic examination, although they can sometimes be difficult to appreciate when miniaturized. The three most common forms of non-cicatricial alopecias are androgenetic alopecia, telogen effluvium, and alopecia areata. Table 1.4 compares the key clinical features that distinguish these three conditions from each other. These conditions are discussed at length in other chapters of the book.

Assessment of the patient with alopecia

17

Table 1.4 Common non-scarring alopecias

Cicatricial (scarring) alopecia Localized areas of cicatricial alopecia of the scalp may result from trauma, burns, acute fungal infections such as tinea capitis, viral infections such as herpes zoster, and bacterial infections. Discoid lupus erythematosus (DLE) is the most common primary cause of scarring alopecia, and lichen planus is another common etiology. Lesions of DLE demonstrate marked erythema, atrophy, telangiectasia, and follicular hyperkeratosis. A biopsy is necessary to establish an accurate diagnosis. Evidence of cutaneous disease elsewhere on the skin, oral or genital mucous membranes, and nails should be looked for carefully. Scarring

alopecias are considered true trichologic emergencies, as there is irreversible hair loss once hair follicles have become scarred. The importance of prompt appropriate therapy is crucial. The most common causes for scarring alopecia are discussed at length in Chapter 7.

Conclusion The majority of common hair disorders can be readily diagnosed in the physician’s office through the recognition of the characteristic differential features of each disorder. The first task of the physician is to acknowledge the patient’s concerns and have an empathetic approach to the problem of hair loss. The diagnosis depends upon a combination of find-

18

Hair Loss: principles of diagnosis and management of alopecia

ings obtained from meticulous history, physical examination and any necessary investigations. An organized diagnostic and management strategy will help both to identify the cause of alopecia and to direct therapy.

References 1. Shapiro J., Wiseman M. and Lui H. Practical management of hair loss. Can Fam Physician, 2000; 46:1469–77. 2. Cotsarelis G., Sun T.T. and Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell, 1990; 61(7):1329–37. 3. Sun T.T., Cotsarelis G. and Lavker R.M. Hair follicular stem cells: the bulge-activation hypothesis. J Invest Dermatol, 1991; 96(5): 77S–78S. 4. Lavker R.M., Cotsarelis G, Wei Z.G. and Sun T.T. Stem cells of pelage, vibrissae, and eyelash follicles: the hair cycle and tumor formation. Ann N Y Acad Sci, 1991; 642: 214–24; discussion, 224–5. 5. Lavker R.M., Miller S., Wilson C. et al. Hair follicle stem cells: their location, role in hair cycle, and involvement in skin tumor formation. J Invest Dermatol, 1993; 101(1 Suppl):16S–26S. 6. Cotsarelis G., Kaur P., Dhuailly P., et al. Epithelial stem cells in the skin: definition, markers, localization and functions. Exp Dermatol, 1999; 8(1):80–8. 7. Lyle S., Christofidou-Solomidou M., Liu Y.,

8.

9.

10.

11.

12.

13.

14.

15.

et al. Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype. J Invest Dermatol Symp Proc, 1999; 4(3):296–301. Reynolds A.J., Lawrence C., CserhalmiFriedman P.B., et al. Trans-gender induction of hair follicles. Nature, 1999; 402(6757): 33–4. Orfanos C. Androgenetic alopecia: clinical aspects and treatment. In Hair and Hair Diseases, ed. C.Orfanos, pp. 485–527. 1990; Berlin: Springer-Verlag. Rushton H., James K.C. and Mortimer C.H. The unit area trichogram in the assessment of androgen-dependent alopecia. Br J Dermatol, 1983; 109(4):429–37. Olsen E. Clinical tools for assessing hair loss. In: Disorders of Hair Growth Diagnosis and Treatment, ed. E.Olsen, pp. 59–69, 1994; New York: McGraw-Hill, Inc. Madani S. and Shapiro J. The scalp biopsy: making it more efficient. Dermatol Surg, 1999; 25(7):537–8. Headington J.T. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol, 1984; 120(4): 449–56. Whiting D.A. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia [published erratum appears in J Am Acad Dermatol 1993 29(4):554]. J Am Acad Dermatol, 1993; 28(5 Pt 1): 755–63. Frishberg, D.P., Sperling L.C. and Guthrie V.M. Transverse scalp sections: a proposed method for laboratory processing. J Am Acad Dermatol, 1996; 35(2 Pt 1):220–2.

2 Alopecia areata: Pathogenesis, clinical features, diagnosis and practical management

Alopecia areata (AA) is an unpredictable, usually patchy, non-scarring hair loss condition affecting any hair-bearing surface. AA is generally felt to be mediated by T lymphocytes directed at hair follicles. The exact cause is unknown, but is likely to be an interaction between genetic and environmental factors. Within the past decade, there have been significant advances in our understanding of alopecia areata. Most recent research and future directions in alopecia areata originate from three major research workshops co-sponsored by the National Alopecia Areata Foundation (NAAF) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in 1990, 1994 and 1998. At these meetings, numerous subspecialties, including immunologists, molecular biologists, biochemists, dermatologists, pathologists, and geneticists, discussed alopecia areata in an open forum. The proceedings of these meetings have been published in the Journal of Investigative Dermatology.1–3 This chapter will review the latest information on etiology, clinical features and state of the art treatment for AA.

Etiology The etiology of A A is unknown. Genetic and immunologic factors have been important ar-

eas of attention. Other proposed etiologies include infectious agents, cytokines, emotional stress, intrinsically abnormal melanocytes or keratinocytes and neurological factors.

Genetic factors Genetic factors play an important role in the etiology of AA. There is a high frequency of a positive family history of AA in affected individuals, ranging from 10% up to 42 % of cases.4,5 There is a significantly higher incidence of a positive family history in patients with early onset of AA.6 Familial incidence of AA has been reported to be 37% in patients who had their first patch by 30 years of age and 7.1% with the first patch after 30 years of age.6–9 Also, there have been reports of AA in identical twins,10–14 with up to 55% concordance rate in identical twins.13 Scerri 14 presented a case of 11-year-old identical twin boys, with ophiasis occurring simultaneously. Several closely linked genes, such as the human leukocyte antigens (HLA) are located on the short arm of chromosome 6, forming the Major Histocompatibility Complex (MHC).6,15 The HLA complex has been investigated in AA patients because of the association of other autoimmune diseases with increased frequencies of HLA antigens.15,16 Associations with

20

Hair Loss: principles of diagnosis and management of alopecia

Figure 2.1 (a, b) Alopecia areata and Down’s syndrome. There is up to an 8.8% increased frequency of AA in patients with Down’s Syndrome, suggesting involvement of a gene located on chromosome 21 in determining susceptibility to AA.

both HLA class I (HLA-A, -B, -C) and class II (HLA-DR, -DQ, -DP) have been studied in AA. The earlier studies identified the association of AA with several class I antigens, such as HLA-A9, B7, and B8,16 B12,17 B18,18 B13, and B27.19. There have also been studies showing no correlation with HLA Class I antigens.20,21 Recently, there has been an increased consist-

ency in evidence revealing associations between AA and HLA class II antigens. The studies reveal a significant association of HLA-DR11 and DQ3 in patients with AA.7–9,22– 29 The HLA alleles DQB1*03 (DQ3) and HLADRB1*1104 (DR11) appear to be markers of general susceptibility for all forms of AA.7–9,28,29 The HLA alleles DRB1*0401 (DR4) and DQB1*

Alopecia areata

0301(DQ7) are markers for more severe longstanding alopecia totalis/universalis.7–9 with a relative risk for AA of 30.2 for DRB1*0401. The investigators 9 suggest that amino acid sequencing of the antigen binding grooves of these HLA antigens may indicate the structure and identity of the elusive AA target antigens. Other investigators 26 also suggest that DRB3*52a may confer resistance to AA. By identifying these HLA genetic correlations, we are a step closer to understanding the structure of the epitopes recognized by T cells, which are key to the follicular inflammatory immune response responsible for AA. Identification of the AA antigens will be a major step in understanding the mechanisms of AA and in the design of therapies for prevention and treatment. However, one must bear in mind that the presence of predisposing HLA is but one component in a cascade of factors leading to autoimmune disease. Alopecia areata is a complex trait expressed by a number of genes. Polygenic influences are clearly involved. There is up to an 8.8% increased frequency of AA in patients with Down’s Syndrome, suggesting involvement of a gene located on chromosome 21 in determining susceptibility to AA (Figure 2.1).30,31 Thirty per cent of patients with autoimmunepolyglandular syndrome have AA. The defective gene in this syndrome is mapped to chromosome 21, again implicating this chromosome.59 Tarlow et al. reported an association between the severity of AA and inheritance of allele 2 of a five-allele polymorphism in intron 2 of the interleukin-1 receptor antagonist gene.32 The IL-1 gene cluster on chromosome 2 includes genes for the proinflammatory IL-1 proteins, their cell membrane receptors and the anti-inflammatory IL1 receptor antagonist. Polymorphism within the IL-1 cluster may modulate IL-1 responses. IL-1 has a direct effect on hair growth. In hair

21

follicle organ cultures, IL-1 inhibits growth of the hair fiber33 and induces morphological changes that resemble those seen in AA.34 In conclusion, many studies indicate that AA is a polygenic disease with certain genes correlated with susceptibility and others with severity. Most probably, there is an interaction between genetic and environmental factors that triggers the disease. At this point, the exact causative genes have not been discovered. With the discovery of animal models for AA, and with the final data on the Human Genome Project just completed, it is expected that our understanding of this complex trait will be further clarified. Genetic research may ultimately explain why, how and who develops AA.

Immunological factors Indirect clues for autoimmunity There are indirect clues for autoimmunity that include the association of the disease with a HLA haplotype, other autoimmune diseases and a responsiveness to immunosuppressive therapy. HLA associations have been discussed above. There are reported associations between AA and classic autoimmune disorders. The main associations are with thyroid diseases and vitiligo. Several reports reveal an 8.0–11.8% incidence of thyroid disease in patients with AA, compared to only 2% in the general population.4,5 This evidence has been further confirmed by documentation of an increased prevalence of anti-thyroid antibodies35 and thyroid microsomal antibodies.35 However, Puavilai et al. showed no increase in microsomal antibodies compared to normal controls.36 AA has been shown to have a significant association with vitiligo, with a fourfold greater incidence of vitiligo in AA

22

Hair Loss: principles of diagnosis and management of alopecia

patients.4,37,38 Other studies have revealed an increased prevalence of gastric parietal cell antibodies and anti-smooth muscle antibodies in sera of patients with AA.39,40 There are also reported associations of AA with pernicious anemia,40 diabetes mellitus,40 lupus erythematosus,41 myasthenia gravis,42–46 polymyalgia rheumatica,47 ulcerative colitis,46,48–50 lichen planus, 51–55 and autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy, also known as autoimmune polyglandular syndrome Type 1(APS-1).56–59 Thirty per cent of patients with APS-1 have AA. Successful treatment of AA with immunosuppressive agents such as oral cyclosporine 60,61 and systemic steroids 62 also supports the idea of immune-mediated pathogenesis in AA.

Direct clues for autoimmunity Humoral immunity Studies in the past with direct immunofluorescence have failed to show particular antibodies to epidermal cells or hair follicles in AA.63 Studies of passive transfer of serum from AA patients to nude mice failed to inhibit hair growth in grafted transplants of human scalp skin.64 However, Tobin and coworkers reported detection of antibodies to pigmented hair follicles by Western blotting in the sera of 100% of the AA patients examined, as compared to only 44% of normal controls.65 In another study by Tobin et al,66 much higher levels of autoantibodies to multiple structures of anagen hair follicles in AA patients have been reported, as compared to controls using indirect immunofluorescence. The antibody response to hair follicles in patients with AA has been found to be heterogeneous, because different patients develop different patterns of an-

tibodies to different hair follicle structures. The most common target structures were the outer root sheath, followed by the matrix, inner root sheath, and hair shaft.66

Cell-mediated immunity Studies of cell-mediated immunity in AA have given conflicting results. Circulating total numbers of T-lymphocytes have been reported as reduced40,67 or normal.68 Friedmann40 suggested that the number of circulating T-cells is reduced in AA, and that the level of this reduction is related to disease severity. In addition, he suggested that the impairment of helper T-cell function and the change in suppressor T-cell numbers may also reflect changes in disease activity. A slight increase in helper T-cells (CD4) and decrease in number of suppressor T-cells (CD8), resulting in an increase in the ratio of helper to suppressor cells, may be correlated with the amount of hair loss.67 The dense peribulbar lymphocytic infiltrate affecting anagen follicles is one of the most consistent and reproducible immunologic abnormalities in AA. The cellular infiltrate first becomes evident around the bulbar blood vessels, particularly in the dermal papilla/capillary network, and consists mostly of T lymphocytes and, to a lesser extent, macrophages and Langerhans cells. The infiltrate is most prominent in active disease. The infiltrate subsides in inactive disease and disappears in the regrowth phase. Most of the T cells are activated, as can be seen by the expression of DR antigens and IL-2 receptors. The T cell helper to suppressor ratio is 2:1– 4:1. The implication of these observations is that there may be an immune response to antigens in the lower half of hair follicles or in the peribulbar blood vessels in AA. The presence of cellular infiltrates around unaffected hair

Alopecia areata

follicles suggests that the process precedes rather than results from injury to hair follicles. Gilhar69 and Tsuboi70 have shown that grafting affected scalp AA skin from humans on to SCID mice results in regrowth of hair, with the disappearance of the T cell infiltrate. Tsuboi has shown that the CD8+ cells had disappeared completely from almost all portions of the hair follicle, while CD4+ cells still remained in the upper portions of the hair follicle. This may imply the greater importance of CD8+ in the expression of alopecia areata. Furthermore, more recently, Gilhar et al.69 reported that AA can be induced in human scalp explants from AA patients transplanted on to SCID mice by transfer of autologous Tlymphocytes isolated from involved scalp. In this study, T-lymphocytes that had been cultured with hair follicle homogenate along with antigen-presenting cells and melanocytederived protein were capable of inducing the changes of AA. These changes include hair loss, perifollicular T-cell infiltration, HLA-DR and intercellular adhesion molecule-1 (ICAM1) expression of follicular epithelium. T-cells that had not been cultured with follicular homogenate were not able to induce AA. The necessity of the follicular homogenate to inducing AA suggests that T cells recognize a follicular auto-antigen. Furthermore, AA induction followed upon injection with CD8+ cells cultured with follicular homogenate, but not on injection of the cultured CD4+ cells. This study also suggests that AA is mediated by T-cells, particularly CD8+ cells.69 In order for a medical condition to fit as an autoimmune disease, the following criteria should be met: 1. Unique antigens in the affected organ 2. An autoimmune response to that antigen 3. An autoimmune response specifically associated with the disease

23

4. The autoimmune response producing, not following, the condition 5. The disease being transferred passively by autoantibodies or T cells. For AA, many of the above criteria are indeed met. Increased frequency of hair-specific antibodies, antibodies to pigmented hair follicles, high levels of autoantibodies to multiple structures of anagen hair follicles, an increase in the ratio of helper to suppressor cells, and induction of AA on SCID mice by transfer of T-lymphocytes cultured with follicular homogenates are evidence supporting the view that AA is an autoimmune disease targeting the hair follicle. Figure 2.2 illustrates

Figure 2.2 The pathogenesis of alopecia areata. Antigenpresenting cells, such as Langerhans cells, are increased in the bulb of the affected follicles. They present the responsible epitope to the peribulbar lymphocytes. This leads to a cascade of immunologic events with increased interleukin-2 (IL-2), gamma interferon (γIFN) and intercellular adhesion molecules (ICAM). This series of events helps to induce hair loss. This is considered to be a Type 1 T helper cell response (Th ). 1

24

Hair Loss: principles of diagnosis and management of alopecia

some of the immunologic cascade events that take place in alopecia areata. The hair follicle has a distinct immune system71 that differs from that of its surrounding skin. The cellular components of the hair follicle immune system are composed of intrafollicular T lymphocytes and Langerhans cells, located exclusively in the distal outer root sheath, and perifollicular mast cells and macrophages.71 There is also a unique expression of follicular MHC class Ia/Ib, and ICAM1.71 Human hair follicles may even serve as a Langerhans cell reservoir. The epithelium of the proximal anagen hair follicle is immune-privileged, since the inner root sheath and hair matrix do not express MHC class I molecules. This immune privilege may collapse in alopecia areata. A recent theory for AA proposed by Paus et al.72 involves the upregulation of MHC antigens and/or downregulation of locally produced immunosuppressants (melanocyte- stimulating hormone, adrenocorticotropin and transforming growth factor), allowing the immune system to recognize the immune-privileged hair follicle antigens, leading to onset of AA.

Cytokines It appears that cytokines have a significant pathogenic role in AA. Cytokines are immunomodulators mediating inflammation and regulating cell proliferation. Cytokines derived from epidermal keratinocytes, interleukins IL-1α, IL-1β and tumor necrosis factor-α (TNF-α) are potent inhibitors of hair follicle growth, and in vitro produce changes in hair follicle morphology similar to those in AA.34,73 T helper cells produce cytokines divided into two subgroups depending on the pattern of cytokine production. Type 1 T helper (Th1) cells produce interferon γ (IFN-γ) and IL-

2. Type 2 helper (Th2) cells produce IL-4 and IL-5.74 Aberrant expression of cytokines of the Th1 type (see Figure 2.2) and IL-1β have been detected in affected areas of the scalp in patients with AA.73 As hair regrows with topical immunotherapy, these cytokine profiles change.

Infection There has been a report regarding the possibility of cytomegalovirus (CMV) infection found within the patches of scalp AA. This initial report showed a convincing positive association with CMV,75 but this has not been confirmed, as other investigators have reported negative findings.76–78 The whole concept of molecular mimicry of the hair follicle with a virus is intriguing, but the evidence for a viral etiology of AA at this point in time is not conclusive.

Emotional stress Several studies suggest that stress may be a precipitating factor in some cases of AA. Acute psychotrauma before the onset of AA,79–81 a higher number of stressful events in the 6 months of preceding hair loss,80 higher prevalence of psychiatric disorders81 and psychosomatic factors in patients with AA have been reported.82 In contrast, there are reports revealing that emotional stress does not play any role in the pathogenesis of AA.83

Intrinsically abnormal melanocytes or keratinocytes Morphological analysis of follicles in active AA lesions has revealed regressive changes in

Alopecia areata

the hair bulbs of anagen hair follicles.84–86 Abnormal melanogenesis and melanocytes are common findings. This evidence, together with the presence of antibodies to pigmented hairs of AA, may explain some of the associated pigmentary anomalies seen clinically in acute AA and the preferential effect of AA on pigmented hairs (Figure 2.12). Also, degeneration of pre-cortical keratinocytes has been shown in follicles of active AA lesions.85 Abnormal melanosomes in clinically normal regions, together with degenerative changes, including vacuolation, in outer root sheath of all hair follicles from non-balding lesions of AA,85 correspond well with the hypothesis of a sub-clinical condition of the disease in clinically normal areas of AA.

Neurological factors It has been suggested that local changes in the peripheral nervous system at the level of the dermal papilla or bulge region may play a role in the evolution of AA, since the peripheral nervous system can deliver neuropeptides that modulate a range of inflammatory and proliferative processes.87 This theory has been supported by Hordinksy et al., who revealed a decrease in calcitonin gene-related peptide (CGRP) and substance P (SP) expression in the scalps of patients with AA.88 The neuropeptide CGRP has a potent anti-inflammatory action,88,89 and neuropeptide SP is capable of inducing hair growth in the mouse. 88,90 In addition, application of capsaicin, which causes neurogenic inflammation and releases SP, to the entire scalp of two AA patients revealed an enhanced presence of SP in AA perifollicular nerves and induced vellus hair growth.91

25

Animal models Alopecia areata animal models In the past our understanding of the pathogenesis of AA was slow to progress owing to the lack of animal models for this disease. Recently, investigations of AA have been facilitated by using animal models with either spontaneous or induced AA. Animal models with spontaneous AA include the C3H/HeJ mouse,92 the Dundee experimental bald rat (DEBR)93 (Figure 2.3) and the Smyth chicken.94 The Smyth chicken model also has vitiligo, and may suggest a link between vitiligo, melanogenesis and the development of AA. AA can be induced in normal C3H/HeJ mice using full-thickness skin grafts from affected C3H/HeJ mice.95 AA developed 8–10 weeks after grafting. These same investigators95 noted that AA could be induced in 8–10 weeks by taking skin-draining lymph node cells from

Figure 2.3 Alopecia areata animal models: the C3H/HeJ mouse and the DEBR rat.

26

Hair Loss: principles of diagnosis and management of alopecia

AA-affected mice and transferring them to normal-haired recipients.95 The ability to induce AA in a model suggests that, whereas individuals may be genetically predisposed toward AA, susceptibility genes are not enough to develop the condition. AA induction can also be used to produce large numbers of mice for testing pharmaceutical agents. A preliminary study using C3H/HeJ mice examined potential chromosome locations that may contain genes involved in AA. 96 Three gene loci common to AA susceptibility were located. A region on mouse chromosome 6 may contain genes involved in inflammatory events associated with AA.96 A separate investigation on human AA by Tarlow et al.32 identified the equivalent chromosome region 2p12–13 as being a location for AA susceptibility. These human-animal correlations may have importance to understanding the mapping of the putative genes. Lymphocyte cells from C3H/HeJ AA mice were screened, and T cell clones expressing a Vß8.2/Jß2.5 T cell receptor (TCR) arrangement predominated.97 The receptor arrangement of these cell clones may help identify targeted antigens in AA. This may eventually permit selective immune therapy using antiTCR antibodies or clonal vaccination treatments. Animal models are now used in research for new and improved treatments. Lui et al. have shown that leflunomide, an IL-2 inhibitor, has some efficacy in the DEBR rat.98 Shapiro et al.99 have shown efficacy of diphenylcyclopropenone in the C3H/HeJ mouse (Figure 2.4). FreyshmidtPaul has shown the efficacy of squaric acid dibutyl ester in the C3H/HeJ AA mouse.100 Animal models with AA-like hair loss are significantly useful in investigations regarding pathogenesis, disease behavior, efficacy and side-effects of available or future treatments.

Figure 2.4 Diphencyprone was applied to half the C3H/ HeJ alopecia areata mouse, showing significant regrowth on the treated portion of the mouse.

Non-alopecia areata animal models The hairless mouse has an autosomal recessive allelic mutation that maps to chromosome 14.101,102 These mice develop a normal pelage at about 14 days and then lose their hair over 1 week. Recently investigations have correlated this hairless gene in mice with congenital atrichia in humans. The human hairless gene has been cloned to chromosome 8p12.103 This gene does not cause AA. However, this gene may have importance in maintaining hair follicle integrity by balancing cell proliferation, differentiation and apoptosis within the hair follicle. Hox genes are involved in controlling the position, density and development of hair in vertebrate embryos. Transgenic Hoxc13 defi-

Alopecia areata

cient mice were unable to synthesize hair keratins and have sparse brittle hair.104 Hoxc13 may play a significant role in follicular proliferation and differentiation.104 More knowledge of Hoxc13 expression in epidermal appendages will in turn provide further insight into the functioning of the normal ordered follicle, which in turn will allow us to understand the disordered follicle more clearly. Non-AA animal hair mutations may eventually help us to unravel the delicate mechanisms of the hair cycle and subsequently bring us closer to understanding the disordered hair follicle as it is found in AA.

Pathology In early active AA, the hair cycle is abnormal, with hair follicles entering the telogen or late catagen stage prematurely in the involved areas.105 There are distinct stages in the histopathology of AA: (a) acute alopecia; (b) persistent alopecia; (c) recovery.106 A peribulbar lymphocytic infiltrate (‘swarm of bees’) with no scarring is characteristic of the diagnosis of AA (Figure 2.5). The inflammatory cellular infiltrate is composed chiefly of activated Tlymphocytes together with macrophages and Langerhans cells.107,108 Also, miniaturization of hairs, with numerous fibrous tracts along with pigment incontinence within these fibrous tracts, is appreciable (Figure 2.5). During the acute phase of hair loss, matrix cell and matrical melanocyte failure with a formation of dysplastic hair shafts is noted. Following complete matrix failure, the involved follicle enters the end-stage telogen. A decreased anagen to telogen ratio, resulting in marked increase in telogen and catagen hairs, can be observed in horizontal sections of scalp

27

biopsies109,110 (Figure 2.5e). The terminal to vellus ratio is decreased and even reversed by the increased numbers of miniaturized hairs. Inflammatory changes in the mid and upper dermis are generally not prominent unless many vellus hairs are affected by the disease. In patients with long-standing persistent alopecia, the involved hair follicles arrest in the end-stage telogen phase. In these cases, peribulbar infiltration along with an increase in Langerhans cell numbers,111 a decrease in follicular density and follicular miniaturization may be present. In patients with complete recovery, normal hair follicles with little or no peribulbar lymphocytic infiltration and no decrease in hair density are noted. Eosinophils are also detectable in all stages of AA, both within the peribulbar infiltrate and the fibrous tracts. Although clinical correlation is necessary, this feature is helpful in diagnosis of AA in some biopsy specimens without peribulbar lymphocytic infiltrate.112 Mast cells were also noted in a small series of AA slides.113 Electron-microscopic examination of microdissected hair follicles from AA scalps demonstrated ultrastructural abnormalities in the dermal papillae of both lesional and clinically normal hair follicles.114 This shows that, with patchy involvement, AA is not a localized process. Immunohistochemical evaluation of clinically normal AA specimens reveals a prominent expression of ICAM-1 in the dermal papilla and keratinocytes of the matrix and outer root sheath.115 Histopathologically, AA should be differentiated from androgenetic alopecia, telogen effluvium, trichotillomania and syphilitic alopecia. In androgenetic alopecia, miniaturization of hairs is present with lack of lymphoid infiltration at the level of the bulb and a lack of pigment incontinence within fibrous tracts. In

28

Hair Loss: principles of diagnosis and management of alopecia

telogen effluvium, miniaturization of follicles is not present. Trichotillomania is characterized by empty anagen follicles, multiple catagen hairs, trichomalacia and pigment casts in the follicular infundibulum. Syphilitic alopecia is very difficult to distinguish from AA. Presence of plasma cells along with no peribulbar eosinophils and abundant lymphocytes in the isthmus are features of syphilitic alopecia, while the presence of peribulbar eosinophils and lymphocytes strongly suggests AA.116

Clinical features AA occurs all over the world. It accounts for about 2% of new dermatology outpatient attendances in the UK and the USA. 117 The prevalence of alopecia areata in the United States, as reported by the First National Health and Nutrition Examination Survey conducted from 1971 through 1974, was 0.1 to 0.2 per cent of the population.117 The lifetime risk has been estimated at 1.7%. 117 AA affects men and women equally.4 Patients are frequently quite

Alopecia areata

29

Figure 2.5 Histopathology of alopecia areata. (a) ‘Swarm of bees’ noted in the deep subcutaneous peribulbar area of the follicle. (b) Close-up the lymphocytic infiltrate, with matrix destruction. (c) Two follicles, with one showing marked lymphocytic infiltration, while the other does not. This highlights the fact that AA is a very heterogeneous condition, not only on the same scalp, but within the same follicular bundle. (d) Follicular stellae (ST) remnants in alopecia areata. (e) The large number of telogen hairs in alopecia areata. Almost all follicles within this field are telogen. (f) Reduction of follicular numbers in chronic alopecia areata. (Courtesy of Drs Magda Martinka, David Shum and Martin Trotter.)

young. Sixty per cent of patients present with their first patch under the age of 20.118,119 (Figure 2.6). Colombe et al.8 suggest a bimodal pattern for AA, with an early-onset form associated with greater severity, long duration, and family history of the disease and a lateonset form characterized by milder severity, shorter duration, and low family incidence. Alopecia areata can manifest with several different clinical features. Patients usually complain of abrupt hair loss and marked hair shedding. Frequently, patients will present to the physician with one or several bags of hair.

The characteristic lesion of AA is commonly a round or oval, totally bald, smooth patch involving the scalp or any hair bearing area on the body (Figure 2.7). The patch may have a mild peachy or pinkish-red color (Figure 2.7). Hair loss is seen both as intact and as fractured hairs (Figure 2.7). The intact hairs are dystrophic anagen or telogen hairs. The fractured hairs develop owing to damage involving both cortex and medulla, resulting in distal fractures.120 These hairs are described as ‘exclamation-mark’ hairs, because the distal segment is broader than the proximal end (Figure 2.7).

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.6 Alopecia universalis for 1 year in a 3-yearold girl. (a) Front view showing loss of hair on scalp, eyebrows, and eyelashes. (b) Side view. (c) Back view. This early-onset form of AA is associated with greater severity, longer duration, and greater probability of a positive family history of AA. HLA studies suggest this early-onset group of severe AA patients are a genetically distinct group. They are prognostically and therapeutically distinguishable, too.

The pull test may be positive at the margins of the patch, indicating very active disease. Although hair loss is usually asymptomatic in most cases, some patients describe paresthesias, with mild to moderate pruritus, tenderness, burning sensation or pain, before the appearance of the patches. The clinical presentation of alopecia areata is subcategorized according to pattern or extent of the hair loss. If categorized according to pattern, the following forms are seen: patchy AA—round or oval patches of hair loss (most common);

reticular AA—reticulated pattern of patchy hair loss; ophiasis-bandlike AA—hair loss in temporo-occipital scalp; ophiasis inversus (sisapho)119—a rare bandlike pattern of hair loss in fronto-parieto scalp (the exact opposite of ophiasis);121 and diffuse AA—a diffuse decrease in hair density over the entire scalp (Figure 2.8). If categorized by extent of involvement, the following forms may be seen: alopecia areata: partial loss of scalp hair; alopecia totalis: 100% loss of scalp hair; and alopecia universalis: 100% loss of hair on scalp and body (Figure 2.9).

Alopecia areata

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Figure 2.7 Alopecia areata circumscripta. Patients frequently present with just a patch. (a) A single small circular patch. (b) A single large circular patch totally devoid of hair ‘bare as a baby’s bottom’. (c) The patch may be skin-colored with broken-off hairs. (d) The color of an AA patch may be peach, (e) Another peach-colored patch of AA. (f) The AA patch may be red. This patient complained of burning on the patch before the hair fell out.

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Hair Loss: principles of diagnosis and management of alopecia

(g) Exclamation point hairs may be seen during an active phase of the condition. (Courtesy of Dr Harvey Lui.) (h) Circumscript patches can be very constant and persistent. This is a patch on a 40-year-old male that has been present in the same place and has been the same size for 10 years. He has not had any other spots for over a decade. (i) Simultaneous circumscript alopecia in mother and son.

Alopecia areata

Figure 2.8 Clinical forms of AA based on pattern: (a) Patchy alopecia areata in multifocal areas. (b) Reticulated patches in AA. (c) Ophiasis (d) Simultaneous ophiasis in mother and daughter. (e) Sisapho—the diametric opposite of ophiasis, mimicking androgenetic alopecia. (f) Early diffuse A A with no distinct patches. (g) Advanced diffuse AA.

33

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.9 Clinical forms of AA based on extent: (a) Alopecia areata with its characteristic circular patches. (b) Alopecia totalis affecting 100% of the scalp. (c) Alopecia universalis in an adult affecting all hairs on the body, including eyelashes and eyebrows.

Any hair-bearing surface can be affected. Where there is hair, there can be alopecia areata! Beard AA is very common, as well as body AA, affecting the limbs or the thorax area. (Figure 2.10 and 2.11). Most patients present with the limited patchy type that is easily camouflaged. The initial regrowth in AA is frequently white, followed by repigmentation. Frequently AA preferentially affects pigmented hair, and only the white hairs remain (Figure 2.12). Both regrowth in one site and extension of the alopecia on another site may be seen at the same time in the same patient.

Nail dystrophy may be associated with AA. The reported incidence of onychodystrophy in AA ranges from 10 to 66%,122 depending on how diligently it is looked for. Changes may be seen in one, many or all the nails. The dystrophy may precede, coincide or follow resolution of the AA. Pitting with an irregular pattern or in organized transverse or longitudinal rows, trachyonychia (longitudinal striations resulting in sandpaper appearance), Beau’s lines (grooves through the nail matching that of the lunula’s margin), onychorrhexis (superficial splitting of the nail extending to the free edge), thinning or thickening

Alopecia areata

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Figure 2.10 Extracranial AA: (a) AA affecting just the eyelash. (b) AA affecting one eyebrow. (c) AA affecting the chest. (d) AA affecting the dorsa of the arms. (e) A A affecting just the lateral portion of the leg.

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.11 Alopecia areata of the beard is very common. (a) Random patches on the beard area. (b) The characteristic peach color on an A A of the beard. (c) Extensive AA of the beard, but not affecting the great head of dreadlocks.

(pseudomycotic), onychomadesis (onycholysis with nail loss), koilonychia (concave dorsal nail plate), punctate or transverse leukonychia and red spotted lunula may be associated with AA.123-128 (Figure 2.13).

Prognosis The only predictable thing about the progress of the AA is that it is unpredictable. Patients usually present with several episodes of hair loss and hair regrowth during their lifetime. The recovery from hair loss may be complete, partial or non-existent. The majority of patients will regrow their hair entirely within one year without treatment. However, 7–10%

Alopecia areata

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Figure 2.12 White hairs, vitiligo and alopecia areata. (a) Hair regrowth in a young child who had been diagnosed as a case of trichotillomania. The white hair regrowth proves the diagnosis had always been AA. (b) and (c) White regrowth on the side of the scalp. (d) White regrowth in an area of previous ophiasis.

can eventually end up with the severe chronic form of the condition. Poor prognostic indicators are atopy, the presence of other immune

diseases, a positive family history of AA, a young age of onset, nail dystrophy, extensive hair loss and ophiasis.82,129

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Hair Loss: principles of diagnosis and management of alopecia

(e) Circumscript AA, sparing white hairs. (f) AA and vitiligo in the same person. (g) White moustache in a vitiliginous area in the patient illustrated in 12f.

Differential diagnosis Clinically, the differential diagnosis is usually between telogen effluvium, androgenetic alopecia (AGA), trichotillomania, traction alopecia, triangular temporal alopecia, pressure-induced alopecia, tinea capitis and pseudopelade (Figure 2.14). In telogen effluvium, hair loss is generalized over the whole scalp, whereas in AA it is usually patchy. Hairs

that are shed are either telogen or dystrophic anagen in AA, and purely telogen in telogen effluvium. Patients with AGA usually demonstrate the typical predictable pattern of balding, and shedding is not prominent. The pull test is usually negative in AGA. In trichotillomania and traction alopecia twisted and broken hairs are frequently evident. In tinea capitis, usually, there is an inflammatory component. However, non-inflammatory tinea

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Figure 2.13 Nail changes and alopecia areata. (a) Trachyonychia, and red-spotted lunula on the fingernails. (b) Red-spotted lunula on the toenails. (c) Koilonychia present in AA. (d) and (e) Severe nail dystrophy in AA.

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.14 Differential diagnosis of AA. (a) This is an early case of biopsy-proven diffuse AA which can be difficult to differentiate from telogen effluvium. (b) Temporal triangular alopecia can mimic AA. (c) AA may be linear and mimic morphea. (d) Morphea mimicking AA. It is crucial to look for the presence of follicular ostia, which may be difficult to see on a shiny smooth scalp. (e) & (f) AA

Alopecia areata

41

mimicking AGA in a female patient. (g) Trichotillomania, which can easily mimic AA. (h) Simulaneous trichotillomania in a mother and daughter. (i) Broken hairs in trichotillomania. (j) & (k) Pseudopelade mimicking AA. Note the loss of follicular ostia. (l) Post surgical pressureinduced alopecia can appear like AA, but usually has a significant scarred component to it.

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Hair Loss: principles of diagnosis and management of alopecia

capitis may be most difficult to distinguish from AA. Look for the characteristic scaling in tinea capitis. A KOH preparation and fungal culture may be necessary to distinguish noninflammatory tinea capitis from AA. Woods light examination may help if the patient is in or has been in an area where the fluorescent tineas predominate. In British Columbia, the most common cause of tinea capitis is Microsporum canis, which does fluoresce. Temporal triangular alopecia (TTA) may mimic AA. The lifetime incidence of TTA is 0.11%.130 This is ten times less frequent than AA. Lesions present as a triangular, oval or lancet-shaped patch of non-scarring alopecia overlying the fronto-temporal suture. There is controversy as to whether the lesions are present at birth or acquired later in life. A biopsy may occasionally be necessary to distinguish TTA from AA. Histologically, peribulbar lymphocytic infiltrates are not present. Pressure-induced alopecia131–134 (PIA) may also mimic AA. Usually the history of coma or surgery is present. Clinically, there is usually some scarring with PIA. Occasionally in AA, the scalp may be so shiny and smooth that follicular ostia may be difficult to see, and patchy AA may be difficult to differentiate from pseudopelade. A 4 mm punch biopsy may be necessary to make a definitive diagnosis in some cases.135 Diffuse AA can be especially difficult to diagnose clinically from other non-cicatrizing alopecias. See above for histologic differentiation of noncicatrizing alopecias.

Treatment Modern therapy for AA is best appreciated within a historical framework. Bateman,136 in the 1800s, wrote about AA and concluded that

the application of a caustic substance with the subsequent production of bullae was often successful in the treatment of AA. He advocated the use of ointments prepared with oil of mace, turpentine, mustard and black pepper. Although this may seem crude, some current treatment regimens have similar objectives. They cause blisters and erythema, and an immunologic patient response to modify the perifollicular immunologic milieu. Despite the advance of medicine over the last 200 years, some of the fundamental principles in the treatment of AA remain unchanged. There is great difficulty in evaluating the literature on treatment modalities for alopecia areata, as there is so much variability as to baseline patient populations and the terms ‘successful regrowth’ or ‘responders’. Most studies have grouped patients with alopecia totalis (AT) and alopecia universalis (AU) with those with just patchy alopecia areata (AA). There is no question that AT/AU is a distinct prognostic and therapeutic group, and results can be skewed by this more difficult and severely affected population. There is a paucity of studies that distinguish AT/AU from patchy AA. This lack of stratification of patient population can have a profound influence on evaluating therapeutic efficacy. Unfortunately, the treatment of AA is very difficult, and there are no consistently reliable treatments. While the FDA has never approved any drug for AA, this does not mean that there are no effective treatments. Evaluating efficacy is most difficult, especially for patchy AA, as it is so unpredictable and frequently improves on its own. In order to prove efficacy with sufficient power and statistical significance, large patient populations are necessary. Most published studies for AA have been small. Half-head studies are very powerful; but again, much of this published work has involved patient

Alopecia areata

populations with a preponderance of AT/AU. The new Alopecia Areata Investigational Assessment Guidelines are helpful in establishing criteria for selecting and assessing patients for clinical studies of AA, facilitating collaboration, comparison of data, and measuring the extent of scalp involvement.137 These guidelines highlight the fact that AT and AU are considered a separate entity from AA, and must be separated out in order to determine the efficacy of any trichogenic agent. It is of paramount importance that dermatologists should be knowledgeable and conscious of this important segregation when evaluating modalities in the treatment of AA. Otherwise, all results are skewed and will probably show ineffectiveness. The terms ‘responder’ and ‘successful regrowth’ are not used in the same way from one study to another. The Guidelines help us to evaluate what is ‘successful regrowth’. Most dermatologists consider successful regrowth to be cosmetically acceptable regrowth, meaning being able to abandon one’s wig or cap. When comparing studies, it is important to ascertain clearly what the authors have defined as a ‘responder’. At present, all treatments are palliative, only controlling the problem, and not curing the condition. All local treatments may help the treated areas, but do not prevent further spread of the condition. In addition, any mode of treatment may require long periods of usage, owing to the chronic nature of AA. At the present time, topical, intralesional and systemic steroids, topical immunotherapy, anthralin, minoxidil and photo-chemotherapy are available for the treatment of AA. Treatment guidelines for AA have been published by the American Academy of Dermatology.138 All treatment plans for patients depend on three major factors: the extent of scalp involvement, the age of the patient, and the motivation level of the patient.

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Corticosteroids The main mechanism of action is immunosuppression. However, some biochemical abnormalities relating to steroid chemistry have been discovered in AA patients by Sawaya and Hordinsky.139 They showed that patients with AA have abnormalities in glucocorticoid receptors (GCR) for type 2 binding. This receptor is found to influence long-term, slowgrowth cellular processes. Scalp biopsies from 15 untreated AA patients showed a twofold increase in unoccupied GCR. This suggests suppressed cellular transcription. It was found that low concentrations of calmodulin stimulate a cytosol kinase, and thus hormone binding to GCR. This suggests that patients with AA have abnormalities in type 2 GCR activation because of abnormal calcium-calmodulin metabolism. These abnormalities may explain why patients with AA show a varied response in hair area growth when treated with glucocorticoids.139 Topical corticosteroids Fluocinolone,140,141 halcinonide142 and dexamethasone in a penetration-enhancing vehicle have been reported to have some success.143 Only one of these studies was performed in a double-blind controlled manner. Price and Khoury144 have not had success with topical steroids. Fiedler145 believes that a combination of 0.05% betamethasone dipropionate cream and minoxidil may be more beneficial than either alone. She reports that quality of response in severe recalcitrant AA was fair to good after 16 weeks of treatment with placebo in 13%, with 0.05% betamethasone dipropionate in 22%, with 5% minoxidil in 27% and with 5% minoxidil and 0.05% betamethasone dipropionate in 56%. This suggests a synergistic benefit of using both modalities.

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.15 Intralesional corticosteroid injections for AA. (a) Injecting triamcinolone acetonide 5 mg/ ml with a 3 ml syringe and a 30 gauge needle. (b) Patch of alopecia before injection. (c) Same patch after 2 months of injections. (d) Best position for injecting eyebrows: patient lying flat, physician positioned at one end of the table and approaching with needle from the top of the patient.

Alopecia areata

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(e) Injection of eyebrows with triamcinolone 2.5 mg/ml for a total of 0.5 ml per eyebrow. (f) Regrowth in eyebrow area after 4 weeks. Injections are performed every 4 weeks, with the next set in between areas of regrowth. (g) Atrophy secondary to injection with triamcinolone acetonide 40 mg/ml, which is at least 4–8 times what is recommended.

Intralesional corticosteroids Intralesional corticosteroid injection is first-line therapy for adult patients with less than 50% of scalp involvement.146 For circumscribed AA, intradermal corticosteroids remain the therapeutic standard.147 They are not indicated when more than 50% of the scalp is involved. Porter and Burton148 demonstrated response rates of 64% using triamcinolone acetonide and 97% using the less soluble and more atrophogenic triamcinolone hexacetonide. Price, 146 Shapiro,149 Mitchell and Krull,129 Whiting,150 Bergfeld,151 and Thiers152 prefer triamcinolone acetonide. Concentrations of triamcinolone ac-

etonide vary from 2.5–10.0 mg/ml diluted either in xylocaine or sterile saline. Price146 prefers 10mg/ml, Whiting150 prefers 5–10 mg/ml. Shapiro149 prefers 5 mg/ml. Bergfeld prefers 2.5–5.0 mg/ml151 and Thiers152 prefers 3.3 mg/ ml. At the University of British Columbia Hair Clinic, for scalp A A, we inject a concentration of 5 mg/ml with a maximum total of 3 ml of triamcinolone acetonide. A weaker concentration of 2.5 mg/ml is used for the beard area and the eyebrows. Triamcinolone acetonide is administered with a 0.5 inch long 30-gauge needle as multiple intradermal injections of 0.1 ml per site, approximately 1 cm apart. Initial regrowth is often seen in 4–8 weeks. Treatments

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.16 The chronic use of systemic steroids for AA can have significant side-effects. (a) & (b) Striae in a patient with alopecia universalis who had been on systemic steroids for 1 year.

are repeated every 4 to 6 weeks. The main sideeffect is minimal transient atrophy. This can be prevented by avoiding injections that are too great in volume per injected site, too frequent, or too superficial (intraepidermal). Topical anesthesia cream (2.5% lidocaine and 2.5% prilocaine in a cream) in a thick layer with occlusion 1 hour prior to injection can be used. However, this cream can be difficult to use on the hairy scalp. Children under 10 years of age are not usually treated with intralesional steroids owing to the local pain at the injection sites. After 6 months of treatment, if there is no response, discontinue, intralesional corticosteroids, because these patients may lack adequate corticosteroid receptors in the scalp.139 (Figure 2.15). Ferrando et al.153 recently published a paper on the use of a multi-injection plate for intralesional corticosteroid injection of patchy AA. This disposable device has some advantages, in that it permits the simultaneous injec-

tion in 5–7 different points at a fixed distance, leading to uniformity in treatment applications. With this method there is only one painful stimulus instead of five to seven, and an extensive alopecic area can be treated in a shorter period of time. One disadvantage is the needle calibre. The 27 gauge needles are large, and therefore likely to produce pain if the procedure is not performed gently, and atrophy can occur if the application is not followed by a local massage that spreads the steroid solution uniformly through the treated area.

Systemic steroids Systemic corticosteroids are frequently effective in the treatment of AA, but their use is controversial. They are not routinely used, because of side-effects, and they do not alter the long-term prognosis (Figure 2.16). Abdulkareen et al.154 recently showed success

Alopecia areata

with systemic steroids in 38% of patients with extensive patchy AA and AT/AU. However, in all patients, once the steroid was discontinued, the hair fell out. At the UBC Hair Clinic, we use systemic steroids only in exceptional cases. Winter et al.155 reported the occurrence of numerous side-effects such as striae, acne, obesity, cataracts and hypertension while using alternate-day prednisone. The authors concluded that alternateday prednisone does not appreciably alter the course of AA. Unger and Schemmer,156 however, believe that the initial administration of somewhat lower doses of prednisone, 30–40 mg/d, together with the use of topical and intralesional steroids, frequently yields good results while minimizing the risk of side-effects. Price146 feels that systemic corticosteroids may be indicated in select patients with progressive AA, either to slow progression or to initiate growth. For patients weighing more than 60 kg with active, extensive or rapidly spreading AA, she recommends prednisone 40 mg/day for 1 week, 35 mg/day for 1 week, 30 mg/day for 1 week, 25 mg/day for 1 week, 20 mg/day for 3 days, 15 mg/day for 3 days, 10 mg for 3 days and 5 mg for 3 days. She will use this regimen in combination with minoxidil 5% solution twice daily with or without intralesional corticosteroid injections every 4– 6 weeks. For active, less extensive AA, she uses prednisone 20 mg daily or every second day, which can be tapered slowly by decrements of 1 mg after the condition is stable. Whiting150 has found systemic steroids useful in reversing some cases of rapidly progressing alopecia that appear to be evolving into alopecia totalis. In adults, prednisone, 20–40 mg/d for 1–2 months may be necessary to control the hair loss. Reduction of the dosage after that depends on the patient’s progress. Whiting tries to maintain hair regrowth with the lowest possible dose

47

of prednisone, even if it is necessary to continue it for 6 months or until concomitant treatments such as minoxidil can take effect. Sharma et al. have used pulsed oral prednisolone at 300 mg once per month for a minimum of 4 months for patients with extensive patchy AA and AT/AU.157 They showed an initial response at 2.4 months and a 58% success rate for cosmetically acceptable regrowth after 4 months. They feel this treatment is safe on an outpatient basis. This study was uncontrolled. The long-term safety of this regimen has yet to be determined. Intramuscular corticosteroid therapy has a very high rate of recurrence, and as a result has very little to offer patients.158 Pulse therapy with intravenous methylprednisolone 250 mg twice daily for three successive days for rapidly progressive extensive multi-focal AA was found to be effective in controlling the active phase of hair loss. Twelve out of 20 with extensive patchy disease showed 50–100% regrowth after 12 months. This regimen was not effective for ophiasic AA or AT/AU.159 This study was not controlled, and a controlled-randomized study needs to be performed to confirm efficacy. The treatment of AA with systemic steroids is not recommended for children.

Minoxidil Minoxidil is a biologic response-modifier that enhances hair growth. Minoxidil stimulates follicular DNA synthesis, has a direct effect on the proliferation and differentiation of follicular keratinocytes in vitro, and regulates hair physiology independently of blood flow influences.144,160 Minoxidil does not have an immunomodulatory effect. 161 Topical minoxidil 5% solution is the most effective concentration compared to other lower con-

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Hair Loss: principles of diagnosis and management of alopecia

Figure 2.17 The use of minoxidil and topical betamethasone dipropionate. (a) 4-year-old patient with a 2year history of AA. (b) After 8 months of treatment there was cosmetically acceptable regrowth. It is difficult to know if this was truly the effect of therapy or spontaneous regrowth.

centrations.162–166 There clearly is a dose-response effect.162–166 Cosmetically acceptable hair regrowth using topical 5% minoxidil solution has been shown in approximately 40% in patients, with 20–99% scalp involvement after one year.163 More successful results are seen in less severe cases of the disease. This treatment should not be expected to be effective in patients with alopecia totalis/ universalis.163 At the University of British Columbia Hair Clinic only the extrastrength topical minoxidil 5% solution is used for patchy AA. It must be applied twice daily. Initial hair regrowth is usually seen after 12 weeks. The response is usually maximized at 1 year. It must be continued until remission occurs. It can be used on the scalp and eyebrows. It can also be used on the beard area in men. There are negative studies with topical minoxidil.167–169 However, all these studies did not maximize on the 5% solution. More im-

portant, the vast majority of patients within these studies had AT/AU. One would not expect efficacy with topical 5% minoxidil solution in this difficult sub-population. The efficacy of minoxidil solution can be enhanced with anthralin170 or betamethasone dipropionate.145 In combination with topical minoxidil, anthralin is applied 2 hours after the second minoxidil application. Betamethasone dipropionate cream is applied twice daily, 30 minutes after each use of minoxidil (Figure 2.17). Although combination therapy has been found to be more effective than monotherapy, this therapy is not effective in patients with alopecia totalis/ universalis. Side-effects of minoxidil are rare. These include local irritation, allergic contact dermatitis and facial hair growth (Figure 2.18), which tends to diminish with continued treatment. Systemic absorption is minimal.146

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Figure 2.18 Hypertrichosis with topical minoxidil solution. (a), (b) 5-year-old boy who had used topical 5% minoxidil solution for over 6 months. There is marked symmetrical hypertrichosis on the forehead and cheeks.

Anthralin Anthralin may have a non-specific immunomodulating effect (anti-Langerhans cell), as it does in psoriasis.171 Clinical irritation is not necessary for efficacy, just as clinical irritation is not necessary in psoriasis. There are citations in the literature that suggest that skin irritants are not effective in AA.172,173 Cosmetically acceptable regrowth has been reported to vary from 20% to 25% for patchy AA.174 Schmoekel et al.175 have shown with photographs that anthralin has benefit in a half-head study and is effective for patchy AA. Anthralin 0.5%–1.0% cream is applied once daily.146,147,149,174 Short-contact therapy is preferred. It is left on 20–30 minutes daily for 2 weeks, and then 45 minutes daily for 2 weeks, up to a maximum of 1 hour daily. It is

not to be used on the eyebrows or the beard area. Some patients may tolerate overnight therapy.146 When therapy is effective, new hair growth is usually seen within 3 months. It may take 24 or more weeks for a cosmetically acceptable response. Because of its good safety profile, anthralin is a good choice for children. Combination therapy with minoxidil may have a synergistic effect, as was mentioned above.170 Nelson and Speilvogel report a negative study with anthralin.176 However, AT/AU patients were grouped in with patchy AA in this small study of 10 people—it is not specified how many AT/AU. It is unlikely that anthralin has as much efficacy, if any, in AT/AU as it does in patchy AA. Side-effects of anthralin are irritation, scaling, folliculitis, and regional lymphadenopathy. Patients are cautioned to avoid getting

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Hair Loss: principles of diagnosis and management of alopecia

Alopecia areata

Figure 2.19 Anthralin for alopecia areata. (a) 27-year-old female with AA for 8 months. Baseline, left side; treated with anthralin 1 % cream for 1 hour daily. (b) Baseline, right side; untreated side. (c) 4 months of treatment: left (treated) side showing regrowth. (d) 4 months of treatment: right (untreated) side showing regrowth, but less than the treated side. There was clearly unilateral preference for the treated side. (e) Unilateral preferential regrowth of hair with anthralin on the C3H/ HeJ mouse on the treated half. (f) Marked redness can occur from anthralin.

anthralin into the eyes, to protect treated skin against sun exposure, and to be aware of staining of the treated skin, clothes and linens (Figure 2.19).

Topical immunotherapy Topical immunotherapy is the most effective therapeutic modality with the best safety profile in the treatment of chronic severe AA. Systemic steroids may be the most effective modality, but their safety profile is unacceptable to most dermatologists. Three contact sensitizers have been used extensively in alopecia areata—dinitrochlorobenzene (DNCB), squaric acid dibutyl ester (SADBE) and diphenylcyclopropenone (DPCP). The mechanism of action of topical immunotherapy is unclear. The immunomodulating effect of the topical sensitizers is supported by

51

a decrease in the peri-bulbar CD4+/CD8+ lymphocyte ratio,177 and a shift in the position of the T-lymphocytes away from perifollicular areas to the interfollicular area and dermis.99,100 It has been suggested that the immunogen may attract a new population of T cells into the treated area of the scalp that could eliminate the antigenic stimulus present in AA. 178 Happle has proposed the concept of antigenic competition.179 This theory presumes that the generation of T-suppressor cells into the area may exert a non-specific inhibitory effect on the autoimmune reaction to the hair-associated antigen, and thus allow hair to regrow. Immunogens may interfere with the initial or continued production of proinflammatory cytokines by the follicular keratinocytes. Careful dissection of the mechanism by which contact dermatitis is able to suppress alopecia areata is important, because it may be possible in the future to mimic the effect on the dermatitis by providing specific cytokines or specific inhibitors of cytokines.

Dinitrochlorobenzene Rosenberg and Drake178 first reported regrowth of hair in two patients following application of DNCB. The overall efficacy of DNCB treatment for AA has been investigated and has varied from 25% to 89%.180,181 Concerns have been raised about the safety of DNCB. DNCB is rapidly absorbed after topical application, with 53% recoverable in the urine. Excretion is primarily renal, and serum half life is 4 hours. Kratka et al.,182 Stobel and Rohrborn183 and Summer and Goggelman184 found DNCB to be mutagenic in Salmonella typhimurium in the bacterial plate incorporation assay (Ames assay). Therefore, extreme caution must be used with DNCB. The issue of DNCB safety is controversial. Weisburger et al.185 found DNCB to

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Hair Loss: principles of diagnosis and management of alopecia

be non-carcinogenic when fed in large doses to mice and rats up to 4 months. The purity of DNCB samples is also an issue. Certain chloronitrobenzenes that are known mutagens are possible contaminants in preparations of DNCB.186 Side-effects of DNCB include a marked blistering reaction, auto-eczematization, adenopathy, urticaria and tolerance. Tolerance can sometimes be reversed with cimetidine 300 mg orally three times a day for 3–4 weeks.129

Squaric Acid Dibutyl Ester Happle achieved good results in 70% of patients treated with topical squaric acid dibutyl ester (SADBE). 187 Flowers et al. 188 found SADBE to be effective in 4/8 cases. Case et al.189 showed excellent responses in 11/26 (52%) of cases. Caserio190 showed a success rate of 28% (4/14 cases). Giannetti and Orecchia191 reported a good response in 5/26 cases. Micali et al.192 showed a 49% success rate in 73 cases with over 50% scalp involvement. Chua et al.193 reported a 68% (13/19) success rate in a half-head study. Orecchia194 has used SADBE in children under 13 and showed a 32% (9/28) chance of cosmetically acceptable regrowth. Tosti et al.195 also treated children, with an initial success rate of 30% (10/33). Two-thirds of the initial responders no longer responded to the SADBE, with subsequent relapses over the long term. Barth et al.196 showed only minimal signs of terminal hair regrowth in 3/17 patients and do not recommend the use of SADBE in AA. Orecchia et al.197 used SADBE in combination with PUVA on three patients and did not find increased efficacy with combined treatment. They concluded that the two associated therapies showed an impaired efficacy because of the inhibition of the SADBE action by PUVA. PUVA impairs Langerhans cells, and

thus inhibits induction and elicitation of allergic contact dermatitis. PUVA also results in a systemic immuno-suppression through direct or indirect (via interleukin-1) stimulation of prostaglandins (PGE2), with the effect of an efferent lymphatic blockade. This would clearly affect any benefits of a contact allergen. SADBE has been shown to be Amesassaynegative. No mutagenic contaminants were detected on gas chromatography-mass spectrometry.198 Furthermore, lifetime subcutaneous injections of squaric acid into ICR/Ha Swiss mice resulted in a low incidence of tumors at the injection site, equaling that of control animals.199 It is an ideal immunogen in that it is a strong topical sensitizer, is used only rarely in industry, is not found in the natural environment and does not react with other chemicals. However, it loses its stability in the presence of water.

Diphenylcyclopropenone Diphenylcyclopropenone (DPCP) has been used not only in the treatment of alopecia areata, but also as an immunomodulator in the treatment of melanoma200 and warts.201 Efficacy in alopecia has varied from study to study. Van der Steen et al.202 showed a response rate (on 139 patients) of 50.4%, with excellent or satisfactory results. Of 107 who showed a unilateral response, 30 relapsed and were resistant to further therapy. In 8/ 107, a tolerance phenomenon was seen, defined as a required continuous increase in DPCP concentration until a concentration of 2.0% was reached without producing an adequate dermatitis, resulting in loss of all regrown hair. In 3/107, a paradoxical regrowth of hair on the untreated side of the scalp was seen. This phenomenon is known as castling.

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MacDonald-Hull and Norris203 reported 29% (8/28) of patients had a cosmetically acceptable result. MacDonald-Hull and Cunliffe204 studied post-therapy relapse rates within 6 months after treatment. They found that 7 of 19 (37%) showed no hair loss after treatment had been stopped for 6 months. In 68%, the appearance of the scalp 6 months later was cosmetically acceptable, although 53% developed patchy alopecia and 10% lost all hair that had re-grown. In 1991, MacDonald Hull et al.205 reported further results with DPCP on a larger series of patients. Of 78 patients, 25 (32%) showed complete regrowth of hair. The authors felt that eliciting an allergic reaction was an integral part of successful treatment resulting in hair growth. Wiseman et al.206 utilized Kaplan-Meier survival analysis to determine cosmetically acceptable regrowth over time and a cox regression model to determine factors predictive of regrowth in the largest series to date of 148 AA patients. Using the survival analysis model, the cumulative patient response at 32 months was 77.9%. A cosmetically acceptable endpoint was obtained in 17.4% of subjects with 100% hair loss, 60.3% of subjects with 75–99% hair loss, 88.1% of subjects with 50–74% hair loss, and 100% of subjects with 25–49% hair loss. A lag period of 3 months was present between initiation of therapy and detection of the first clinical response. Factors affecting response were clearly extent of condition and age of onset. Those patients with a younger age of onset are less likely to respond. It appears those with AT/ AU and an early age of onset are prognostically a separate group. This fits well with Colombe et al’s8 data that this group is a distinct sub-population of AA. Duration of condition, the presence of atopy and nail changes were not correlated to response. Gordon et al.207 showed that 38% of 48 patients responded to DPCP with cosmetically acceptable regrowth. Pericin208 showed that in

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68 patients, 70.6% showed a response, with complete regrowth in 30.9%. The only prognostic indicator correlated with response was extent of the condition. Monk209 showed cosmetically acceptable results in 33% (6/18). Hatzis et al.210 showed satisfactory regrowth in 24% (11/45). Ashworth et al. showed efficacy in only 1/26.211. Orecchia and Rabiossi212 also had a success rate of 1/26. Berth-Jones and Hutchinson213 showed only an 18% response rate over 6 months, with no significant difference in response with inosine pranobex (inosiplex). Shapiro et al.214 showed that topical 5% minoxidil solution combined with DPCP showed no benefit over DPCP alone. Regarding children, MacDonald-Hull et al.215 treated 12 children aged 5–15 years, with 33% showing complete regrowth. Six months after treatment was discontinued three of the four children with complete regrowth maintained their hair. DPCP is not mutagenic in the Ames test, and teratogenicity and organ toxicity could not be detected in the hen’s egg test or in the mouse teratogenicity test.216 Analysis on serum and urine samples following application of at least 0.5 ml of a 1% solution of diphencyprone to the scalp of 18 patients under treatment for alopecia areata revealed no detectable amounts of diphencyprone in any sample of serum or urine from these subjects. These data suggest that diphencyprone is not absorbed following application to the skin.217 Commercial DPCP may contain a precursor, dibromoketone, that is positive in the Ames test.218,219 It is therefore recommended that all DPCP samples be purified as described by van der Steen et al.216 or that a pharmaceutical chemist do high-pressure liquid chromatography on the DPCP sample to ensure that there are no detectable amounts of this dibromoketone compound. DPCP is degradable upon exposure to light, and must be stored

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Figure 2.20 Topical immunotherapy for alopecia areata. (a) Standard diphencyprone (DPCP) tray concentrations varying from 0.0001–2.0%. (b) Intermediate concentrations may be necessary. (c) DPCP is stored away from the clinic in the fridge in a plastic container. (d) The cotton is wound around the stick to make a reinforced swab approximately three times the thickness of an average cotton-tipped applicator. (e) The physician or nurse must wear gloves when

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handling the bottles. (f) After the application, gloves must be removed carefully from the inside out. (g) Cotton swab is dipped directly into the bottle. If the swab needs to be remoistened, an eyedropper is used to saturate the swab. (h) An area that has been sensitized one week before with a 2% solution. (i) and (j) One coat is painted is the anteroposterior direction. k. Another coat is painted in the lateral direction. Only unilateral application is performed until hair regrowth is seen on one side.

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in amber bottles. At the University of British Columbia, DPCP is dissolved in acetone and stored away from the staff in the fridge in a special container. For adults with more than 50% scalp hair loss, topical immunotherapy with DPCP is our treatment of choice at the University of British Columbia Hair Clinic. We use DPCP on patients with less than 50% hair loss only if all other modalities have failed, such as intralesional corticosteroids, topical minoxidil 5% solution in combination with topical corticosteroids, or topical anthralin. As Peret and Happle220,221 suggest, patients should be thoroughly informed about the experimental character of the treatment, the lack of sufficient toxicologic data, the chance for regrowth, the possible side-effects, and the possible failure to respond. Patients must be warned that the induction of an allergic contact dermatitis is a desired side-effect, and one that is necessary for a good result. A local ethics committee should be asked for consent. DPCP is used at the University of British Columbia Hair Clinic as follows: Prior to commencing treatment, risks and benefits are carefully reviewed with all patients and an informed consent is signed. The patient is encouraged to meet with and observe other patients undergoing treatment. Post-treatment guidelines for the patient include: 1. Scalp/hair should not be washed in the 48 hours following treatment. 2. The scalp must be protected from all sources of light. The wearing of a hairpiece or scarf is sufficient. 3. A commitment is made to return for weekly treatments for at least 24 weeks. 4. A low-potency topical corticosteroid is given to the patient for mild inflammatory reactions post-treatment. The physician must be notified of severe reactions.

DPCP is compounded in an acetone base and stored in opaque bottles to protect the solution from photodegradation. All bottles are dated on first use, because we have found that the shelf life after opening is approximately 6 months. We periodically check the DPCP for purity with high-pressure liquid chromatography. All the screw-top lid bottles of DPCP are stored in a large plastic bin with a lid to prevent both accidental spillage and inadvertent staff sensitization. The standard DPCP tray for AA includes the following concentrations: 0.0001%, 0.001%, 0.01%, 0.1%, 0.5%, 1.0% and 2%. Intermediate concentrations may be necessary. The transition from 0.1% to 1.0% is best bridged with a 0.5% solution of DPCP (Figure 2.20). Although not routinely used, it has occasionally been necessary to use 0.05% and 0.25% strengths for sensitive patients. Safety precautions must be implemented when handling DPCP, because of the risk of sensitization of staff administering the treatment. Gloves must be worn and caution used to prevent the DPCP from coming in contact with the skin of the staff member. If the person administering the DPCP develops eczema, the use of a barrier cream and double gloving is helpful. A gown covering the arms should be worn and laundered after each treatment session. Spills should be wiped up immediately using a dry towel, followed by a moist towel, to eradicate all traces of the DPCP. There is a report in the literature where DPCP treatment had to be abandoned in a clinic owing to the large number of staff becoming sensitized to DPCP.222 The DPCP solution is applied to the scalp using a thick cotton swab that has been dipped into the bottle. If the swab needs to be remoistened, an eye-dropper is used to saturate the swab and prevent contamination. These swabs are constructed with long wooden applicator sticks and cotton balls. The

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Figure 2.21 40-year-old female with an 18-year history of alopecia involving 99% of the scalp. (a) baseline. (b) 12 weeks of unilateral DPCP treatment. (c) 24 weeks of unilateral treatment. (d) 30 weeks of treatment of the left side and 6 weeks on the contralateral side. (e) 1 year of treatment. (f) 5 years of intermittent treatment.

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Figure 2.22 Ophiasis in a 43-year-old female of 2 years’ duration. (a) baseline. (b) 12 weeks of DPCP treatment, showing some white regrowth. (c) 24 weeks of DPCP treatment.

cotton is wound around the stick to make a firm swab approximately three times the thickness of an average cotton-tipped applicator (Figure 2.20). Cotton-tipped applicators do not retain enough moisture to paint the scalp adequately. Once the patient commits to DPCP treatment, an initial sensitizing dose of 2% DPCP is administered to a 4×4 cm circular area on the occipital region of the scalp, Patients return for weekly visits until hair growth is established. After 1 week, if no reaction or only a mild to moderate reaction is observed, a 0.0001% solution is applied to half the scalp. Two coats are applied, the first coat in an anteroposterior direction and the second coat in

a lateral direction. We avoid application on to the nape of the neck, as well as the area where the tape for the hairpiece is applied. If this area becomes irritated, it is difficult for the patient to continue wearing a hairpiece. The nape of the neck is a very sensitive area that will react when other parts of the scalp do not. This can be confusing when attempting to titrate the patient to the correct dosage. Titration must be conducted carefully, because severe reactions can discourage the patient and preciptate discontinuation of treatment. If there is a marked reaction, we do not apply any solution until the following week. DPCP is left on the scalp for 48 hours and then washed off. The patient must protect the scalp from light with a cap,

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wig or scarf during this period of time, as DPCP is degraded when exposed to light. The following week, DPCP is reapplied to the same half of the scalp. The aim is to maintain erythema and pruritus, or a low tolerable eczema, on the treated side for 36–48 hours after application. The concentration is adjusted individually on the basis of the severity of the previous reaction. Concentrations vary (0.0001%, 0.001%, 0.01%, 0.05%, 0.1%, 0.5%, 1.0%, 2.0%). Once hair growth is established one one side, the other side is treated (see Figure 2.20). Each week when the patient returns, the severity of reaction and the presence of any hair growth are assessed. The tolerance to the discomfort from the eczema varies with patients. It is important to listen to your patients. It is better to be cautious than to be very aggressive and cause a severe reaction.

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Figure 2.23 Unilateral treatment with DPCP, showing circular areas refractory to treatment. These refractory areas can be injected once monthly. DPCP is applied weekly for 3 weeks out of every month. Intralesional corticosteroid is injected once monthly.

Figure 2.24 Delayed DPCP response. The patient had been treated unilaterally for 6 months without a response. (a) She returned to the clinic after treatment had been discontinued for 6 months with a unilateral response on the treated side. (b) Both sides were then subsequently treated, with full regrowth.

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Figure 2.25 Treatment of eyebrows with DPCP. (a) Position used to apply DPCP to eyebrows. Eyes are well shielded. (b) Baseline before treatment in a 40-year-old female with no eyebrows for 18 years. (c) Complete regrowth with treatment.

Figure 2.26 Eczematous eruptions from DPCP. (a) Unilateral eczematous response one week after application. This reaction is too strong. No application for 1 full week with a lower concentration applied the following week. (b) Marked bulla formation is possible.

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(c),(d),(e) The neck area is a common area for a bad reaction. (f) Frontal unilateral edema and eczema. (g) Contact dermatitis to remote areas.

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Figure 2.27 Lymphadenopathy occurs in 100% of patients.

Figure 2.28 Pigmentary changes with DPCP: (a) Hypo- and hyperpigmentation (‘dychromia in confetti’) after 24 weeks of treatment in an East Indian patient. (b) The same patient, with most pigmentary changes resolved. (c) Hypo- and hyperpigmentation in an African-American patient. (d) Vitiligo on the back of the neck.

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If patients have discontinued treatment because of intolerable effects, it is difficult to get them to resume therapy. The strength can always be increased later when the patient becomes familiarized with the treatments. Once full regrowth has occurred (Figures 2.21 and 2.22), the frequency of treatment is gradually reduced, using the rule of four: treatment is adminstered every other week for 4 weeks,

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then every third week for 4 weeks, and so on. This reduction of visits continues until the patient experiences some hair loss and establishes the maintenance requirement. Maintenance requirements vary with individuals and commonly range from biweekly to bimonthly treatments. One patient was able to discontinue treatments for 4 years before she experienced any hair loss. The requirement for

(e) Vitilgo on half of the scalp in a patient who had been applying DPCP at home. (f), (g), (h). Vitiliginous patches on areas remote to the scalp.

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maintenance therapy illustrates the palliative nature of the treatment. Regrowth of hair will take at least 12 weeks. However, we have had patients that have taken 41 weeks to see unilateral regrowth. If the patient has not responded by 52 weeks, we consider the patient unlikely to respond, and we may abandon topical immunotherapy and proceed to another modality of therapy. In certain responders, most of the scalp regrows hair except for a few small areas refractory to DPCP. These resistant areas are treated with intralesional triamcinolone acetonide 5 mg/ml once monthly, and usually respond well (see Figure 2.23). We have had a few patients that we identify as ‘slow growers’. They consistently grow new hair in more areas and do not seem to lose hair. The process of complete regrowth is lengthy, with gradual new growth in multiple areas. Another phenomenon we have seen is the ‘initial non-responder’. These patients initially do not respond, and discontinue treatment. Within 2 years of stopping treatment, a small number of individuals have returned with hair growth only on the orginally treated side. Upon recommencing treatment, growth was obtained (Figure 2.24). DPCP has been used with success to treat eyebrows. Extreme caution must be used. The patient should be lying flat, the eyes shielded with gauze, and the swab should be minimally moist. This is best done at the end of the treatment, after the scalp has been treated (see Figure 2.25). Side-effects include eczema (Figure 2.26), autoeczematization,223 severe blistering and lymphadenopathy (Figure 2.27) in the neck behind the ears. Consort dermatitis to spouse/partner has also been reported.223 Shah et al.222 report the risk to medical and nursing staff. Pigment changes (Figure 2.28), such as hyperpigmentation, hypopigmentation,224 a combination of

both referred to as ‘dyschromia in confetti’225 and vitiligo226–229 have been reported. Vitiligo is more common in AA patients, and because vitiligo has a tendency to koebnerize on to inflamed skin, one must be very cautious about rapid extension of vitiligo in an AA patient who already has the condition. Vitiligo is a relative contraindication for treatment with topical immunogens. Extreme caution should be exercised when treating patients of dark pigmentation. Contact urticaria, 230,231 severe dermographism, 232 and erythema multiforme233 have also been reported. Because of the possible side-effects, we do not ever give DPCP to the patient for self-application. DPCP is contraindicated in pregnancy, although teratogenicity has not been demonstrated. All female patients are counselled to use reliable birth control while on DPCP. At our clinic, six women have become pregnant while on DPCP therapy, despite all the warnings on the informed consent form. DPCP therapy was immediately halted once our clinic was informed. All six pregnancies have produced normal children.

Photochemotherapy (PUVA) The mechanism of action of PUVA on AA is believed to be a photoimmunologic action.234 It may effect T cell function and antigen presentation, and possibly inhibit local immunologic attack against the hair follicle by depleting Langerhans cells. 234 (see Figure 2.29). The psoralen is administered either topically or orally, and is followed in 1 hour or 2 hours with UVA irradiation. Treatments are administered two to three times a week, with gradual increase in UVA dosage. Burns are more likely to occur with topical therapy, but ocular toxicity is avoided.

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Figure 2.29 PUVA therapy in alopecia areata: a 22-year-old patient with extensive alopecia affecting 95% of his scalp for 2 years. He was unresponsive to 24 weeks of topical immunotherapy with DPCP. (a) Baseline before PUVA. (b) After 1 year of PUVA. He still has refractory patches that are amenable to intralesional corticosteroid therapy.

Mitchell and Douglas234 used a combination of topical 0.1% 8-methoxypsoralen (8-MOP) and UVA and showed excellent regrowth in 8/ 22 (36.3%) and good regrowth in 2/22 (9%). Mean total UVA exposure for responders was 171.1 joules/cm2, with a mean total number of treatments of 47. Almost all the patients available for follow-up experienced relapse when PUVA was tapered. Claudy and Gagnaire 235 used systemic PUVA with total body irradiation and showed a success of rate of 70%. Larko and Swanbeck236 studied 40 patients with systemic PUVA, comparing whole body irradiation and scalp irradiation only. Whole body treatment did not produce significantly better hair growth. Thirty-five percent experienced hair regrowth, but only 20% experienced a full regrowth. Relapses were frequent, with median time to relapse being 10 weeks.

Lassus et al.237 studied 41 patients with oral 8-MOP and whole body irradiation, and local 8-MOP plus local UVA irradiation. No significant differences were seen. There was a response rate of almost 50% in each group. Only 10% relapsed after 6–12 months. The major problem with PUVA therapy is the high relapse rate that frequently sets in after tapering the treatment.238,239 Today’s concern about PUVA and its promotion of all types of skin cancer, including melanoma, 240 together with the need for long-term therapy in AA, make PUVA therapy less than satisfactory.

Cyclosporin Systemic cyclosporin has been shown to have some benefit in AA.60,61 (Figure 2.30). As with systemic corticosteroids, owing to the side-effect profile, the high recurrence rate following

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Figure 2.30 Cyclosporin in alopecia areata. (a) Mechanism of action by inhibiting the Th response to the 1 hair follicle. (b) A 28-year-old male with alopecia universalis for 2 years. (c) 3 months of systemic cyclosporin (4 mg/kg/day) and prednisone 5 mg/day. (d) 5 months of therapy. The patient had to discontinue therapy owing to serum transaminase changes and cholesterol elevation.

discontinuation of the treatment, the long treatment periods and the inability to change the ultimate prognosis of the disease, this treatment is simply not practical in AA. Gilhar et al.241 and De Prost et al.242 could not prove any cosmetic benefit from topical cyclosporin with concentrations of 10%.

Treatment plan Therapeutic selection for AA depends on patient age, extent of alopecia and motivation for treatment. The dermatologist should first discuss all therapeutic options and outcomes, al-

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Figure 2.31 University of California at San Francisco-University of British Columbia Treatment protocol for alopecia areata (permission granted by Drs Jerry Shapiro, Vera H.Price, and Harvey Lui).

lowing the patient to become an active member of the therapeutic team. Topical therapies with minoxidil, corticosteroids and anthralin are considered in children of less than 10 years of age, while in adults other options to be considered include intralesional corticosteroids or immunotherapy. A practical treatment algorithm for the treatment of AA is the University of California, San Francisco—University of British Columbia Alopecia Areata Treatment Protocol (see Figure 2.31). Patients are divided into those less than 10 years of age and those over 10 years of age. Pa-

tients over 10 are then subdivided into those with less than 50% scalp hair loss and those with more than 50% scalp hair loss. For those with less than 50% scalp hair loss, the following options are offered. Firstly, we always offer the patient the option of no treatment, as many AA patients will regrow their hair without treatment. However, most of our patients are well-motivated and want treatment. First-line therapy for scalp AA is intralesional corticosteroid injections into the alopecic patches. If there is no response after 3–4 months, we will add a minoxidil 5% solution twice daily and a superpotent corticoster-

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Figure 2.32 Scalp prostheses come with different linings that are light and allow air to circulate. (a) A lining that will allow one’s own natural hair to be pulled through. (b), (c) Net meshes that are typical.

oid cream such as clobetasol propionate applied 30 minutes after the minoxidil in addition to the monthly injections. If there is no benefit, another option is short-contact anthralin therapy with anthralin 1.0% cream applied for up to 1 hour daily combined with topical minoxidil 5% solution applied twice daily. For those patients with more than 50% scalp involvement, our first line is topical immunotherapy with DPCP. If there is no response by 52 weeks, topical immunotherapy is discontinued. Other options that can be offered to the patient are systemic PUVA,

minoxidil 5% solution, short-contact anthralin and superpotent topical steroids. A scalp prosthesis should be available to all patients with more than 50% scalp involvement, and can give great satisfaction to a majority of patients. Scalp prostheses come in an assortment of net linings that are light, and cool and allow air to circulate (see Figure 2.32). It should be emphasized to the patient that a prosthesis does not imply permanent hair loss, but having one on hand is comforting for episodes of extensive hair loss. Use of eyeliner or alopecia masking lotion (Figure 2.33) can give the AA

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Figure 2.33 Camouflage with eyeliner. (a) The patient is a 23-year-old who likes his hair short. He has a small patch of alopecia areata. (b) Camouflage with eyeliner, giving the illusion of hair in the area.

patient considerable camouflage. Dermatography of eyebrows is a technique that can be recommended for AA patients with prolonged eyebrow loss243 (Figure 2.34). Children: Therapeutic modality choices depend upon patient age. Those older than 10 years are treated with the same protocols as adults. In those younger than 10 years intralesional corticosteroids are avoided and topical immunotherapy is not implemented, although several European studies have demonstrated efficacy and safety in children as young as 5 years.194,195 For those under 10 years of age, therapeutic options include minoxidil alone or in combination with a mid-potency topical corticosteroid or anthralin. The ultimate therapeutic plan is developed through team interaction between the patient, the patient’s family and the physician. For some patients, support groups play an important role in the overall therapeutic strategy, and the dermatologist needs to become familiar with sup-

Figure 2.34 Dermatography: a semi-permanent tattoo for the eyebrows.

port groups and suppliers of hairpieces. Physicians need to take the time to address the psychological needs of their patients, exploring the impact of alopecia on the patient’s emotional

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well-being. It is the role of dermatologist to explain the diagnosis and inform the patient of all the therapeutic options, safety profiles and outcomes. It is imperative that the physician spend sufficient time with the patient, just as one would with a patient who had recently been diagnosis as diabetic. The National Alopecia Areata Foundation (710 C Street, Suite 11, San Rafael, California 94901–3853; www.alopeciaareata.org) offers patients and physicians information, including brochures, bimonthly newsletters, research updates, sources for scalp prostheses, penpals for children, videos for children to take to school and information about support groups, which are present in many large cities in the USA and Canada. The National Alopecia Areata Foundation (NAAF) has an annual convention for patients and their families, and this is often the turning-point for them in terms of coping with the condition. Physicians are welcome to attend.

Outlook for the future for alopecia areata treatments New therapeutic directions for alopecia areata will involve specifically targeted immunomodulatory agents. Rodent models currently available have become an important part of therapeutic research. The eventual discovery of cytokines specific for hair growth promotion in topical immunotherapy will offer more focused treatments. Newer immunomodulators specific for CD4 or CD8 and IL-2 receptors may further enhance treatments. Other biotechniques to interrupt the peptide-antigen or T-cell receptor are being evaluated. Gene replacement therapy based on current genetic studies may eventually allow lasting correction of abnormal gene expression.

Phototherapy beyond PUVA, involving new photosensitizers and novel non-UV light sources (lasers, light-emitting diode arrays), has the potential to immunomodulate. The role of this therapy in the treatment of AA holds great potential for the future.

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alopecia (Brauer nevus). Pediatr Dermatol, 1995; 12(4):301–3. Dominguez E., Eslinger M.R. and McCord S.V. Postoperative (pressure) alopecia: report of a case after elective cosmetic surgery. Anesth Analg, 1999; 89(4):1062–3. Wiles J.C. and Hansen R.C. Postoperative (pressure) alopecia. J Am Acad Dermatol, 1985; 12(1 Pt 2):195–8. Kosanin R.M., Riefkohl R. and Barwick W.J. Postoperative alopecia in a woman after a lengthy plastic surgical procedure. Plast Reconstr Surg, 1984; 73(2):308–9. Poma P.A. Pressure-induced alopecia. Report of a case after gynecologic surgery. J Reprod Med, 1979; 22(4):219–21. Madani S. and Shapiro J. The scalp biopsy: making it more efficient [In Process Citation]. Dermatol Surg, 1999; 25(7):537–8. Bateman T. Practical Synopsis of Cutaneous Disease, 4th edn. 1817. Olsen E., Hordinsky M., McDonald-Hull S., et al. Alopecia areata investigational assessment guidelines. National Alopecia Areata Foundation. J Am Acad Dermatol, 1999; 40(2 Pt 1):242–6. Drake L.A., Dinehart S.M., Farmer E.R., et al. Guidelines of care for alopecia areata. J Am Acad Dermatol , 1992; 26(2 Pt 1):247–50. Sawaya M.E. and Hordinsky M.K. Glucocorticoid regulation of hair growth in alopecia areata. J Invest Dermatol, 1995; 104(5 Suppl):30S. Perret C.M., Steijlen P.M. and Happle R. Alopecia areata. Pathogenesis and topical immunotherapy. Int J Dermatol, 1990; 29(2):83–8. Gill K. Alopecia totalis—treatment with fluocinolone acetonide. Arch Dermatol, 1963; 87:384. Montes L.F. Topical halcinonide in alopecia areata and in alopecia totalis. J Cutan Pathol, 1977; 4(2):47–50. Leyden J.L. and Kligman A.M. Treatment of alopecia areata with steroid solution. Arch Dermatol, 1972; 106(6):924.

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144. Price V. Progress in Dermatology. Bull Dermatol Foundation, 1991; 25:1. 145. Fiedler V.C. Alopecia areata: current therapy. J Invest Dermatol, 1991; 96(5):69S–70S. 146. Price V.H. Treatment of hair loss. New Engl J Med, 1999; 341(13):964–73. 147. Shapiro J. and Price V.H. Hair regrowth. Therapeutic agents. Dermatol Clin, 1998; 16(2):341–56. 148. Porter D. and Burton J.L. A comparison of intra-lesional triamcinolone hexacetonide and triamcinolone acetonide in alopecia areata. Br J Dermatol, 1971; 85(3):272–3. 149. Shapiro J. Alopecia areata. Update on therapy. Dermatol Clin, 1993; 11(1):35–46. 150. Whiting D.A. The treatment of alopecia areata. Cutis, 1987; 40(3):247–50. 151. Bergfeld W. Alopecia areata symposium. Pediat Dermatol, 1987; 4:144. 152. Thiers B. Alopecia areata symposium. Pediat Dermatol, 1987; 4:136. 153. Ferrando J. and Moreno-Arias G.A. Multiinjection plate for intralesional corticosteroid treatment of patchy alopecia areata. Dermatol Surg, 2000; 26(7):690–1. 154. Alabdulkareem A.S., Abahussein A.A. and Okoro A. Severe alopecia areata treated with systemic corticosteroids. Int J Dermatol, 1998; 37(8):622–4. 155. Winter R.J., Kern F. and Blizzard R.M. Prednisone therapy for alopecia areata. A follow-up report. Arch Dermatol, 1976; 112(11):1549–52. 156. Unger W.P. and Schemmer R.J. Corticosteroids in the treatment of alopecia totalis. Systemic effects. Arch Dermatol, 1978; 114(10):1486–90. 157. Sharma V.K. Pulsed administration of corticosteroids in the treatment of alopecia areata. Int J Dermatol, 1996; 35(2):133–6. 158. Michalowski R. Alopecia areata totalis/ universalis and systemic corticosteroids [letter; comment]. Int J Dermatol, 1999; 38(12):947. 159. Friedli A., et al. Pulse methylprednisolone therapy for severe alopecia areata: an open

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prospective study of 45 patients. J Am Acad Dermatol, 1998; 39(4 Pt 1):597–602. Buhl A.E. Minoxidil’s action in hair follicles. J Invest Dermatol, 1991; 96(5):73S–74S. Khoury E.L., Price V.H., Abdel-Salam M.M., et al. Topical minoxidil in alopecia areata: no effect on the perifollicular lymphoid infiltration. J Invest Dermatol, 1992; 99(1):40–7. Fiedler V.C. Alopecia areata. A review of therapy, efficacy, safety, and mechanism [editorial] [see comments]. Arch Dermatol, 1992; 128(11):1519–29. Price V.H. Topical minoxidil in extensive alopecia areata, including 3-year follow-up. Dermatologica, 1987; 175(Suppl 2):36–41. Fiedler-Weiss V.C. Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol, 1987; 16(3 Pt 2):745–8. Fiedler-Weiss V.C., West D.P., Buys C.M. and Rumsfield J.A. Topical minoxidil doseresponse effect in alopecia areata. Arch Dermatol, 1986; 122(2):180–2. Price V.H. Topical minoxidil (3%) in extensive alopecia areata, including longterm efficacy. J Am Acad Dermatol, 1987; 16(3 Pt 2):737–44. Ranchoff R.E., Bagfeld W.F., Stack W.D. and Subichin S.J. Extensive alopecia areata. Results of treatment with 3% topical minoxidil. Cleve Clin J Med, 1989; 56(2): 149–54. Fransway A.F. and Muller S.A. 3 percent topical minoxidil compared with placebo for the treatment of chronic severe alopecia areata. Cutis, 1988; 41(6):431–5. Vestey J.P. and Savin J.A. A trial of 1% minoxidil used topically for severe alopecia areata. Acta Derm Venereol, 1986; 66(2): 179–80. Fiedler V.C., Wendraw A., Szpunar G.J., et al. Treatment-resistant alopecia areata. Response to combination therapy with minoxidil plus anthralin. Arch Dermatol, 1990; 126(6):756–9.

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171. Morhenn V.B., Orenberg E.K., Kaplan J., et al. Inhibition of a Langerhans cell-mediated immune response by treatment modalities useful in psoriasis. J Invest Dermatol, 1983; 81(1):23–7. 172. Swanson N.A., Mitchell A.J., Leahy M.S., et al. Topical treatment of alopecia areata. Arch Dermatol, 1981; 117(7):384–7. 173. Buchner U. Irritant versus allergic contact dermatitis for the treatment of alopecia areata. Arch Dermatol Res, 1979; 264:123. 174. Fiedler-Weiss V.C. and Buys C.M. Evaluation of anthralin in the treatment of alopecia areata. Arch Dermatol, 1987; 123(11):1491–3. 175. Schmoeckel C., Weissman I., Plewig G. and Braun-Falco O. Treatment of alopecia areata by anthralin-induced dermatitis. Arch Dermatol, 1979; 115(10):1254–5. 176. Nelson D.A. and Spielvogel R.L. Anthralin therapy for alopecia areata. Int J Dermatol, 1985; 24(9):606–7. 177. Happle R., Klein H.M. and Macher E. Topical immunotherapy changes the composition of the peribulbar infiltrate in alopecia areata. Arch Dermatol Res, 1986; 278(3):214–8. 178. Daman L.A., Rosenberg E.W. and Drake L. Treatment of alopecia areata with dinitrochlorobenzene. Arch Dermatol, 1978; 114(7):1036–8. 179. Happle R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res, 1980; 267(1):109–14. 180. Happle R., Cebulla K. and EchternachtHapple K. Dinitrochlorobenzene therapy for alopecia areata. Arch Dermatol, 1978; 114(11):1629–31. 181. Hehir M.E. and du Vivier A. Alopecia areata treated with DNCB. Clin Exp Dermatol, 1979; 4(3):385–7. 182. Kratka J., Goerz G., Vizethum W. and Strobel R. Dinitrochlorobenzene: influence on the cytochrome P-450 system and mutagenic effects. Arch Dermatol Res, 1979; 266(3):315–18.

183. Strobel R. and Rohrborn G. Mutagenic and cell transforming activities of 1-chlor-2,4dinitrobenzene (DNCB) and squaricaciddibutylester (SADBE). Arch Toxicol, 1980; 45(4):307–14. 184. Summer K.H. and Goggelmann W. l-chloro2,4-dinitrobenzene depletes glutathione in rat skin and is mutagenic in Salmonella typhimurium. Mutat Res, 1980; 77(1):91–3. 185. Weisburger E.K., Russfield A.B., Homburger F., et al. Testing of twenty-one environmental aromatic amines or derivatives for longterm toxicity or carcinogenicity. J Environ Pathol Toxicol, 1978; 2(2):325–56. 186. Wilkerson M.G., Wilkin J.K. and Smith R.G. Contaminants of dinitrochlorobenzene. J Am Acad Dermatol, 1983; 9(4):554–7. 187. Happle R., Kalveram K.J., Buchner U., et al. Contact allergy as a therapeutic tool for alopecia areata: application of squaric acid dibutylester. Dermatologica, 1980; 161(5): 289–97. 188. Flowers F.P., Slazinski L., Fenske N.A. and Pullara T.J. Topical squaric acid dibutylester therapy for alopecia areata. Cutis, 1982; 30(6):733–6. 189. Case P.C., Mitchell A.J., Swanson N.A., et al. Topical therapy of alopecia areata with squaric acid dibutylester. J Am Acad Dermatol, 1984; 10(3):447–50. 190. Caserio R.J. Treatment of alopecia areata with squaric acid dibutylester. Arch Dermatol, 1987; 123(8):1036–41. 191. Giannetti A. and Orecchia G. Clinical experience on the treatment of alopecia areata with squaric acid dibutyl ester. Dermatologica, 1983; 167(5):280–2. 192. Micali G., Cicero R.L., Nasca M.R. and Sapuppo A. Treatment of alopecia areata with squaric acid dibutylester. Int J Dermatol, 1996; 35(1):52–6. 193. Chua S.H., Goh C.L. and Ang C.B. Topical squaric acid dibutylester therapy for alopecia areata: a double-sided

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patientcontrolled study. Ann Acad Med Singapore, 1996; 25(6):842–7. Orecchia G., Malagoli P. and Santagostino L. Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients. Pediatr Dermatol, 1994; 11(1):65–8. Tosti A., Guidetti M.S., Bardazzi F. and Miscali C. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol, 1996; 35(2 Pt 1):199–201. Barth J.H., Darley C.R. and Gibson J.R. Squaric acid dibutyl ester in the treatment of alopecia areata. Dermatologica, 1985; 170(1):40–2. Orecchia G., Perfetti L., Borroni G. and Rabbiosi G. Photochemotherapy plus squaric acid dibutylester in alopecia areata treatment [letter]. Dermatologica, 1990; 181(2):167–9. Wilkerson M.G., Henkin J., Wilkin J.K. and Smith R.G. Squaric acid and esters: analysis for contaminants and stability in solvents. J Am Acad Dermatol, 1985; 13(2 Pt 1): 229–34. Van Duuren B.L., Melchionne S., Blair R., et al. Carcinogenicity of isosters of epoxides and lactones: aziridine ethanol, propane sultone, and related compounds. J Natl Cancer Inst, 1971; 46(1):143–9. Harland C.C. and Saihan E.M. Regression of cutaneous metastatic malignant melanoma with topical diphencyprone and oral cimetidine [letter]. Lancet, 1989; 2(8660):445. Lane P.R. and Hogan D.J. Diphencyprone [letter]. J Am Acad Dermatol, 1988; 19(2 Pt 1):364–5. Van der Steen P.H., Boezeman J.B. and Happle R. Topical immunotherapy for alopecia areata: re-evaluation of 139 cases after an additional follow-up period of 19 months. Dermatology, 1992; 184(3): 198– 201. Hull S.M. and Norris J.F. Diphencyprone in the treatment of long-standing alopecia areata. Br J Dermatol, 1988; 119(3): 367–74.

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204. MacDonald-Hull S. Post therapy relapse rate in alopecia areata after successful treatment with diphencyprone. J Dermatol Treat, 1989; 1:71. 205. Hull S.M. and Cunliffe W.J. Successful treatment of alopecia areata using the contact allergen diphencyprone [letter]. Br J Dermatol, 1991; 124(2):212–13. 206. Wiseman M., Shapiro J., MacDonald N., Lui H. Predictive model for immunotherapy of alopecia areata with diphencyprone. Arch Derm, 2001; 137: in press. 207. Gordon P.M., Aldridge R.D., McVitie E. and Hunter J.A. Topical diphencyprone for alopecia areata: evaluation of 48 cases after 30 months’ follow-up. Br J Dermatol, 1996; 134(5):869–71. 208. Pericin M. and Trueb R.M. Topical immunotherapy of severe alopecia areata with diphenylcyclopropenone: evaluation of 68 cases. Dermatology, 1998; 196(4):418–21. 209. Monk B. Induction of hair growth in alopecia totalis with diphencyprone sensitization. Clin Exp Dermatol, 1989; 14(2):154–7. 210. Hatzis J., Georgiotono K., Kostakis P., et al. Treatment of alopecia areata with diphencyprone. Australas J Dermatol, 1988; 29(1):33–6. 211. Ashworth J., Tuyp E. and Mackie R.M. Allergic and irritant contact dermatitis compared in the treatment of alopecia totalis and universalis. A comparison of the value of topical diphencyprone and tretinoin gel. Br J Dermatol, 1989; 120(3):397–401. 212. Orecchia G. and Rabbiosi G. Treatment of alopecia areata with diphencyprone. Dermatologica, 1985; 171(3):193–6. 213. Berth-Jones J. and Hutchinson P.E. Treatment of alopecia totalis with a combination of inosine pranobex and diphencyprone compared to each treatment alone. Clin Exp Dermatol, 1991; 16(3): 172–5.

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214. Shapiro J., Tan J., Ho V. and Tron V. Treatment of chronic severe alopecia areata with topical diphenylcyclopropenone and 5% minoxidil: a clinical and immunopathologic evaluation. J Am Acad Dermatol, 1993; 29(5 Pt 1):729–35. 215. Hull S.M., Pepall L. and Cunliffe W.J. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol, 1991; 125(2):164–8. 216. Van der Steen P.H., van Baar H.M., Perret C.M. and Happle R. Treatment of alopecia areata with diphenylcyclopropenone [see comments]. J Am Acad Dermatol, 1991; 24(2 Pt 1):253–7. 217. Berth-Jones J., Mc Burney A. and Hutchinson P.E. Diphencyprone is not detectable in serum or urine following topical application. Acta Derm Venereal, 1994; 74(4):312–3. 218. Wilkerson M.G., Connor T.H., Henkin J., et al. Assessment of diphenylcyclopropenone for photochemically induced mutagenicity in the Ames assay. J Am Acad Dermatol, 1987; 17(4):606–11. 219. Wilkerson M.G., Henkin J. and Wilkin J.K. Diphenylcyclopropenone: examination for potential contaminants, mechanisms of sensitization, and photochemical stability. J Am Acad Dermatol, 1984; 11(5 Pt 1): 802–7. 220. Perret C.M., Steijlen P.M. and Happle R. [Alopecia areata; pathogenesis and topical immunotherapy]. Ned Tijdschr Geneeskd, 1989; 133(25):1256–60. 221. Perret C. Treatment of alopecia areata. In Hair and Hair Diseases, ed. C.O.R.Happle, p. 529. 1990; New York: Springer Verlag. 222. Shah M., Lewis P.M. and Messenger A.G. Hazards in the use of diphencyprone [letter] [see comments]. Br J Dermatol, 1996; 134(6):1153. 223. Fernandez-Redondo V., Gomez-Centeno P., Florez A. and Toribio J. Hazards in the use of diphencyprone. Allergy, 2000; 55(2): 202–3.

224. Orecchia G. and Stock J. Diphenylcyclopropenone: an important agent known to cause depigmentation [letter; comment]. Dermatology, 1999; 199(2):198. 225. Van der Steen P. and Happle R. ‘Dyschromia in confetti’ as a side effect of topical immunotherapy with diphenylcyclopropenone. Arch Dermatol, 1992; 128(4):518–20. 226. Orecchia G. and Perfetti L.Vitiligo and topical allergens [letter; comment]. Dermatologica, 1989; 179(3):137–8. 227. Hatzis J., Gourgiotou K., Tosca A., et al. Vitiligo as a reaction to topical treatment with diphencyprone [see comments]. Dermatologica, 1988; 177(3):146–8. 228. Henderson C.A. and Ilchyshyn A.Vitiligo complicating diphencyprone sensitization therapy for alopecia universalis [letter]. Br J Dermatol, 1995; 133(3):496–7. 229. Duhra P. and Foulds I.S. Persistent vitiligo induced by diphencyprone [letter]. Br J Dermatol, 1990; 123(3):415–16. 230. Alam M., Gross E.A. and Savin R.C. Severe urticarial reaction to diphenylcyclopropenone therapy for alopecia areata. J Am Acad Dermatol, 1999; 40(1):110–12. 231. Tosti A., Guerra L. and Bardazzi F. Contact urticaria during topical immunotherapy. Contact Dermatitis, 1989; 21(3):196–7. 232. Skrebova N., Nameda Y., Takiwaki H. and Arase S. Severe dermographism after topical therapy with diphenylcyclopropenone for alopecia universalis. Contact Dermatitis, 2000; 42(4):212–15. 233. Perret C.M., Steijlen P.M., Zaun H. and Happle R.Erythema multiforme-like eruptions: a rare side effect of topical immunotherapy with diphenylcyclopropenone. Dermatologica, 1990; 180(1):5–7. 234. Mitchell A.J. and Douglass M.C. Topical photochemotherapy for alopecia areata. J Am Acad Dermatol, 1985; 12(4):644–9.

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235. Claudy A.L. and Gagnaire D. Photochemotherapy for alopecia areata. Acta Derm Venereal, 1980; 60(2):171–2. 236. Larko O. and Swanbeck G. PUVA treatment of alopecia totalis. Acta Derm Venereal, 1983; 63(6):546–9. 237. Lassus A., Kianto U., Johansson E. and Juvakoski T., et al. PUVA treatment for alopecia areata. Dermatologica, 1980; 161(5):298–304. 238. Healy E. and Rogers S. PUVA treatment for alopecia areata—does it work? A retrospective review of 102 cases. Br J Dermatol, 1993; 129(1):42–4. 239. Taylor C.R. and Hawk J.L. 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(6):914–18.

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240. Stern R.S., Nichols K.T. and Vakeva L.H. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study [see comments]. New Engl J Med; 1997; 336(15):1041–5. 241. Gilhar A., Pillar T. and Etzioni A. Topical cyclosporin A in alopecia areata. Acta Derm Venereal, 1989; 69(3):252–3. 242. de Prost Y., Teillac D., Paquez F., et al. Placebo-controlled trial of topical cyclosporin in severe alopecia areata [letter]. Lancet, 1986; 2(8510):803–4. 243. Van der Velden E.M., Drost B.H., Ijsselmuiclen O.E., et al. Dermatography as a new treatment for alopecia areata of the eyebrows. Int J Dermatol, 1998; 37(8): 617–21.

3 Androgenetic alopecia: Pathogenesis, clinical features and practical medical treatment 16

Introduction Androgenetic alopecia (AGA) is by far the most common cause of hair loss. It affects approximately 50% of men by the age of 50 and 20% to 53% of women by the age of 50.1–3 Although it is a medically benign condition, it can have a significant psycho-social impact for patients. 4–6 This chapter will highlight the pathogenesis, clinical features and state of the art medical management of AGA.

Pathogenesis Knowledge of the patho-physiology of AGA is essential in understanding the mechanism of action of current therapeutic agents. We are only beginning to understand the different factors underlying AGA. The following is a summary of the current knowledge on AGA pathogenesis. As its name implies, AGA involves both genetic and hormonal factors.1 Genetics determine both the density and the location of androgen-sensitive hair follicles on site-specific areas of the scalp. After puberty, androgens trigger a series of events within these genetically-programmed hair follicles, predominantly of the fronto-parietal scalp, that transform terminal to miniaturized follicles.7–

The hair cycle is altered, with progressive shortening of the anagen phase occurring over many cycles. This shortening of anagen and subsequent miniaturization of hairs leads to decreased scalp coverage.1,17,18 These finer small vellus-like hairs of varying lengths and diameters are the hallmark of AGA (Figure 3.1). However, in AGA the number of follicles per unit of area remains the same. It is still controversial what becomes of these miniaturized follicles. Complete permanent regression is unlikely, since cases of severely advanced balding male to female transsexuals have experienced considerable regrowth using finasteride, minoxidil, spironolactone and estrogen (personal observation).

Genetic factors The exact inheritance pattern of AGA is still debated. It is believed to be most likely autosomal dominant,3 polygenic,19 and inherited from either parent.19 The gene frequency appears to be most common in Caucasians, less so in Africans, and least frequent in Amerindians, Asians and Inuits.20 The McKusick Mendelian Inheritance in Man (MIM) number for AGA is 109200. A MIM entry that begins with the number one indicates an autosomal dominant inheritance.21

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Figure 3.1 In androgenetic alopecia, there is miniaturization of coarse terminal hairs into small vellus-like hairs with each subsequent cycle.

Some previous work on the genetics of AGA dates back to 1919. Osborn22 stated that AGA was a sex-limited autosomal dominant trait similar to the inheritance of horns in sheep. She believed that men could be either homozygotes (BB) or heterozygotes (Bb), and women who presented with AGA were homozygotes only. Smith and Wells23 have hypothesized that the expressivity of the gene might be partly determined by the androgen level: the genotype BB may lead to the clinical picture of AGA even at low androgen levels in women, whereas the genotype Bb requires higher amounts of androgen. The genotype bb may remain sub-clinical in both sexes. Harris24 found that of 117 men with AGA, 66% of the brothers were bald if the father of the proband was also bald, and 46% of the brothers were bald if the father was not bald. Fifty-six per cent of bald men had bald fathers. The authors concluded that this was consistent with an autosomal dominant gene. Salomon25 felt that AGA is inherited through multifactorial or conditioned dominance via an autosomal dominant gene of variable expressivity. He studied 119 males with AGA. Sixteen had no family history, 65 had two generations, 24 three generations and 3 four generations involved. Eleven had two generations of families with both parents affected. There was an association of increasing amounts of chest hair, but not back hair, in affected individuals. This observation is quite interesting, in that Shapiro has noted the same trend in increased body hair distribution in a disproportionately large number of his balding male patients, although no formal study has been performed. A family has been described in which common baldness with early onset occurred in females only.26 Kuster and Happle.19 favor a polygenic inheritance rather than a simple Mendelian model. They present very credible arguments

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supporting multi-allelic inheritance. The high prevalence rate, the distribution of the balding patterns in the general population along a Gaussian curve of variation, and the fact that the risk increases with the number of relatives already affected, and that there is an increased risk to relatives of severely affected women as compared to the relatives of mildly affected women all support a more complex polygenic inheritance. Carey et al. described several families in which premature balding in male members appeared to denote carrier status for an autosomal dominant gene responsible for polycystic ovarian disease.27,28 There was an association with one allele of the steroid metabolism gene CYP17, although this genetic change was not the primary cause of either condition.27,28 The search for the gene continues. The X-linked mutation for adrenoleukodystrophy, which is correlated to premature AGA in men, may be a part of the polygenic spectrum of genes responsible for AGA.29 The human hairless gene responsible for papular atrichia was shown not to be correlated to AGA when studying 31 heterozygous male carriers of this mutation with respect to onset or extent of AGA.30 Sreekumar et al.31 did not find any evidence of linkage of early-onset AGA to any markers of chromosomes 2 and 5 that are known to code for 5 a-reductase Type I and II. It is expected over the next decade that the information from the Human Genome Project will have great relevance in mapping out the genes that express the complex trait of AGA.

Hormonal factors A major determinant of AGA is intracellular androgen metabolism, which involves two steroid-metabolizing enzymes (5a-reductase and aromatase) and androgen receptor pro-

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teins. Other important factors may still remain to be discovered. Variances in levels of these androgen-metabolizing enzymes and androgen receptor proteins help explain the differences between balding and non-balding scalp at various ages and the different clinical patterns and severities between men and women.1,32,33 5a-reductase isoenzymes, type I and II, are both part of normal androgen metabolism and reduce testosterone (T) to dihydrotestosterone (DHT). The 5a-reductase type I isoenzyme is located mainly in sebaceous glands, epidermal and follicular keratinocytes, dermal papilla cells, and sweat glands.34 The 5a-reductase type II isoenzyme is located mainly in the root sheaths of the scalp hair follicle33,34 as well as in the epididymis, vas deferens, seminal vesicles, prostate, and fetal genital skin.34 Both type I and type II isoenzymes play an important role in AGA.33,35–37 Both isoenzymes are increased in frontal balding follicles compared to occipital non-balding follicles, but to a lesser extent in women.33 DHT levels are increased in balding scalp when compared to non-balding scalp.35,38–40 Women have 3.0–3.5 times less 5α-reductase (I and II) than men,33 and this may explain why female AGA is usually less severe than male AGA. Individuals with a genetic deficiency of 5a-reductase type II isoenzyme do not develop AGA,41–43 further supporting the DHT requirement for AGA expression. A recent case report by Orme et al.44 described a young women with hypopituitarism who presented with clinical and histologic features of female AGA in the absence of detectable androgens or other signs of post-pubertal androgenization, showing that this pattern of hair loss is not necessarily androgen-dependent. Shapiro has seen a female teenager with androgen-insensitive syndrome, lacking androgen receptors, with typical female AGA (unpublished personal observa-

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tion). These findings are intriguing. Norwood and Lehr45 have proposed that female AGA may be a separate entity. However, they admit that it is impossible to distinguish male from female hair shaft miniaturization either clinically or histologically. The cytochrome P450 aromatase enzyme is also part of normal androgen metabolism, and may have a protective effect on hair follicles.33 Aromatase results in the conversion of T to estradiol and estrone, and therefore the resulting shift will lessen conversion of T to DHT. Aromatase is significantly higher in the hair follicles of women. There is 6 times more aromatase in the frontal follicles and 4 times more in the occipital follicles of women than in those of men. This likewise helps explain why women with AGA usually retain their frontal hairline and have less hair loss than men with AGA.17,33 Androgen receptor proteins (ARP) are found in the outer root sheath and dermal papilla fibroblasts of scalp hair follicles.8,13,32,33 The receptor levels were found to be 30% greater in balding frontal hair follicles than in nonbalding occipital follicles in both men and women with AGA, but the total receptor content is 40% less in women than in men.33 The binding of androgens to ARP results in modification of signal transduction between the mesenchymal-derived dermal papilla and the epithelial-derived follicular cells. These events within the follicle result in the transformation of terminal to miniaturized hair follicles on the scalp in AGA. Paradoxically, in other androgensensitive areas such as the beard and mustache, androgens upsize, rather than downsize, hair follicles at puberty. The explanation for this bifurcated action is not known.17 Studying the quail-chick model, Ziller46 found differences of embryonic origin of the

dermis of the fronto-parietal scalp compared to the occipital scalp. Dermis of the frontoparietal scalp is derived from the neural crest, whereas dermis of the occipital/temporal scalp is derived from the mesoderm. One can speculate that this difference in embryonic origin may influence the well-known differential response of follicles in the occipital region as against the rest of the scalp in AGA.

Clinical features of AGA History Thinning of the hair can occur as early as the age of 12 (Figure 3.2a) and as late as the age of 45 in both sexes. However, AGA usually manifests at an early age and progresses slowly. Most cases start between the ages of 15 and 25.47 The clinical course is gradual, consisting of acute episodic phases with increased loss of telogen hair, alternating with periods when there is little shedding. The shedding may be seasonal in a small number of individuals.47 For many individuals, the condition may seem stable for years.47 Many men reach their maximum pattern by their forties, although hair density does decrease as they age further. Usually there is a positive family history. However, 12% in one study showed a completely negative family history.25 Hair loss in women may be triggered by hormonal changes, including starting or stopping the oral contraceptive pills and post-partum and peri- and post-menopausal states. These events, which can elicit a telogen effluvium, may unmask a tendency for AGA. Women

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Figure 3.2 (a) Male androgenetic alopecia can appear early. This is a 13-year-old boy showing frontotemporal thinning and hair miniaturization. (b) The presence of miniaturized hairs helps to confirm a diagnosis of AGA. A contrast paper is placed in a parted area of the scalp. The hair is then closely examined against this backdrop.

must be questioned about the regularity of their periods and the presence or absence of hirsutism in an attempt to determine if hyperandrogenism is a problem. SAHA syndrome, standing for seborrhea, alopecia, hirsutism and acne, frequently indicates an androgen excess in the female patient. However, in the vast majority of women with AGA, hyperandrogenism is not a problem.48 An increased risk for coronary artery disease has recently been correlated to vertex balding in men.49–51 In one study there appeared to be lipoprotein and triglyceride level differences between males with vertex thinning and non-balding men,50 with an increased risk for atherosclerotic and coronary heart disease in balding men. Lotufo et al.52 showed that vertex pattern balding appears to be a marker for increased risk of coronary heart disease, especially among men with hypertension or high cholesterol levels. The biologic mecha-

nisms for this relationship are unknown. It was felt by these authors that early vertex balding may be a useful marker to identify men at increased risk who may benefit from aggressive screening and primary prevention efforts directed toward other known modifiable risk factors for coronary heart disease. Herrera et al.53 assessed the relation between the extent and progression of baldness and coronary heart disease. Baldness was assessed twice, in 1956 and in 1962, in a cohort of 2,017 men from Framingham, Massachusetts. The cohort was followed for up to 30 years for new occurrences of coronary heart disease, coronary heart disease death, cardiovascular disease, and death due to any cause. The relations between the extent and progression of baldness and the aforementioned outcomes were assessed using a Cox proportional hazards model, adjusting for age and other known cardiovascular disease risk factors. Extent of baldness was not associ-

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ated with any of the outcomes. However, the amount of progression of baldness was associated with coronary heart disease occurrence (relative risk (RR)=2.4, 95% confidence interval (CI) 1.3–4.4), coronary heart disease mortality (RR=3.8, 95% CI 1.9–7.7), and all-cause mortality (RR =2.4, 95% CI 1.5–3.8). It was concluded that rapid hair loss may be a marker for coronary heart disease. A practice-based case-control study in men aged 19–50 years showed a strikingly increased risk of hyper-insulinemia and insulinresistance-associated disorders such as obesity, hypertension, and dyslipidemia in men with early onset of AGA (< 35 years), when compared to age-matched controls.54 This finding supports the hypothesis that early AGA could be a clinical marker of insulin resistance. These authors suggest that men with early AGA might benefit from screening for cardiovascular risk factors and for insulin resistance. On the other hand, in a study of 478 men, no association between coronary heart disease and androgenetic alopecia was found.55 A total of 3,421 men age 25–75 years (median age at baseline 55) without a history of prostate cancer were examined for AGA in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey. 56 Participants were followed from baseline (1971–4) through to 1992. Incident cases of prostate cancer were identified by interviews, medical records and death certificates. Prostate cancer was diagnosed in 214 subjects over 17–21 years of follow-up. The investigators noted that the age-standardized incidence of prostate cancer was greater among men with baldness at baseline (17.5 vs 12.5 per 10,000 person years). Men with AGA had a consistently higher incidence of prostate cancer compared with those without

AGA, beginning at approximately 60 years of age. The adjusted relative risk for prostate cancer among men with any degree of baldness was 1.5, and was similar regardless of the severity of baldness at baseline and was independent of other risk factors, including race and age. The authors concluded that men with AGA had a 50% excess risk for clinical prostate cancer. The major strengths of this study included its prospective design, large sample size, extended follow-up, and national representative sampling. A drawback was that approximately 1/3 of their cohort had not yet reached the advanced age-range in which clinical prostate cancer is typically present, thus limiting the effective power of their study. Hawk et al.56 further hypothesize that AGA in men may predict other age-related pathological processes, such as atherogenesis, that tend to remain clinically silent until they are advanced. In some women with AGA, and occasionally in men, AGA may unmask a psychological lability and/or psychiatric disturbance.47 In some individuals, AGA becomes a preoccupation, and is blamed for all social and professional problems. Psychoneurotic attitudes may ensue, in which the alopecia is merely a symptom that the patient may clutch on to.47

Physical examination Hair loss is patterned and non-scarring, with preservation of follicular ostia. A hair pull test is usually negative, although there may be a mild increase in telogen hairs, though only in involved areas of the scalp. Miniaturized vellus-like hairs can usually be seen with contrast paper placed over a part (Figure 3.2b). In terms of the pattern of hair loss, women usually have less severe hair loss than men and

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Figure 3.3 In female AGA, most women present with an intact frontal hair line. retain their frontal hairline (Figure 3.3). The hair thinning is mostly on the crown. This pattern is recognized as the Ludwig pattern, and is divided in 3 stages according to severity (Figures 3.4–3.8).57 Ludwig Stage I is the most common pattern. Hair loss may only be evident when one compares the relative widths

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of the division of bare scalp between areas of combed hair (‘part’, ‘parting’) in the centro-parietal area with that in the occipital area. Ludwig Stage III is rare, and women affected may require an endocrine work-up if they show other signs of androgen excess. In a significant percentage of female patients with AGA, diffuse hair thinning may be present (Figure 3.9a and b). Olsen58 feels that 5% show a global decrease in scalp hair density. Shapiro feels that approximately 30% of women have a more global thinning. This generally occurs in those women with more advanced hair loss, and usually in those with early-onset AGA. Even with this diffuse loss, there still remains a variance of hair density on the top of the scalp versus the sides or the back of the scalp. The presence of global thinning clearly decreases the chances of being a successful female hair transplant candidate. In men, there is a frontal hairline recession associated with thinning or balding on the

Figure 3.4 (a) Ludwig classification of female AGA, showing the three different stages of severity. (b) The characteristically narrow division of bare scalp between areas of combed hair (‘part’, ‘parting’) found in a woman without AGA. Reproduced with permission from the British Journal of Dermatology 1977; 97:247–54.

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Figure 3.5 Ludwig Stage I: A widening of the division of bare scalp between areas of combed hair (‘part’, ‘parting’) may be the first complaint of the female patient. She will also notice her ponytail diameter may be reduced one-third to one-half of what it used to be. The elastic band that she usually uses to tie up her ponytail can now be wound several times around her hair in contrast to only once or twice, as before.

Figure 3.7 Mother (left) with Ludwig Stage II and daughter (right) with Ludwig Stage I.

Figure 3.8 Ludwig Stage III: Considerable loss of hair.

Figure 3.6 Ludwig Stage II: The width of the division of bare scalp (‘part’, ‘parting’) is now considerably more evident than in Ludwig I.

crown or vertex. There are exceptions, with certain individuals showing no recession and only vertex thinning, as in Figure 3.10a and b. Hamilton originally classified male AGA on the basis of fronto-parietal/fronto-temporal recession and vertex thinning. 59 Norwood, 60 more than 25 years later, improved on this pictorial classification. This pattern is known as the Norwood-Hamilton pattern, and is divided

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Figure 3.9 Female AGA may be totally diffuse, involving not only (a) the centro-parietal area but also (b) the sides and the back of the scalp.

Figure 3.10a and b A rare case of a 55-year-old male with absolutely no recession and simply vertex thinning.

into 7 stages according to severity (Figures 3.11–3.16).60 The first change is bitemporal recession, which is seen in 96% of sexually mature Caucasian males, including those men not destined to progress to further hair loss. Resculpturing of the frontal hairline with some bi-temporal recession, seen post-puberty in

most men, does not necessarily herald the expression of AGA, and is unlikely to reverse with current therapies. However, a deeper bitemporal recession of greater than 1 inch from the frontal hair line is part of the AGA phenotype, and, if treated early, may respond to therapy.40

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Figure 3.11 Norwood-Hamilton Classification of Hair Loss based on severity.

These patterns are not restrictive, and some women can present with the Norwood-Hamilton pattern (Figures 3.17–3.19) and some men with the Ludwig pattern (Figures 3.20 and 3.21). Norwood and Lehr45 feel that 10% of their male AGA patients present with a female AGA pattern. Venning and Dawber48 when they examined 564 women aged over 20 years found that 80% of pre-menopausal women had thinning in the Ludwig pattern and 13% had Hamilton Type II–IV patterns. After menopause the proportion exhibiting the male pattern increased to 37%, and, although they did not progress to beyond Hamilton Stage IV, some had marked M-shaped recession at both temples.

Figure 3.12 (a) A 33-year-old male showing the classic M hairline with fronto-temporal recession. (b) He also has vertex thinning, making him a Norwood-Hamilton Stage III. Reproduced with permission from Southern Medical Journal 1975; 68:1359–65.

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Figure 3.13 Early Norwood-Hamilton Stage IV, with the emergence of a bridge connecting lateral portions of the scalp.

Figure 3.15 Norwood-Hamilton Stage V, with the bridge gone but still a significant number of miniaturized hairs on the top of the scalp.

Figure 3.14 Late Norwood-Hamilton Stage IV, with the bridge less intact.

Figure 3.16 Norwood-Hamilton Stage VI, with very little hair on the top of the scalp.

Differential diagnosis

•

Usually the diagnosis of AGA is not a difficult one in men. However, in women, the diagnosis may be more difficult. The diagnosis of AGA is usually supported with the following cardinal features:

• • • •

usual focal balding pattern with miniaturized hairs gradual onset with progression thinning with or without gradually developing bare patches onset after puberty negative pull test

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Figure 3.17 Norwood-Hamilton Stage VII, with preservation of the ‘horseshoe’ of hair at the sides and back of the scalp.

Figure 3.18 Women can show the Norwood-Hamilton pattern. A 40-year-old female with NorwoodHamilton Stage II AGA with fronto-temporal recession. (a) Frontal view (b) Lateral view, with miniaturized hairs.

Figure 3.19 A female with AGA with a Norwood-Hamilton Stage V pattern.

Figure 3.20 A female with AGA with a NorwoodHamiltion Stage VI pattern.

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Figure 3.22a A 40-year-old male with Ludwig Stage II.

Figure 3.22b Patterns of hair loss can intermix within the same family and within the same sex. Norwood-Hamilton Stage VII in a 48-year-old father (right) and Ludwig Stage I occurring in his 20-year-old son (left).

Figure 3.21 Two male teenagers with the Ludwig Stage I pattern. (a) A fourteen-year-old male with Ludwig Stage I. (b) A seventeen-year-old male with the Ludwig Stage I pattern.

The other two diagnoses that may be difficult to distinguish are telogen effluvium and alopecia areata. Both these entities are discussed at length in other chapters. Telogen effluvium is usually generalized (Figure 3.23a), with an abrupt onset, frequently with an iden-

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Figure 3.23a and b Telogen effluvium consists of hair thinning in a generalized manner not only (a) on top of the scalp but also (b) on the sides.

Figure 3.23c Patients with telogen effluvium frequently present with bag of hair to show the physician. This is unusual with AGA.

Figure 3.23d A 28-year-old female with telogen effluvium who kept a diary of hair loss for 5 years. This amount of hair loss would not be seen in AGA.

tifiable trigger. There is thinning, with no bare patches. Shedding is prominent. Onset is at any age, but usually not childhood. The pull test is positive with telogen hairs. Alopecia areata (AA) is usually randomly patchy, but can be generalized. Onset is usually abrupt,

with remissions and relapses. Onset is at any age, with over 60% presenting under the age of 20. Shedding is prominent, with a positive pull test for both dystrophic anagen and telogen hairs. Overlapping of AGA and alopecia areata can occur. (Figure 3.24). It is ex-

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Figure 3.24a and b Overlapping of AGA and alopecia areata (AA) can occur. It is expected that almost 2% of patients with AGA have had, have, or will have AA. This may have great significance if one is contemplating hair transplantation surgery for AGA. If an AGA patient has a previous, recent or remote history of AA, he or she must be warned that that it could recur after surgery. (a) A 25-year-old female with female AGA with a 6-month history of a patch of AA. (b) A 35-year-old male with AGA with a 3-month history of a patch of AA. pected that 1.7% of patients with AGA have had, have, or will have AA. This may have great significance if one is contemplating hair transplantation surgery for AGA. If an AGA patient has a previous recent or remote history of AA, he or she must be warned that that it could recur after surgery. The 4.0 mm scalp biopsy with transverse sectioning is the best laboratory test to distinguish AGA from AA or telogen effluvium. Standard trichograms, involving the hair pluck, are very popular in Europe and are useful. However, the scalp biopsy will give the physician not only the same information with

respect to anagen/telogen and terminal/vellus ratios, but also more information on hair density and inflammatory perifollicular changes. The meticulous ‘unit area trichogram’ introduced by Rushton61 will also give information on hair density. However, it requires special skill and is fairly labor-intensive.

Laboratory tests In men, no laboratory work-up is necessary unless there is concomitant diffuse hair loss. In

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Figure 3.25a and b Stelae or fibrous streamers (FSt) commonly seen in AGA (courtesy of Dr Magdalena Martinka). women, this author recommends a routine thyroid stimulating hormone test (TSH), because of the frequency of thyroid abnormalities and the difficulty of distinguishing AGA from telogen effluvium. Ferritin levels are also ordered routinely on menstruating females, as low iron levels can trigger a telogen effluvium that may mimic AGA. Androgen levels should only be ordered in those women who appear clinically to have an androgen excess. The vast majority of women with AGA do not display hyper-androgenism, and therefore an androgen work-up is not indicated. If one suspects an androgen excess, a free testosterone and dehydroepiandrosterone sulfate (DHEAS) test should be ordered.

Pathology The histologic features of AGA are similar in males and females.62 Vertical sections show terminal hairs and follicular stelae in the subcutaneous tissue and reticular dermis and terminal and vellus hairs and stelae in the

papillary dermis.62–64 (Stelae are the residual fibrous tracts that mark the upward migration of the catagen, telogen or miniaturizing hair shaft and bulb (Figure 3.25).) Horizontal sections show distinctive changes in papillary and reticular dermis and in the deeper subcutaneous sections. In papillary dermis, both terminal, vellus, and vellus-like hairs are identified. Vellus and vellus-like hairs are less than 0.03 mm in diameter. Primary vellus hairs are small hairs, have a thin outer root sheath, and originate in the upper half of the dermis (Figure 3.26). Vellus-like hairs are miniaturized hairs that have a thick outer root sheath and originate from a terminal hair rooted in reticular dermis or subcutaneous fat with underlying stelae (Figure 3.27). Usually, hairs on horizontal section are arranged in follicular bundles of 2–4 hairs with sebaceous glands and arrector pili muscle63 (Figure 3.28). This patterning is typical of scalp hair. In reticular dermis there are no vellus or vellus-like hairs. Terminal hair bulbs predominate in anagen phase. Catagen and telogen terminal hairs are noted as well (Figure 3.29). In fat, only the

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Figure 3.26 Primary vellus hair (V) with a small hair shaft and small outer root sheath (ORS) (courtesy of Dr Magdalena Martinka).

Figure 3.28 Follicular bundles with miniaturized hairs (courtesy of Dr Magdalena Martinka).

deeper anagen terminal hairs are present (Figure 3.30). Follicular counts vary from level to level. Normally, in the upper papillary dermis counts are usually around 40–50. In the

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Figure 3.27 Secondary vellus hair (V) with small hair shaft and large outer root sheath (ORS), indicating true miniaturization (courtesy of Dr Magdalena Martinka).

Figure 3.29 A close-up of a follicular bundle in AGA, showing a vellus hair (V) and a telogen hair (T). Note the prominence of the sebaceous glands (SG) when hairs are miniaturized (courtesy of Dr Magdalena Martinka).

reticular dermis the number is usually reduced to 35, and in the fat is usually around 30. The difference of counts between papillary dermis and reticular dermis represents the number of

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Figure 3.30 In AGA, subcutaneous fat (F) contains anagen hairs (AH) (courtesy of Dr Magdalena Martinka).

Figure 3.31 Inflammatory infiltrate in AGA is not uncommon. Note the perifollicular lymphocytic infiltrate around this follicular bundle, which contains a miniaturized hair (MH) (courtesy of Dr Magdalena Martinka).

vellus hairs present in the papillary dermis. The difference in follicular counts between reticular dermis and fat represents the number of terminal telogen hairs. In AGA, the total number of follicular counts is usually normal in the papillary dermis. However, Whiting has seen a reduction in 10% of cases of AGA, indicating a decreased capacity for follicular regrowth in this small number of AGA patients.63 Ratios of anagen to telogen and terminal to vellus change in AGA. Normally 90–94% of hairs are in anagen and 6–10% in telogen. In AGA, as few as 80% of hairs are in anagen and up to 20% in telogen. In AGA, since miniaturization is due to the shortening of the anagen phase, with no decrease in telogen, there is clearly an increase in telogen hairs. The terminal to vellus ratio is normally 7:1. In AGA, the ratio is 2:1, indicating a marked shift to miniaturization in AGA. A characteristic microscopic finding in AGA is volumetric reduction of terminal follicles. Initially the follicles are only minimally de-

creased in diameter, but eventually a mixture of follicular sizes is apparent. Sebaceous glands seem enlarged in relation to these miniaturized follicles (Figure 3.26). Arao-Perkins bodies may be seen. These are small clusters of elastic fibers in the neck of dermal papillae. They are clumped in catagen and located at the lowest point of origin of the follicular stela. Stacks of these Arao-Perkins bodies may be seen, like rungs of ladders, in these stelae of miniaturized anagen hairs. One-third of patients with AGA show mild inflammation, just as one-third of normal controls do. Forty per cent of patients with AGA show moderate lymphohistiocytic inflammation, compared to only 10% of normal controls.62 (Figure 3.31). The role of inflammation is controversial. Possible causes for inflammation include seborrheic dermatitis, actinic damage, and the application of comedogenic, irritant, sensitizing or otherwise toxic cosmetics and grooming agents to the scalp. Even porphyrins elaborated by follicular bacteria and activated by UV

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light could cause some inflammation. These causes may be more pronounced in the less protected scalp.62

Treatment The whole raison d’être for treating AGA is the psycho-social aspect. Hair loss can truly detract from an individual’s holistic sense of well-being. It is important to address AGA in the context of overall patient health by taking the time to discuss the impact that AGA has on the patient’s life. Balding men are perceived as older and less physically and socially attractive.4–6 Some balding men feel less attractive, and struggle to cope with hair loss.4– 6 They worry and search for ways to compensate or restore body image. Behavioral coping mechanisms include changing hairstyle, improving physique or growing a beard or mustache.4–6 Women also experience great stress from AGA, which can affect their lives significantly. 5 These psycho-social issues should be addressed before the implementation of medical or surgical therapy.

Treatment options Two decades ago hair-growth promoters were non-existent. From a medical perspective, little could be offered to patients with AGA. Today there are new classes of evidence-based hair-growth promoters with unquestionable proven efficacy. A hair-growth promoting agent must either prolong the anagen phase or increase matrix girth by influencing follicular growth controls. For example, in AGA, drug targets may include steroid receptors, steroid metabolizing en-

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zymes and growth factors or cytokines that are implicated in controlling cell cycling and conversion of terminal to miniaturized hairs. We are currently just beginning to unravel the molecular control mechanisms and their location within the hair follicle. Further understanding of this cascade of orchestrated events is crucial for the development of more effective agents. Hair-growth promoters can be classified according to their mode of action: hormone modifiers versus biologic response modifiers. Hormone modifiers for AGA alter the perifollicular endocrine milieu by blocking either 5areductase or androgen receptor proteins. Biologic response modifiers have a non-endocrine effect on follicular cycling. The aim of all these agents is to prevent the apoptotic events precipitating catagen/telogen and to maintain a longer anagen state, so that genetically programmed miniaturization will be delayed or prevented. Another aim is to reverse miniaturization by providing the appropriate hormonal and cytokine factors that nurture hair growth and inhibit factors that have a negative effect on hair growth. There is still no cure for AGA and, without any treatment, those affected by AGA can experience a mean steady decrease in hair weight of about 6% per year.65 If treatment is desired, options can be summarized as follows: For men, options include finasteride, minoxidil, hair transplantation (HT) or a hairpiece. For women, options include minoxidil, spironolactone, cyproterone acetate, hair transplantation or a hairpiece. It is important that patients have realistic expectations regarding their medical treatment outcome, and the emphasis should be placed on the prevention of further hair loss. Medical treatments will only be effective if there is sufficient hair to salvage, with at least miniaturized hairs to convert into terminal hair. For those with more advanced

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hair loss, surgery or hairpiece may be the only options. Each option will be discussed in detail on the basis of classification.

Hormone modifiers Androgen blockade 5a-reductase inhibitor Finasteride: Finasteride (Propecia™) is a synthetic 4-azasteroid compound that is a specific inhibitor of type II 5a-reductase, an intracellular enzyme that converts T into DHT.38,40,66 Finasteride does not have any hormonal properties in itself,38,40 and has no estrogenic, antiestrogenic or progestational effects. By inhibiting type II 5a-reductase, it blocks the peripheral conversion of T to DHT, resulting in significant decreases in serum and tissue DHT concentrations.38,40,67–71 A recent study by Drake et al.69 showed that median scalp DHT levels decreased by 13% with placebo and by 64.1% and 69.4% with 1 mg and 5 mg of finasteride, respectively, after 42 days of treatment. Median serum DHT levels decreased by 71.4% and 72.2% with 1 mg and 5 mg on the same schedule. This study also showed that doses as low as 0.2 mg daily decreased .scalp and serum DHT. The study by Roberts et al.70 confirmed that finasteride 1 mg daily was the optimal dose, with 1 mg and 5 mg superior to lower doses such as 0.2 mg/daily. The daily 5 mg dose was not more efficacious than the 1 mg dose. In 1997 the FDA approved finasteride for use in the United States at a dose of 1 mg/day in men with AGA. Three double-blind, randomized, placebo-controlled studies were conducted in 1879 men ages 18 to 41 years with mild to moderate hair loss.40,72 Two of the studies enrolled men with predominantly vertex hair loss40 and one

study enrolled men with predominantly frontal hair loss.72 Finasteride 1 mg oral tablets or placebo tablets were taken once daily for 24 months in the vertex studies and 12 months in the frontal study. All three studies showed a significant hair count increase at 6 and 12 months in men treated with finasteride, while a significant decrease in hair counts was demonstrated in men treated with placebo. In the second year, hair counts remained stable at the increased level in the men who continued to receive finasteride. In the vertex studies, those individuals who were crossed over after 12 months from finasteride to placebo showed loss of the benefit achieved in the first 12 months by hair count, and those who were switched from placebo to finasteride showed significant gains. A histologic study by Whiting et al.73 showed a significant increase in terminal anagen hairs from baseline in scalp biopsies taken from men at baseline and after 12 months of finasteride. This was also significantly different from the placebo group. Histologically, vellus-like hairs decreased, and the terminal to vellus ratio increased, in the finasteride group compared with the placebo group, suggesting reversal of the miniaturization process. Therapeutic efficacy was assessed with a blinded rating of standardized photographs, patient self-assessment and investigator assessment. From these studies, it can be concluded that finasteride can stabilize hair loss in 83% of the cases with vertex hair loss after 2 years, and in 70% of cases with frontal hair loss after 1 year. The chances of mild to moderate regrowth are 61% on the vertex after 2 years and 37% on the frontal area after 1 year. Continued daily use of 1 mg oral finasteride is needed for sustained benefit. In two studies in men with vertex hair loss, treatment with finasteride 1 mg/day or placebo was continued for 5 years. Based on photographic assessment, treatment with finasteride for 5 years resulted in stabilization of hair loss

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in up to 90% of men, compared with 25% on placebo. Based on hair counts, regrowth was observed in 65% of men treated with finasteride for 5 years compared to gradual hair loss observed in 100% of men treated with placebo, leading to a net improvement in hair count of 277 hairs (31%) for men treated with finasteride compared with placebo after 5 years. While improvement for finasteride-treated men compared to baseline was greater at 24 months, the difference between the group treated with finasteride and the placebo group continued to increase throughout the 5 years of the study.74 In a study of hair weights done by Price, significant differences between finasteride and placebo were seen with small numbers of subjects. Sixty-six men aged 18–40 years with Norwood-Hamilton Stage III and IV were enrolled in a randomized, double-blind, placebocontrolled study. Thirty-three men received finasteride 1 mg daily and 33 received placebo for 48 weeks. The study was extended for 48 weeks for a total of 96 weeks. In the extension study, 26 men continued to receive finasteride 1 mg and 23 men remained on placebo. At 6week intervals, hair in a marked site was handclipped using a magnifying light. All hair samples were weighed in a single session by a technician who was blinded to patient, visit number and treatment. After 96 weeks, the total hair weight showed a statistically significant increase from baseline weight in the finasteridetreated subjects. The hair weight study demonstrated that treatment with finasteride 1 mg provides continued maintenance and improvement of hair growth over 96 weeks.75 Van Neste et al., 76 using the phototrichogram method, provided direct evidence that finasteride 1 mg daily promotes the conversion of hairs into the anagen phase. This study enrolled 212 men age 18–40 years with AGA. Patients were randomized to receive either finasteride 1 mg daily or placebo for 48 weeks.

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Macrophotographs were taken to measure total as well as anagen hair counts in a 1 cm2 target area of the scalp. In this study, treatment with finasteride 1 mg per day for 48 weeks significantly increased both total and anagen hair counts and improved anagen to telogen ratios compared to placebo. Treatment with finasteride resulted in a net improvement in the anagen to telogen ratio of 47%. Finasteride may show improvement in older men. A small 24-month double-blind placebocontrolled study on 28 men aged 53– 76 years taking finasteride 5 mg per day for benign prostatic hypertrophy showed statistically significant improvement in hair counts in a circular balding 1-inch target area in the finasteride group compared to the placebo group.77 A 2-year study in balding men between the ages of 41 and 60 years is ongoing. A study of finasteride in 136 postmenopausal women with AGA showed no benefit compared with placebo. 78,79 In this 1-year, double-blind, placebo-controlled, randomized, multicenter trial, 136 postmenopausal women (41–60 years of age) with AGA received finasteride 1 mg/day or placebo. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, blinded ratings of standardized photographs by an expert panel, and histologic analysis of scalp biopsy specimens. After 1 year of therapy, there was no significant difference in the change in hair count between the finasteride and placebo groups. Both treatment groups had significant decreases in hair count in the frontal/parietal (anterior/mid) scalp during the 1-year study period. Similarly, patient, investigator, and photographic assessments did not demonstrate any improvement in slowing hair thinning, increasing hair growth, or improving the appearance of the hair in finasteride-treated subjects compared with the placebo group. Finasteride was generally well tolerated. In

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post-menopausal women with AGA, finasteride 1 mg/day taken for 12 months did not increase hair growth or slow the progression of hair thinning. This was confirmed by histologic analysis on 94 women with AGA.73,79 Propecia™ 1 mg is to be taken every day, on a regular schedule, with or without food. The bioavailability after oral intake is 65%. 80 Ninety per cent of circulating finasteride is bound to plasma proteins and can cross the blood-brain barrier.80 Finasteride is metabolized in the liver, and therefore caution should be taken in patients with liver function abnormalities.80 Dosage does not need to be adjusted in case of renal insufficiency.80 Finasteride does not affect the cytochrome P450 metabolizing enzyme system, and no drug interactions have been reported.80 Finasteride is well tolerated, and side-effects occur in less than 2% of patients.40,72 Side-effects include 1.8% decreased libido (1.3% placebo), 1.3% erectile dysfunction (0.7% placebo) and 0.8% decreased ejaculate volume (0.4% placebo).40,72 There was no significant difference from the placebo group for each of these side-effects taken alone, but there is a statistical difference when all side-effects are considered together (3.8% vs 2.1%).40 Side-effects will subside spontaneously in 58% of those who decide to continue the treatment, and are reversible upon cessation of treatment.1 A recent study by Overstreet et al.81 confirmed that finasteride 1 mg daily for 48 weeks did not effect spermatogenesis or semen production in men aged 19– 41 years. The effect on prostate volume and serum PSA in this young population without benign prostate hypertrophy was small and reversible upon discontinuation of the drug.81 Finasteride can decrease PSA levels by 50% in older men.82 At the University of British Columbia Hair Research and Treatment Centre, it is recommended a baseline PSA be taken for older

men prior to initiation of therapy with finasteride. We also advise the patient’s family doctor to double the PSA value while patients are taking finasteride. Women who are or potentially may be pregnant should not take finasteride or handle crushed or broken tablets.80 Finasteride tablets are coated to prevent contact with the active ingredients during manipulation. The risk of teratogenicity in humans has not been directly evaluated,80 but there is a risk that finasteride exposure during pregnancy may cause hypospadias in the developing male fetus.17 Exposure to semen of men who are taking finasteride does not pose a risk to a pregnant woman’s male fetus.

Androgen-receptor blockers (ARP inhibitors) Systemic ARP inhibitors decrease both T and DHT by binding to the androgen receptor. They are suitable only in women and are contraindicated in men because of side-effects such as impotence, decreased libido, gynecomastia and feminization. Cyproterone acetate: Cyproterone acetate (CPA) is a potent progestin and an androgen receptor antagonist. CPA is available in Europe, Asia and Canada, but not in the United States. CPA is an effective treatment for hirsutism and acne.83–85 There are no large controlled clinical studies in AGA with CPA. It may have some effect on stabilization of hair loss, although regrowth is quite rare in this author’s experience.83,86–88 Fifty to 100 mg per day of CPA taken on days 5 to 14 of the menstrual cycle can be used in combination with an oral contraceptive to regulate menstrual cycles and to avoid pregnancy.17 Diane-35 contains 2 mg of CPA. This is adequate for the treatment of acne, but may be too low for female AGA.

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Side-effects include depression, nausea, menstrual irregularity, weight gain, breast tenderness and loss of libido.17 Women of childbearing potential must use an effective birth control method and be warned of the potential for feminization and the unknown teratogenicity risk if they become pregnant.17 Spironolactone: Spironolactone is an aldosterone antagonist, and its anti-androgenic effect is only mild. It is a competitive inhibitor of androgen receptor protein binding, and interferes with the translocation of this complex into the cell nucleus.85,89,90 It also depletes the cytochrome P450 enzyme (CYP 450) complex, which weakly inhibits androgen biosynthesis in the adrenal glands.89,90 Spironolactone is effective mostly for hirsutism.84,85 The drug is less effective in female AGA, and 200 mg per day is usually required. Small open trials have shown some clinical effect in AGA,91,92 but Spironolactone rarely offers the benefit of hair regrowth. The main side-effect is menstrual irregularities. Minimal increases in serum potassium may occur, but are uncommon.89 Women of childbearing age must use acceptable birth control methods and be aware there is a risk for feminization of a male fetus if they become pregnant. Estrogen mediated: Estrogens increase levels of sex hormone binding globulin (SHBG), thereby reducing circulating free T. They also inhibit secretion of luteinizing hormonereleasing hormone (LH-RH) by the hypothalamus, reducing androgen synthesis by the gonads. Estrogens are weak 5a-reductase inhibitors. Topical and oral estrogens have been used in women with AGA. Clinically, estrogens may help to maintain the status quo and to slow the progression of AGA,93 but appear to have little effect on stimulating regrowth, although no controlled studies have been done.

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Biologic response modifiers Minoxidil Minoxidil (Rogaine™) was the first agent shown to promote hair regrowth. It is a piperidinopyrimidine derivative that is used orally as an antihypertensive drug.66 Since one of its sideeffects is hypertrichosis, a topical solution was developed to treat hair loss. Its exact mechanism of action is still unclear. It does not appear to have either a hormonal or an immunosuppressant effect.94 Minoxidil increases duration of anagen and enlarges miniaturized and suboptimal hair follicles.1 It has been shown to have a direct mitogenic effect on epidermal cells both in vitro and in vivo; 95 plucked anagen hair bulbs from men applying minoxidil show a significant increase in proliferation index as measured by DNA flow cytometry.96 It has also been shown to prolong the survival time of keratinocytes in vitro.95 Another possible mechanism of action is the opposition to intracellular calcium entry. Calcium normally enhances epidermal growth factors (EGF) and inhibits hair growth. 97 Minoxidil is converted to minoxidil-sulfate, which is a potassium channel agonist and enhances potassium ion permeability, thus opposing the entry of calcium into cells.97,98 This would decrease EGF and subsequently enhance hair growth. Local vasodilatation does not seem to play a major role in hair growth.98,99 Minoxidil was approved for men by the FDA as a 2% solution in 1988 and as a 5% solution in 1997. For women, the 2% solution was approved in 1991. The 5% solution has not yet been approved for women, but it has been used worldwide by many dermatologists for many years. Both solutions are available without a prescription in the United States. In men with AGA, a double-blind, placebo-controlled trial,

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using hair weight measurements, found that topically minoxidil solutions of both 2% and 5% were significantly more effective than a placebo lotion or no treatment.65 The 5% solution produced a 35% increase in hair weights, compared to 25% with the 2% solution.65 The major increase in hair weight was observed within the first 20 weeks following initiation of therapy. Minoxidil application halted hair loss over the 96 weeks, while both the placebotreated men and the untreated men had an approximately 6% decrease in hair weight per year.65 Discontinuation of therapy results in loss of hair weight over 6 months to match the level in the placebo-treated group and untreated men.65 In women, one study of 32 weeks used hair weights to assess efficacy, and a 42.5% increase was found with the 2% solution compared to 1.9% with placebo.100 Clinically, loss of hair is evident once treatment with topical minoxidil is discontinued. Thus, topical minoxidil solution must be continued indefinitely.101–107 The rapid loss of hair weight after treatment confirms its trichogenic effects. Minoxidil can be used for either frontal or vertex scalp thinning.108 The increase in density is mostly due to miniaturized hairs that are converted into terminal hairs rather than a de novo regrowth.1 The major increase is usually seen within the first 4 months of therapy.104 The hair loss becomes stabilized after the initial period of regrowth.103 In a multicenter, double-blind study involving 2294 men between the ages of 18 and 50, approximately 30–35% of patients, applying 2% topical minoxidil solution twice daily, showed moderate to dense regrowth as assessed by hair counts using macro-photographs.108 Twicedaily application is needed for efficacy. In a multi-center, double-blind placebo-controlled study of 256 women between the ages of 18 and 45 with AGA, 63% who applied 2% topical minoxidil solution twice daily showed

minimal to moderate regrowth using hair counts in macrophotographs for assessment.109 One study in the stump-tailed macaque showed additive benefit in using both minoxidil and finasteride,110 but there are no data on this combination therapy in humans. Practically, if one starts both medications simultaneously in a male patient, he will not know whether it is either minoxidil, finasteride or the combination that is having the effect. For some patients, this may not be an issue, and combination therapy, if affordable, is a reasonable option. For those male patients already using minoxidil and wanting to switch to finasteride, it is important to continue using minoxidil for at least 4 months after starting finasteride to prevent the loss of hair that occurs with the discontinuation of minoxidil.1 Minoxidil should be used for one full year before its efficacy is assessed. Therapeutic efficacy is evaluated by patient satisfaction and physician comparison with a baseline photograph. In patients with very early AGA, it is hard to appreciate any regrowth or hair loss because of the great hair density. In those cases, physicians must rely mostly on the patient’s impression. One millilitre of minoxidil solution must be used twice daily, every day in order to be effective. Twenty-five drops (1 ml) must be applied directly on to a dry scalp and then slightly spread with the fingers.17 No more than 2 ml should be applied every day, regardless of the extent of the affected area. For someone with moderate amounts of hair, the best mode of application is to divide it into 5 parts and apply 5 drops to each part. The spray applicator is not recommended, since most of the sprayed solution will be applied on the hairs, where it is ineffective and thus wasted.17 Patients must be told that minoxidil solution is a scalp lotion, not a hair lotion.

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Figure 3.32 Hypertrichosis of the face can occur in women using topical minoxidil solution. (a) Frontal view. (b) Lateral view.

Minoxidil is poorly absorbed after topical application on normal intact skin.80 Only 0.3 to 4.5% reaches the systemic circulation.80 The effects of concomitant occlusion or abnormal skin are unknown 80 . The percentage of minoxidil that is absorbed is eliminated within 4 days.80 It is metabolized in the liver and excreted in the urine. Studies have not shown any change in blood pressure or any other hemodynamic effect, but minoxidil solution should be used with caution in patients with cardiovascular disease.80,103 Minoxidil should not be used by pregnant or nursing women.80 There is no evidence of teratogenicity in rats and rabbits, but in humans data are lacking.80 Minoxidil is secreted in human milk.80 Accidental ingestion of topical minoxidil could lead to serious adverse effects. Each ml of the 5% solution contains 50 mg of minoxidil. The maximum oral daily dose for the treatment of hypertension is 100 mg.80 Topical minoxidil solution is very safe, and side-effects are mainly dermatologic. The most frequent side-effect is an irritant contact der-

matitis, probably due to the propylene glycol in the vehicle.1,17 Occasionally, minoxidil itself causes an allergic contact dermatitis.111–113 Incidence of scalp irritation is approximately 7% with the 2% solution, and may be slightly higher with the 5% solution.1,17,103 Contact with any mucosal surface (usually the eyes) should be avoided, because it will cause burning and irritation. If such an event occurs, thoroughly rinse the eyes with cool tap water.80 If patients experience an irritant contact dermatitis due to the 5% solution, they should stop the treatment until all symptoms have resolved. If they again develop dermatitis on the second trial, the concentration should be lowered to 2%. Patients will be unlikely to develop a tolerance to this side-effect, and the treatment may have to be discontinued altogether. Facial hypertrichosis (Figure 3.32) may occur in 3–5% of women, and is usually not a problem in men.17 It is not clear yet why the hypertrichosis occurs; but it is possibly either through a systemic effect or via a transfer of

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the drug.17 It affects mostly the forehead, malar areas, and sides of the face.17 Those women who, prior to treatment, already have mild hirsutism are more likely develop this side-effect. Hypertrichosis is totally reversible upon discontinuation of the drug. Those patients who are affected and continue with the treatment usually notice a decrease in and even a disappearance of the facial hair within a year.17 Thorough hand-washing after each use may minimize irritation and possibly hypertrichosis in other body areas.

Tretinoin Tretinoin (all-trans-retinoic acid) is a biologic response modifier. It is a potent cell mitogen that promotes and regulates epithelial cell growth and differentiation.114 It promotes angiogenesis115 and increases percutaneous absorption by affecting the fluidity and the lipid composition of cell membranes.114 It has been proposed that tretinoin may have an effect on AGA by stimulating the growth of suboptimal hairs and could also act synergistically with minoxidil to produce more dense hair regrowth than either compound alone.116 A small study on men with AGA showed some hair regrowth when treated for 1 to 2 years with a combination solution of 0.025% tretinoin and 0.5% minoxidil, formulated using generic powder forms.116 However, Rogaine® and Retin-A®, the proprietary products, are incompatible and become ineffective if compounded in the same solution.17 They must either be mixed using generic powder forms or be applied as separate treatments. Rogaine® must be applied every morning and night and Retin-A ® during the day. Even though there seems to be some benefit in using the combination, most patients are not compliant with the need for an extra application

during the day, making this combination an impractical option for most patients. In addition, the irritation of tretinoin is not always well tolerated.

Treatment of AGA in women Many factors must be considered in the treatment of AGA. An algorithmic approach to AGA in women, structured about the Ludwig classification, is presented in Figure 3.33. In women with stage I or II hair loss, topical 5% minoxidil solution is offered and continued for 1 year (Figures 3.34, 3.35). If patients respond to treatment, then it is continued for as long as hair loss is perceived to be important to the patient. If ongoing hair loss is detected after 1 year, patients may be offered androgen blockade with CPA or spironolactone, or hair transplantation if the patient has a good occipital scalp donor area. Hair transplantation in female AGA will be discussed in Chapter 4. For those with more advanced hair loss and a poor donor area, a hairpiece is suggested. Patients should be reassured on the cosmetic appearance of hairpieces, as they can give excellent results. A partial hairpiece may also give a natural and satisfying appearance. Patients often need guidance as to where to get hairpieces, and it is most appreciated when they are given a few options. For women with Ludwig stage III, topical therapies are usually ineffective. Hyper-androgen excess should be checked by history and physical examination. If there is any sign of virilization (i.e. severe acne, hirsutism, seborrheic dermatitis, menstrual irregularities, or infertility), serum testosterone and dehydroepiandrosterone-sulfate (DHEAS) tests should be ordered and referral to an endocrinologist may be indicated.

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Figure 3.33 An algorithmic approach on the treatment of female AGA: UCSF-UBC Treatment Protocol for androgenetic alopecia in women (courtesy of Jerry Shapiro, MD, Vera H.Price, MD and Harvey Lui, MD).

Treatment of AGA in men For men, the final decision is based on many factors, such as the extent of hair loss, the presence or absence of miniaturized hairs, patient age, preference for topical or systemic therapy, financial considerations and patient expectations. An algorithmic approach to male AGA, structured around the Norwood-

Hamilton classification, is outlined in Figure 3.36. In those with less severe hair loss and numerous miniaturized hairs, medical therapeutic options include finasteride or minoxidil (Figure 3.37). Therapeutic efficacy is evaluated at 1 year (Figure 3.38). If evaluation reveals stabilization or regrowth, then patients are counseled to continue with treatment for as long as they feel hair loss is im-

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Figure 3.34 A 40-year-old female with AGA (a) before topical minoxidil solution; and (b) after 6 months of use of topical minoxidil, showing marked improvement, with narrowing of her part/ parting.

Figure 3.35 A 53-year-old female with AGA (a) before topical minoxidil solution; and (b) after 8 months of topical minoxidil solution, showing marked improvement. portant to them. If ongoing hair loss occurs despite treatment, then a surgical approach or a hairpiece should be discussed. Combination therapy with both finasteride and minoxidil has been shown to have additive hair regrowth effects in a balding stump-tail macaque model,110 and can be prescribed to

very motivated patients. In those with more advanced hair loss and few miniaturized hairs, medical therapy is unlikely to work, and a surgical approach or a hairpiece is recommended. Studies are currently under way evaluating the effect of finasteride on the number of hair transplantation sessions. It is

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Figure 3.36 An algorithmic approach on the treatment of male AGA: the UCSF-UBC Treatment Protocol for androgenetic alopecia in men (courtesy of Jerry Shapiro, MD, Vera H.Price, MD and Harvey Lui, MD).

Figure 3.37 A good candidate for medical treatment of male AGA (note the presence of miniaturized hair).

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Figure 3.38 A 24-year-old male with AGA (a) before the use of finasteride 1 mg/day and (b) one year later, showing improvement.

A 33-year-old male with AGA (c) before the use of finasteride 1 mg/day and (d) after 11 months of therapy, showing improvement. likely that the combination of the two will reduce the number of sessions. This author recommends finasteride on all patients undergoing hair transplants if they are Stage IIIV–V pre-transplantation (Figure 3.39).

Patient monitoring How is response to therapy assessed, and what methods can be used to determine treatment success or failure? First, patient impressions

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Figure 3.40 Digital photography with a stereotactic device (Canfield Scientific, New Jersey, USA) is ideal as a means for monitoring patients.

Figure 3.39 (a) A 35-year-old male with two previous sessions of hair transplants, the last transplant four years before the photo. He was considering another session. (b) The same individual 12 months after the use of finasteride 1 mg/day, showing significant improvement. This patient felt he did not need another transplant session.

not have a digital set-up with a stereotactic device, then an ordinary photograph should be taken. Both patient and physician should realize that these uncontrolled snapshots are not accurate, but do give a general impression of the kind of coverage present at baseline. The photograph is reviewed with the patient at each follow-up and compared to current hairgrowth status, thereby imparting some kind of objective measurement of response. Photographs do not need to be taken annually. Finally, serial part diameters can be taken from the same areas of the scalp with each visit.

Matching therapy to patient expectations

are determined. Unfortunately, many patients are often unreliable and unsatisfied with subjective estimates. Ideally, each patient has digital photography taken at a standardized distance and position (Figure 3.40). If one does

Patient expectations are an important factor when discussing therapeutic options and goals. The key features to distinguish between are prevention and regrowth. Expectations are largely dictated by the extent of hair loss. In men, those

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with stage II or III hair loss have lower expectations and are primarily seeking prevention. It is also important to reset these expectations, emphasizing that regrowth can be difficult to perceive and only stabilization may be detected. Those with more advanced balding have higher expectations and are hoping for regrowth. If expectation levels are high, they may less likely to be satisfied with medical therapy. It is important to keep the expectations of this group low, emphasizing prevention and minimizing expectations of regrowth. Those seeking hair transplants all have high expectations and are usually satisfied.

Conclusions The treatment of AGA has advanced tremendously in the last 10 years. The consultation process is no longer a disappointing meeting with the physician, but consists of an interactive session with choices and discussion. The algorithmic approach to AGA allows the clinician to select an appropriate therapeutic modality based on stage of hair loss. It is important to present patients with all therapeutic options, while addressing realistic expectations.

Outlook for the future There are currently two treatment modalities for AGA: androgen blockade and biologic response modifiers. It is expected that more agents will be developed in both categories. Dual inhibitors, such as combined type I and type II 5a-reductase inhibitors, will probably be evaluated. Topical androgen receptor protein inhibitors and new biologic response modifiers will also undoubtedly be available. Targeted follicular gene therapy has the potential to block or intercept the synthesis of 5a-

reductase or the androgen receptor protein. Follicular stem-cell gene therapy will also be explored in the future, and would allow alteration of specific DNA transcription, RNA translation and modified synthesis of putative enzymes and receptors involved in the process of hair follicle miniaturization.

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androgenetic alopecia as a marker of insulin resistance [letter] [in process citation]. Lancet, 2000; 356(9236): 1165–6. Cooke N.T. Male pattern alopecia and coronary artery disease in men. Br J Dermatol, 1979; 101(4):455–8. Hawk E., Breslow R.A. and Graubard B.I. Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev, 2000; 9(5):523–7. Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol, 1977; 97(3):247–54. Olsen E. Disorders of Hair Growth, ed. E. Olsen, pp. 257–279. 1994; New York: McGraw-Hill, Inc. Hamilton J. Patterned loss of hair in men: Types and incidence. Ann NY Acad Sci, 1951; 53:708–28. Norwood O.T. Male pattern baldness: classification and incidence. South Med J, 1975; 68(11):1359–65. Rushton H., James K.C. and Mortimer C.H. The unit area trichogram in the assessment of androgen-dependent alopecia. Br J Dermatol, 1983; 109(4):429–37. Whiting D. Scalp biopsy as a diagnostic tool in androgenetic alopecia. Dermatol Ther, 1998; 8:24–33. Whiting D.A. Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia [published erratum appears in J Am Acad Dermatol, 1993 Oct; 29(4):554]. J Am Acad Dermatol, 1993; 28(5 Pt 1):755–63. Headington J.T. Transverse microscopic anatomy of the human scalp. A basis for a morphometric approach to disorders of the hair follicle. Arch Dermatol, 1984; 120(4): 449–56. Price V.H., Menefee E. and Strauss P.C. Changes in hair weight and hair count in men with androgenetic alopecia, after

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application of 5% and 2% topical minoxidil, placebo, or no treatment. J Am Acad Dermatol, 1999; 41(5 Pt 1):717–21. Sawaya M.E. Novel agents for the treatment of alopecia. Semin Cutan Med Surg, 1998; 17(4):276–83. Gormley G.J., Stoner E., Bruskewitz R.C., et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group [see comments]. New Engl J Med, 1992; 327(17):1185–91. Stoner E. The clinical development of a 5 alpha-reductase inhibitor, finasteride. J Steroid Biochem Mol Biol, 1990; 37(3): 375–8. Drake L., Hordinsky M., Fiedler V., et al. The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol, 1999; 41(4):550–4. Roberts J., et al. Clinical dose ranging studies with finasteride, a type 2 5 alpha reductase inhibitor in men with male pattern hair loss. J Am Acad Dermatol, 1999; 41(4):555–63. Dallob A.L., Sadick N.S., Unger W., et al. The effect of finasteride, a 5 alpha-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab, 1994; 79(3):703–6. Leyden J., Dunlap F., Miller B., et al. Finasteride in the treatment of men with frontal male pattern hair loss [see comments]. J Am Acad Dermatol, 1999; 40(6 Pt 1):930–7. Whiting D.A., Waldstreicher J., Sanchez M. and Kaufman K.D. Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of finasteride 1 mg treatment of men and postmenopausal women. J Invest Dermatol Symp Proc, 1999; 4(3):282–4. Abstract. Propecia: New Clinical Data—Five Year Experience. In European Academy of Dermatovenereology Annual Meeting. Oct 2000. Geneva.

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75. Price V.H. Changes in hair weight in men with androgenetic alopecia after taking finasteride. Presentation at European Academy of Dermatology. 1999. Amsterdam. 76. Van Neste D., et al. Finesteride increases anagen hair in men with androgenetic alopecia. Br J Dermatol 2000; 143(4):804–10. 77. Brenner S. and Matz H. Improvement in androgenetic alopecia in 53–76-year-old men using oral finasteride. Int J Dermatol, 1999; 38(12):928–30. 78. Roberts J., Price V.H., Olsen E., et al. The effects of finasteride on post-menopausal women with androgenetic alopecia. In Hair Workshop. 1998. Brussels, Belgium. 79. Price V.H., Roberts J.L., Hordinsky M., et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol, 2000; 43(5): 768–76. 80. Canadian Pharmacists Association Monography, Minoxidil and Finasteride. In Compendium of Pharmaceuticals and Specialties (CPS) 34th Edition. 1999; Ottawa, Canada. 81. Overstreet J.W., Fuh V.L., Gould J., et al. Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men. J Urol, 1999; 162(4):1295–300. 82. Matzkin H., Barak M. and Braf Z. Effect of finasteride on free and total serum prostatespecific antigen in men with benign prostatic hyperplasia. Br J Urol, 1996; 78(3):405–8. 83. Hammerstein J., Meckies J., Leo-Rossberg I., et al. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism. J Steroid Biochem, 1975; 6(6):827–36. 84. Namer M. Clinical applications of antiandrogens. J Steroid Biochem, 1988; 31(4B):719–29. 85. Shaw J.C. Antiandrogen therapy in dermatology. Int J Dermatol, 1996; 35(11): 770–8. 86. Ekoe J.M., Burckhardt P. and Ruedi B. Treatment of hirsutism, acne and alopecia

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with cyproterone acetate. Dermatologica, 1980; 160(6):398–404. Mortimer C.H., Rushton H. and James K.C. Effective medical treatment of common baldness in women. Clin Exp Dermatol, 1984; 9(4):342–50. Neumann F. Pharmacology and potential use of cyproterone acetate. Horm Metab Res, 1977; 9(1):1–13. Lobo R.A., Shoupe D., Serafini P., et al. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril, 1985; 43(2): 200–5. Menard R.H., Guenthner T.M., Kan H. and Gillette J.R. Studies on the destruction of adrenal and testicular cytochrome P-450 by spironolactone. Requirement for the 7alphathio group and evidence for the loss of the heme and apoproteins of cytochrome P-450. J Biol Chem, 1979; 254(5): 1726–33. Rushton D. Quantitative assessment of spironolactone treatment in women with diffuse androgen-dependent alopecia. J Soc Cosmet Chem, 1991; 42:317. Burke B.M. and Cunliffe W.J. Oral spironolactone therapy for female patients with acne, hirsutism or androgenic alopecia [letter]. Br J Dermatol, 1985; 112(1):124–5. Orfanos C.E. and Vogels L. Local therapy of androgenetic alopecia with 17 alphaestradiol. A controlled, randomized doubleblind study. Dermatologica, 1980; 161(2): 124–32. Khoury E.L., Price V.H., Abdel-Salam M.M., et al. Topical minoxidil in alopecia areata: no effect on the perifollicular lymphoid infiltration. J Invest Dermatol, 1992; 99(1):40–7. Baden H.P. and Kubilus J. Effect of minoxidil on cultured keratinocytes. J Invest Dermatol, 1983; 81(6):558–60. Kiesewetter F., Langer P. and Schell H. Minoxidil stimulates mouse vibrissae follicles in organ culture [letter; comment]. J Invest Dermatol, 1991; 96(2):295–6.

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97. Ohtsuyama M. Minoxidil sulfate effect of internal calcium of cell in the epidermis and epidermal appendages. In Hair Reseach for the Next Millennium, ed. V.R.D.Van Neste, p. 481. 1996; Amsterdam: Elsevier Science. 98. Buhl A.E. Minoxidil’s action in hair follicles. J Invest Dermatol, 1991; 96(5): 73S–74S. 99. Philpott M.P., Sanders D.A. and Kealey T. Whole hair follicle culture. Dermatol Clin, 1996; 14(4):595–607. 100. Price V.H. and Menefee E. Quantitative estimation of hair growth. I. androgenetic alopecia in women: effect of minoxidil. J Invest Dermatol, 1990; 95(6): 683–7. 101. Olsen E.A. Topical minoxidil in the treatment of androgenetic alopecia in women. Cutis, 1991; 48(3):243–8. 102. Olsen E.A., Buller T.A., Weiner S., DeLong E.R. Natural history of androgenetic alopecia. Clin Exp Dermatol, 1990; 15(1): 34–6. 103. Olsen E.A., Weiner M.S., Amara I.A. and DeLong E.R. Five-year follow-up of men with androgenetic alopecia treated with topical minoxidil. J Am Acad Dermatol, 1990; 22(4):643–6. 104. Olsen E.A. and Weiner M.S. Topical minoxidil in male pattern baldness: effects of discontinuation of treatment. J Am Acad Dermatol, 1987; 17(1):97–101. 105. Olsen E.A., DeLong E.R. and Weiner M.S. Long-term follow-up of men with male pattern baldness treated with topical minoxidil. J Am Acad Dermatol, 1987; 16(3 Pt 2):688–95. 106. Olsen E.A., Weiner M.S., DeLong E.R. and Pinnell S.R. Topical minoxidil in early male

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pattern baldness. J Am Acad Dermatol, 1985; 13(2 Pt 1):185–92. Kidwai B.J. and George M. Hair loss with minoxidil withdrawal [letter]. Lancet, 1992; 340(8819):609–10. Olsen E. Treatment of androgenetic alopecia with topical minoxidil solution. Res Staff Phys, 1989; 35:53. DeVillez R.L., et al. Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution. Arch Dermatol, 1994; 130(3):303–7. Diani A.R., Mulholland M.J., Shull K.L., et al. Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab, 1992; 74(2):345–50. Wilson C, Walkden V., Powell S., et al. Contact dermatitis in reaction to 2% topical minoxidil solution. J Am Acad Dermatol, 1991; 24(4):661–2. Ebner H. and Muller E. Allergic contact dermatitis from minoxidil. Contact Dermatitis, 1995; 32(5):316–17. Tosti A., Bardazzi F., De Padora M.P., et al. Contact dermatitis to minoxidil; Contact Dermatitis, 1985; 13(4):275–6. Elias P.M. Epidermal effects of retinoids: supramolecular observations and clinical implications. J Am Acad Dermatol, 1986; 15(4 Pt 2):797–809. Sporn M.B., Roberts A.B., Roche N.S., et al. Mechanism of action of retinoids. J Am Acad Dermatol, 1986; 15(4 Pt 2):756–64. Bazzano G.S., Terezakis N. and Galen W. Topical tretinoin for hair growth promotion. J Am Acad Dermatol, 1986; 15(4 Pt 2):880–3, 890–3.

4 Surgical management of androgenetic alopecia

Most follicles at the occiput of the scalp have been ‘genetically programmed’ to persist as non-miniaturized terminal hairs throughout the life of a patient with AGA. These hairs are

unlikely ever to become vellus-like. These follicles can be transplanted anywhere on the same individual and will produse coarce terminal hairs for the lifetime of the individual.

Figure 4.1 Hair transplantation two decades ago: (a), (b), (c). Note the unnatural corn-row tufting of hair surgery performed in the 1960s and 1970s. (d). This patient requested laser hair removal to remove his grafts from twenty years ago.

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Figure 4.2 Donor area is chosen in the occipital portion of the scalp.

This is termed donor dominance of the grafts, and is the basis for the success of hair transplantation. The chapter will deal solely with hair transplantation, as this is the most commonly performed surgical procedure for androgenetic alopecia (AGA). The field of hair transplantation has changed markedly within the past 10 years (Figure 4.1). The advent of (1) strip harvesting for the donor area; (2) the introduction of finer, more natural-appearing grafts; and (3) the use of slits for the recipient area have revolutionized the field of hair transplantation. There are many differing approaches to hair transplantation, and these are discussed thoroughly elsewhere.1,2 This chapter will discuss hair transplantation as it is performed at the University of British Columbia Hair Clinic.

The donor site The selected donor area is initially trimmed (Figures 4.2, 4.3) and anesthetized using the

Figure 4.3 Donor area at the back of the scalp is trimmed.

Figure 4.4 Donor area is injected with tumescent anesthesia.

tumescent technique (Figure 4.4). The tumescent technique involves the injection of large volumes of very dilute lidocaine and epinephrine. This anesthetic approach was first developed for patients undergoing liposuction.3 It has been shown that tumescent anesthesia significantly reduces the total

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Figure 4.5 (a) Multiple-bladed knife is prepared. (b) The blades are angled in the direction of the hairs. Constant monitoring of the angle is necessary. This angle is crucial, and varies from 100 to 120 degrees. If the angle is not precise there will be considerable follicular transection and subsequent follicular wastage.

number of milligrams of lidocaine required and maximizes the vasoconstrictive benefits of epinephrine, thus decreasing bleeding.4 A solution prepared by adding 25 ml of 2% lidocaine without epinephrine, 2.5 ml of 8.4% sodium bicarbonate solution and 0.4 ml of 1:1000 epinephrine is added to a 250 ml IV bag of saline. Approximately 6–7 injections are performed with an action pump syringe and a 25 gauge needle into the trimmed occipital area. A mandatory period of 20 minutes is required for the anesthetic to have its full effect in terms of anesthesia and vasoconstriction. Just before excision, repeat injections of anesthesia are given to the patient’s donor area. This increases skin turgor in the area and allows easier visualization and excision of the donor area. Any curly hairs will also become more ‘straightened’ with this increased turgor,

and as a result are less likely to be later transected. Any ‘hot spots’ that are not completely anesthetized can be further anesthetized with small amounts of 2% lidocaine. The hair follicle with its dermal papilla usually extends to a depth of 4–6 mm. Tissue more than 1 mm below the dermal papilla is not necessary for transplanting. It is important to keep this in mind when harvesting strips. If an excision is too deep, it can cause unnecessary harm to underlying arteries and veins. Harvesting with strips as opposed to punches allows for more efficient harvesting and better cosmesis. Strip harvesting has truly replaced the older punch-harvesting methods. A multi-bladed knife with #10 Personna blades is angled parallel to the hair shafts (Figures 4.5a and 4.5b). This angle is crucial and varies from 100 to 120 degrees. If the angle is not pre-

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Figure 4.6 Strips are excised from the donor area. Strips vary in size depending on whether it is a regular or a megasession. Usually three strips of 2.25 mm are removed with a regular session or four strips of 2.5 mm for a megasession. The surgical defect will range from 6.75 mm-1.0 cm in width. Length is usually 10–14 cm.

cise there will be considerable follicular transection and subsequent follicular wastage. After the stab incision, blades are maintained at a constant depth, with avoidance of any kind of ‘sawing’ motions. Most strips are 12–16 cm in length. The width of each strip varies for each individual. For an average regular session, at the University of British Columbia (UBC) Hair Clinic, three strips of 2.25 mm each for a total of 6.75 mm width are excised. This will yield an average total of 600–800 grafts. For an average megasession involving considerably more harvesting, the strips will usually be longer and wider, with four 2.5 mm strips taken for a total width of 1 cm. This will usually yield 1100–1350 grafts on average. The strips are released at the ends with a V shape and from underlying tissue with a #15

Figure 4.7 Strips are released from the rest of the scalp with a #15 blade.

Figure 4.8 Strips are removed with a V shape at the ends.

Personna scalpel blade (Figures 4.6, 4.7, 4.8). This is done meticulously, so as not to harm the lower portions of the follicle as well as not injure any underlying blood vessels. Small bleeders can be cauterized or tied off with 3–0 Vicryl absorbable sutures.

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Figure 4.9 The surgical defect is closed with a continuous stitch.

The size of the strips taken varies according to how much area needs to be covered, hair density, ethnicity and scalp elasticity. Larger areas of alopecia will require greater coverage and thus larger strips. If donor follicular density is low, wider strips are necessary. AfricanAmericans in particular usually have a lower scalp follicular density and frequently require a greater total width of strips. However, if an individual’s scalp is too tight, the total width of strips removed will be lessened. The donor site is sutured with blue nylon 3–0 Novafil. We have found that sutures are more confortable than staples for the patient, and as a result prefer closure by a continuous suture (Figure 4.9). However, certain centers have found the exactly the opposite, and just use staples.5 The resulting scar is linear, usually with a diameter of 1–2 mm (Figure 4.10). These scars can be excised at subsequent sessions, leaving only one final scar. Alternatively, another scar can be created above or below the previous

Figure 4.10 (a) The scar 6 months after the procedure. (b) A rare complication of the donor area is the formation of a keloid, which is more commonly seen in African-Americans or Asians. Keloids can subsequently be treated with intralesional corticosteroid. This particular Asian patient did not mind the keloid, as it was well camouflaged by his donor hair. He did not inform our center of this complication, and it was not discovered until he returned two years later for his subsequent second session.

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Figure 4.11 Strips are placed on a tongue depressor and are sectioned with a #10 blade into smaller grafts.

Figure 4.12 Much of the fat is trimmed away, leaving only 1 mm of fat underneath the follicle.

one. All of this is camouflaged nicely by the patient’s hair, which must have a prerequisite length of 2 cm. Complications in the donor are very rare, and include keloid formation (Figure 4.10b) wound dehiscence, and paresthesias.

During preparation, grafts are grouped according to size and density on Petri dishes on ice (Figures 4.13 and 4.14). It is essential that during this whole process strips and grafts are not permitted to dry out and are well moistened with saline. The most obvious advantage of using these small grafts is the elimination of tufting reminiscent of the old grafts. Because of the natural appearance of the small grafts, the patient is not committed to have to continue through many sessions to get that final natural look.

Graft hair preparation The strips are placed in saline on ice packs and subsequently subdivided into grafts with only one single hair follicle (micrografts) or one to two follicular bundles/follicular units containing two to four hairs (minigrafts). This is performed by meticulous dissection of the strips with a #10 Personna blade and fine jewelers’ forceps (Figure 4.11). Appropriate magnification is necessary to perform this. Excessive amounts of fat, hair without matrices, and any scar tissue (especially from a previous transplant) is removed (Figure 4.12).

The recipient area In the frontal area, facial framing is frequently what the patient wants. Positioning the hairline is critical, and must be discussed at length with the patient. This is drawn in before the surgery. Stough has presented guidelines.6 At

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Figure 4.13 Grafts are subdivided into micrografts containing single hairs (bottom) or minigrafts with single follicular bundles of 2–3 hairs (top).

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Figure 4.14 The grafts are grouped on to Petri dishes according to the number of hairs per graft.

Figure 4.15 (a) and (b). The hairline is drawn onto the recipient area.

the UBC hair clinic we mark an area 8–11 cm midline above the glabella and create a curved, bell-shaped hairline (Figure 4.15a). On lateral

view, the area marked is always parallel to the ground and on the flat portion of the scalp (Figure 4.15b).

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Figure 4.16 On the vertex of the scalp, the hair direction is planned.

Figure 4.17 Slits into the recipient area are made with an Ellis 1.5 or 2 mm spear tip.

Figure 4.18 (a) and (b). Slits are made into the recipient area.

On the vertex, the area is marked as to hair direction prior to the surgery (Figure 4.16). The recipient area is anesthetized with a field block of 2% lidocaine with a mandatory 20-minute waiting period to maximize vasoconstriction. Slits are made with an Ellis 1.5 mm or 2.0 mm spear tip on a handle (Figure

4.17). They are directed parallel to the direction of the hair. Usually we allow 1.5–2.5 mm between the slits laterally and 1 mm anteriorly or posteriorly (Figure 4.18). The majority of patients get satisfactory cosmetic results with 3 sessions of slit grafting in a totally bald area. Those with pre-existing hair may only need 2

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Figure 4.19 Grafts are placed on to the fingers of the nurses.

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Figure 4.20 Grafts are placed into slits with jewelers’ forceps.

Figure 4.21 (a) and (b). Scalp after placement of grafts.

sessions. In the frontal area, a zone of approximately 300 pure micrografts is created. The remaining minigrafts are placed behind this frontal zone. For a regular session, 600–900 total grafts are transplanted, usually covering 30–50% of the anterior portion of the scalp. A megasession increases coverage, with a total

of 1100–1400 grafts, and allows the placement of grafts into the anterior portion as well as the vertex of the scalp. Planting into the slits is done meticulously with jewelers’ forceps (Figures 4.19 and 4.20). Special care is taken not to harm any of the grafts. The hairs in the grafts are aligned with

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Figure 4.22 Post-operative dressing covering donor and recipient area. Graftcyte® dressings are placed over the recipient area.

Patients are warned of a telogen effluvium that can occur with the transplanted grafts as well as with pre-existing recipient hair. Patients must wait for up to six months to see the full benefits of a hair transplant. We perform repeat sessions after a minimum of six months between sessions. This allows the transplanted hair to grow in visibly and allows us to visualize where to put the new set of grafts. The average patient with marked hair loss will receive on the average 3 sessions (Figures 4.23–4.25).

Finasteride and hair transplants the appropriate angle and direction fitting directly into the slits. The grafts can be flush or slightly elevated above the surrounding tissue (Figures 4.21a and 4.21b). A regular session will usually take 5–6 hours. A megasession may take 6–8 hours to complete. Patients leave the office with a moist dressing covering the donor and recipient areas (Figure 4.22). The dressing is removed the next day. With appropriate postoperative care and daily shampooing, after one week virtually all crusting will have disappeared. Facial edema beginning 48 hours after the procedure and lasting for 5 days is certainly common, especially with megasessions. Patients are warned appropriately and are told to expect it. If the facial edema does not then happen, then this becomes a bonus for the patient. Forehead swelling is treated with the frequent application of ice-packs and upright positioning (at at least a 45 degree angle) for one week while sleeping. It is best for patients to take one week off work. A full working schedule and exercise can be resumed 1 week after the procedure.

We frequently recommend our male patients with pre-transplant Norwood-Hamilton Stages III–V to take finasteride 1 mg daily. Finasteride may stabilize any further thinning of pre-existing hair in the recipient area. This would logically reduce the number of sessions necessary. There also is a possibility of regrowth as well as in the patient illustrated in Fig. 3.36. (See Figures 3.39a and 3.39b in Chapter 3 on androgenetic alopecia)

Minoxidil and hair transplants There are reports in the literature that topical minoxidil solution twice daily may lessen the effluvium usually seen postoperatively.7 Many of our female patients continue to use topical minoxidil 5% solution after transplantation to help stabilize any further loss and further reduce the number of sessions.

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Figure 4.23 (a). A 40-year-old male prior to hair transplant, (b). Two years later, after four regular sessions.

Figure 4.24 (a). A 27-year-old male prior to hair transplant, (b). 1 year later, after two regular sessions.

Hair transplantation in Women Because AGA in women may be more diffuse, the occipital donor area may be affected. It is area. important to choose the appropriate fe-

male surgical candidate. Atleast 30% (in the author’s experience) have significant thinning in the donor area and are not good candidates. Another problem with women is the resulting effluvium of pre-existing hair in the recipient This can be somewhat lessened with the use of topical minoxidil solution applied twice

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Figure 4.25 (a). A 43-year-old male prior to hair transplant. (b). Two megasessions and a regular session and 3 years later. (c). Side view of the same patient before hair transplant. (d). Side view after hair transplant.

daily, but frequently will still occur even then. In such cases the patient will experience effluvium of both the transplanted hair and her preexisting hair, and will feel that her situation has worsened significantly compared to her pre-transplant state. Our experience is that as long as the female patient is warned that there may be significant worsening before improvement and that the lag time is 6 months, then she will be prepared emotionally. If she is not

able to accept this fact, she is not a candidate for hair transplant surgery.

Conclusion Hair transplant surgery has become very popular, as its results are cosmetically very natural. Micro-grafting, mini-grafting and strip harvest-

Surgical management of androgenetic alopecia

ing have made the transplant an efficient technique for increasing the number of follicles in specific areas affected by AGA. Combination medical therapy with systemic finasteride or topical minoxidil solution may certainly add to the cosmetic result.

3.

4.

5.

References 1.

2.

Stough D. Hair replacement surgical and medical, 1st edn. 1996, St Louis, Missouri: Mosby. Unger W. Hair Transplantation, 3rd edn. 1995, New York: Marcel Dekker.

6.

7.

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Klein J. The tumescent technique for liposuction surgery. Am J Cosmet Surg 1987; 4:263–7. Coleman W.P.D. and J.A.Klein. Use of the tumescent technique for scalp surgery, dermabrasion, and soft tissue reconstruction. J Dermatol Surg Oncol 1992; 18(2):130–5. Stough D. The donor site. In Hair replacement surgical and medical, ed. D.Stough, pp. 139–49, 1996: St Louis, Missouri: Mosby. Stough D. Determination of hairline placement. In Hair replacement surgical and medical, ed. D.Stough, pp. 425–9, 1996, St Louis, Missouri: Mosby. Kassimir J.J. Use of topical minoxidil as a possible adjunct to hair transplant surgery. A pilot study. J Am Acad Dermatol 1987; 16(3 Pt 2):685–7.

5 Drug-induced alopecia

Drugs can affect hair by causing alopecia. This chapter will review which drugs have been implicated in hair loss and explore the mechanisms of how pharmaceutical agents can alter hair cycling and structure.

Drugs that cause alopecia The true incidence of drug-related alopecia is hard to determine accurately. Practicing dermatologists make the diagnosis infrequently, but it is also true that they rarely see the vast majority of such patients—those receiving chemotherapy. Drugs are capable of producing a wide spectrum of alopecia, from complete baldness to slight, barely noticeable shedding. Subtle cases can be difficult to detect, and it is possible that many patients may lose small amounts of hair and never realize it. Even if they do notice it, the loss of hair is considered to be trivial, and so may go unreported or may be reported without adequate documentation. The work-up for any patient with hair loss must include a thorough drug history. Repeated questioning may be necessary because of forgetfulness or ignorance. Drug-induced alopecia is usually confined to the scalp, although the eyebrows, the axillary and pubic regions and the body may also

be involved. The pattern of hair loss is almost always diffuse. Female androgenetic alopecia (AGA) poses a real problem, because it is very prevalent and can co-exist with diffuse alopecia. A drug-induced alopecia can certainly unmask a tendency for androgenetic alopecia and accelerate the miniaturization process of AGA. The scalp itself is usually unremarkable, except in rare instances. Some drugs can cause a severe drug-induced lichenoid eruption of the scalp. Certain laboratory tests such as scalp biopsy and blood work can be helpful in ruling out other causes of alopecia. A scalp biopsy with obligatory transverse sectioning will give you the anagen-telogen ratio and the terminalvellus ratio, and will detect any inflammatory process. This will help rule out AGA and alopecia areata, as well as helping to confirm an anagen or telogen effluvium. One must understand the basic mechanisms of hair growth and cycling in order to understand drug-induced hair loss. This is all reviewed in detail in Chapter 1. Each human scalp follicle produces hair cyclically and behaves independently of neighboring follicles. The scalp follicle passes through a growing, metabolically active phase known as anagen, which lasts 4–8 years. Following anagen, a brief transitional catagen phase of two weeks leads to a metabolically inactive resting telogen phase. The telogen phase lasts for three

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months, after which the club hair is shed as the hair follicle initiates a new cycle. There are two mechanisms of drug-induced alopecia—direct and indirect effects. Direct effects include anagen growth interruption, precipitation of catagen, and disturbed keratinization, resulting in hair shaft damage. Indirect effects include causing a systemic disease (hypothyroidism or zinc deficiency) or a severe skin disease (lichenoid eruption or toxic epidermal necrolysis) of which alopecia is a feature. Scalp follicles are in differing phases of the hair cycle and are randomly scattered over the scalp. Almost 90% of scalp follicles are in anagen, 10% in telogen, and 1% in catagen. Follicles are susceptible to noxious agents, usually when they are actively growing. During the anagen phase, the mitotic activity of the hair matrix is so high that it can be compared with the most actively kinetic tissues of the body, namely bone marrow and mucous membranes. For this reason anagen hair matrix is highly susceptible to noxious events, while catagen and telogen follicles are relatively safe. The duration of anagen and telogen phases, the percentage of hairs in anagen and telogen phases, and the density of the follicles will account for the varying severity of alopecia in different areas of hair growth. The regions of the body with highest percentage of anagen hairs, such as the scalp and beard, are more likely to be affected by drugs than the regions of the body with the lowest percentage of anagen follicles, such as the eyebrows and eyelashes. Drug-induced alopecia usually involves pharmaceutical alteration of the cycling process. Hair loss occurring a few days after drug intake indicates an effect on hair matrix cells. Hair loss developing weeks to months after drug intake may be due to hair matrix effects, but may result from changes in keratin production or changes in the hair cycle. If one excludes

anti-mitotics, the most common mechanism by far for drug-induced alopecia is the precipitation of catagen. Of course, in the clinical setting, there is confusion, because many diseases for which drugs are administered also produce a precipitation of catagen. An example of such a dilemma is highlighted by Reeves and Maibach. 1 Ahmad 2 in reporting a case of cimetidine-induced alopecia failed to take into account the fact that the stress from a duodenal ulcer might have caused the alopecia.

Anagen effluvium (Table 5.1) Cytostatic drugs Any drug that affects cell division can alter hair growth. Cytostatic drugs suppress hair matrix cell mitosis, impede hair cortex formation and cause an anagen effluvium in almost 100% of patients.3,4 The resultant hair contains fewer cells per unit length, is thin and breaks easily. Only the actively dividing matrix cells of anagen hairs are affected by cytostatic drugs. The intensity of damage to the cortex of the hair shaft depends on the drug dosage and the duration of its administration. A small single dose will produce constriction of the hair shaft. A large single dose that strongly suppresses mitosis produces a sharp point-constriction. The hair breaks at the point of constriction, with hair fall beginning in 7–14 days (see Figure 5.1). Continued treatment with a smaller constant dose produces a slow decrease in hair shaft diameter to a tapered point. Combined therapy with two or more anti-mitotic agents has a greater effect than a larger dose of only one agent. A spectrum of changes seems to occur, and the predominant effect may depend on the dose and timing of the administration. In some cases, especially

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137

Table 5.1 Drug-induced anagen effluvium46

in-patients subjected to multiple cycles of chemotherapy, hair loss may be almost complete. Alopecia most commonly occurs with the use of doxorubicin (adriamycin), cyclophosphamide, chlormethamine (mechlormetha-

mine), methotrexate, fluorouracil, vincristine, daunorubicin, bleomycin and hydroxy-carbamide. Drugs that may aggravate alopecia when used in combination chemotherapy include chlorambucil, thiotepa, cytarabine, vinblastine and dactinomycin.

Figure 5.1 Anagen effluvium. A 33-year-old female with lymphoma on dacarbazine, bleomycin, doxorubicin and vinblastine. Note the marked hair loss over the entire scalp. (a) posterior view (b) lateral view

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Certain drugs affect specific phases of the mitotic process within the actively dividing hair matrix. Those drugs that are S phase-specific include cytosine arabinoside, hydroxyurea, 6-mercaptopurine and methotrexate. The M phase of mitosis is affected greatly by vincristine and vinblastine. Most of the cytotoxic agents are not phase-specific: these include alkylating agents (cyclophosphamide, ifosfamide, melphalan, thiotepa, busulfan, carmustine, dacarbazine), nitrosoureas, antitumor antibiotics, procarbazine, and cisplatin. Colchicine Colchicine, used in the treatment of gout, has anti-mitotic activity operating through failure of spindle formation. Cells with the highest rates of division are affected earliest.5 Colchicine can produce diffuse hair loss in 1–10% of cases. The mode of action is due to metaphase arrest.6 Harms7 reported a case of diffuse alopecia that occurred after 2 months of colchicine therapy. Hairs were dystrophic and broken off 1–2 cm above the scalp. Hair loss is dose-dependent. It may persist for 1–3 months, and may be reversible even if the drug is continued.8 Vasopressin Vasopressin, a vasoconstrictor and anti-diuretic pituitary hormone, has been reported to cause alopecia by causing an anagen effluvium from cutaneous infarcts. All areas affected by anagen effluvium had normal hair growth after the medication was discontinued.9

Telogen effluvium There are 5 functional types of telogen effluvium (TE) as proposed by Headington.10 Three

of these types are related to events in anagen and two related to telogen. The five types are as follows: 1. Immediate anagen release (IAR), characterized by a relatively short onset—usually 3– 5 weeks. Follicles that would normally complete a longer cycle by remaining in anagen prematurely enter telogen. Immediate anagen release probably characterizes most drug-related events. IAR is probably underreported because of reporting inertia by physicians whose clinical judgement is that a probable drug-related hair loss is a trivial event with expected reversal when the drug has been discontinued. 2. Delayed anagen release (DAR), characterized by a prolonged anagen rather than cycling normally into telogen. When follicles are finally released from anagen, if sufficient are involved, the clinical sign of increased shedding will be found. DAR is probably associated with postpartum hair loss and oral contraceptives. Cimetidine has also been implicated as causing DAR. 3. Shortened anagen (SA) occurs when the anagen phase is significantly decreased in time. If anagen is decreased by 50%, there is a corresponding doubling of telogen hairs. Etretinate may cause SA. 4. Immediate telogen release (IMR): normal telogen, which may last 4–12 weeks, is shortened to just a few days. All follicles in telogen may be susceptible. There is some good evidence that topical minoxidil solution may effect IMR, as the affected follicles are promptly stimulated to cycle into anagen. 5. Delayed telogen release (DTR) occurs when telogen is prolonged and there is slightly more synchronous growth and

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Table 5.2 Drug-induced telogen effluvium (incidence less than 1 %)46

fallout on the scalp. No drugs have been implicated with this mechanism conclusively, but reports of delayed-onset shedding with drug treatment might be a result of DTR. The following list of drugs have been implicated as causing telogen effluvium (Tables 5.2–5.5)

Anti-coagulants All forms of anti-coagulants may induce hair loss. These include heparin and coumarins. TE

occurs in more than 10% of patients, appears to be related to drug dosage, and tends to be more frequent in women (Figure 5.2).

Anti-thyroid drugs Reversible alopecia is a constant finding in iatrogenic hypothyroidism, which occurs during treatment of thyrotoxicosis. Telogen effluvium is frequently associated with hair dryness and brittleness. Anti-thyroid drugs that may produce telogen effluvium include iodine, methylthiouracil, propylthiouracil, and carbimazole.

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Table 5.3 Drug-induced telogen effluvium (incidence of 1–5%)46

Table 5.4 Drug-induced telogen effluvium (incidence of more than 5%)46

Psychopharmacologic medications Lithium Hair loss is a possible adverse effect of lithium carbonate, and may be noticed within weeks or years after commencing therapy. 11 Headington feels it is due to immediate anagen release. However, in those patients in whom the onset of the hair loss may take years, this mechanism is less likely. A correlation between hair loss and lithium blood level and/or dosage is suspected, but not established. In most reports, doses ranged from 0.4 to 1.5 g/ day, with serum lithium assays between 0.5 and 1.4 Meq/L.12–17

A review described 101 cases of lithiumrelated hair loss in over 25 years of use.18 A 3year survey of lithium-treated subjects reported a 12% incidence of alopecia.13 About 20% of patients on long-term lithium therapy, who had high lithium levels, reported hair thinning; 23% described their hair as also becoming straighter.19 Patients on lithium who develop alopecia must undergo a thyroid function assessment, since this drug is known for its ability to affect the thyroid gland. Hypothyroidism (commonly) and thyrotoxicosis (rarely) have been described in patients on lithium therapy, and both conditions may manifest with hair

Drug-induced alopecia

Table 5.5 Drug-induced telogen effluvium (exact incidence unreported)46

141

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Figure 5.2 Telogen effluvium. A 63-year-old female on warfarin showing general shedding. Hair loss is not as marked as in anagen effluvium. (a) Top view, with a slightly increased width of hair-part. (b) Lateral view, illustrating marked thinning on the temporal area. (c) Pathology of telogen effluvium, showing a disproportionate number of telogen hairs.

changes.20,21 There is a case report of alopecia areata occurring during lithium therapy.22 This is probably coincidental.

lished whether alopecia is dose-related, but usually dosage reduction leads to regrowth of hair in individuals with valproate-associated alopecia.26

Valproate Carbamazepine Valproic acid (VPA), once ingested, dissociates in the gastrointestinal tract into a salt or ionic form, valproate. VPA and divalproex (a stable combination of valproate sodium and valproic acid) may cause hair changes. A review of the literature mentions 643 cases of valproateinduced alopecia,18 with a 0.5%–12.0% reported frequency.23,24 Patients on VPA who develop hair loss tend to have a high valproate blood concentration.25 It is not completely estab-

There are 177 documented cases of carbamazepine-induced alopecia.18 With a reported incidence of 1.6% and 6%.27,28 A threefold dose reduction of 200 mg/day helped one female patient.29 Carbamazepine and VPA possibly have different mechanisms of hair loss, despite a documented decrease in serum amounts of zinc and copper caused by both medications.30 Some individuals may have an

Drug-induced alopecia

increased genetic predisposition to medicinal alopecias.

Tricyclic/tetracyclic antidepressants A few instances of diffuse hair loss associated with tricyclic antidepressants (TCA) have been documented. All TCA versions have been implicated with alopecia: amitriptyline, amoxapine, despiramine, doxepin, imipramine, nortriptyline, and protriptyline.31 The tetracyclic antidepressant drug maprotiline and trazodone may also result in hair loss.31 However, none of the monoamine oxide inhibitors are known to cause alopecia. Serotonin reuptake inhibitors Several serotonin reuptake inhibitors can also cause hair loss on rare occasions. Fluoxetine is the most frequently prescribed anti-depressant, and with this there are 725 documented cases.18 Sertraline has been reported in 46 instances.32,33 and paroxetine in 30 subjects 18 The majority of these have a typical pattern of reversible diffuse alopecia, with a 2–6 month latency period. Sometimes alopecia may develop 1.5 years following fluoxetine introduction.34,35 In another case, a fluoxetine-induced alopecia was still evident 1.5 years after drug discontinuation.36

Other anti-psychotics/anxiolytics Haloperidol, olanzapine and respiridone have been documented as causing hair loss. Anxiolytic medicines of the barbiturate and benzodiazepine classes, as well as zolpidem, generally do not result in alopecia. Clonazepam is one exception.31 Buspirone is also associated with hair loss on rare occasions.31

143

Oral contraceptives Telogen hair is lost 2–3 months after discontinuation of treatment with oral contraceptives. Pathogenesis is probably similar to that in post-partum hair loss.37 This is believed by Headington to be a delayed anagen release.10 There is prolongation of the anagen phase, owing to the estrogens. The utilization of lowdose estrogen contraceptives is only occasionally associated with this effect. Antihypertensive agents Several anti-hypertensive agents are known to cause hair loss. Beta-blockers may have a direct toxic effect on the hair follicles. This sideeffect is reversible once medication is terminated. Captopril can also cause hair loss. It may form a complex with zinc, and thus decrease zinc levels, particularly in those patients with renal disease.38–40 Low zinc levels can cause hair loss. Topical ophthalmic beta-blockers Topical ophthalmic beta-blockers can cause hair loss. Hair loss is not confined to the scalp alone, but also extends to eyelashes and eyebrows. Females are more commonly affected. It occurs 1–24 months after treatment. Significant recovery is seen after 4–8 months from the time use of the solution is discontinued.41

Interferons Telogen effluvium occurs in 20–30% of patients treated with interferons. There is no relationship between dosage and time of onset or severity of hair loss. In some cases, telogen loss subsides despite continuing treatment.42

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Keratin production interference Thallium Thallium is no longer used as a drug, but may be ingested accidentally in rodent poisons or contaminated foods. Thallium ingestion produces changes in the matrix cells, with subsequent disturbed keratinization. Intrafollicular thinning, accumulation of air bubbles in the hair shaft, breakage of the hair shaft and the induction of telogen is seen in thallium alopecia. Available evidence indicates that thallium inhibits the utilization of cystine in the production of the keratin molecule. Acute poisoning produces hair loss in 10 days, along with ataxia, fatigue, joint pains and weakness. Hair losses of several months’ to years’ duration, with muscle aches, have been reported in chronic thallium intoxication.

Retinoids Soriatane and accutane can produce brittle, dry, unmanageable, loosely anchored hairs. Retinoid-induced alopecia has a later onset and is almost always reversible. It is due to a shortened anagen release, rather than an immediate anagen release, which is what is more commonly seen with other drugs. However, just like any telogen effluvium, retinoids can certainly unmask a tendency for androgenetic alopecia. The package insert for accutane mentions hair loss. Diffuse hair loss is commonly observed during soriatane treatment, with evident alopecia occurring in about 20% of patients.31 Cholesterol-lowering agents Agents that block cholesterol synthesis through a variety of mechanisms can disrupt

keratinization. Cholesterol is a component of cellular lipids, and its synthesis and metabolism are essential for the production of normal epidermal structures. Triparanol, which has been withdrawn from the market because of cataract induction, can cause significant alopecia, loss of hair color and ichthyosis. Clofibrate may occasionally produce hair loss.31

How to manage druginduced alopecia In cases where an effective therapeutic agent causes alopecia and no appropriate alternative can be found, an informed patient and physician should discuss the risks and benefits of continuing, stopping or changing the dose or medication. The advantages and disadvantages of maintaining the drug must be reviewed. Such choices are especially difficult when the offending agent is otherwise effective. Similarly, the negative implications of stopping or changing the regimen also need to be considered. Decisions are based on alternative medications and hair loss severity and its emotional impact. More research may further clarify drug-induced hair-loss issues, and offer new therapeutic recommendations. The use of topical 5% minoxidil solution for drug-induced telogen effluvium in those cases when the offending drug cannot be terminated or switched is certainly a therapeutic option we use at the University of British Columbia Hair Clinic. Minoxidil tends to maintain hairs in anagen and convert telogen hairs into anagen hairs more quickly. It certainly can be offered to the patient. During the early conversion of telogen to anagen hairs, there is surge of ‘telogen release’. Patients may temporarily

Drug-induced alopecia

(for the first month of minoxidil application) experience more hair loss, shedding telogen hairs and subsequently replacing them with the more desired anagen hairs. Patients should be warned of this temporary setback. For drug-induced anagen effluvium, topical minoxidil 5% solution has been reported to work.43 We rarely need to use it, as the alopecia is usually reversible. The use of cooling scalp devices is still controversial.44,45

References 1. Reeves J. and Maibach H. Drug- and chemical induced hair loss, pp. 506–17. 1983; Washington DC: Horizon Books. 2. Ahmad S. Cimetidine and alopecia [letter]. Ann Intern Med, 1979; 91(6):930. 3. Dunagin W.G. Clinical toxicity of chemotherapeutic agents: dermatologic toxicity. Semin Oncol, 1982; 9(1): 14–22. 4. Delaunay M. [Cutaneous side effects of antitumor chemotherapy]. Ann Dermatol Venereal, 1989; 116(4):347–61. 5. J Hardman, Limbird L., Molinoff P., et al. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th edn, 1996; New York: McGraw-Hill, Inc. 647–9. 6. Rook A. Some chemical influences on hair growth and pigmentation. Br J Dermatol, 1965; 77:115–29. 7. Harms M. Alopecia and hair changes following colchicine therapy. Hautarzt, 1980; 31(3):161–3. 8. Blankenship M.L. Drugs and alopecia. Australas J Dermatol, 1983; 24(3):100–4. 9. Maceyko R.F., Vidimos A.T. and Steck W.D. Vasopressin-associated cutaneous infarcts, alopecia, and neuropathy. J Am Acad Dermatol, 1994; 31(1):111–13. 10. Headington J.T. Telogen effluvium. New concepts and review [see comments]. Arch Dermatol, 1993; 129(3):356–63.

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11. Mortimer P.S. and Dawber R.P. Hair loss and lithium. Int J Dermatol, 1984; 23(9):603–4. 12. Dawber R. and Mortimer P. Hair loss during lithium treatment [letter]. Br J Dermatol, 1982; 107(1):124–5. 13. Orwin A. Hair loss following lithium therapy [letter]. Br J Dermatol, 1983; 108(4):503–4. 14. Eustace D.P. Lithium-induced reaction [letter]. Br J Psychiatr, 1986; 148:752. 15. Kusumi Y. A cutaneous side effect of lithium: report of two cases. Dis Nerv Syst, 1971; 32(12):853–4. 16. Yassa R. and Ananth J. Hair loss in the course of lithium treatment: a report of two cases. Can J Psychiatr, 1983; 28(2):132–3. 17. Jefferson J. Lithium and hair loss. Int Drug Ther News, 1979; 14:23. 18. Pillans P.I. and Woods D.J. Drug-associated alopecia. Int J Dermatol, 1995; 34(3): 149–58. 19. McCreadie R.G. and Morrison D.P. The impact of lithium in South-west Scotland. I. Demographic and clinical findings. Br J Psychiatr, 1985; 146:70–4. 20. Kirov G. Thyroid disorders in lithiumtreated patients. J Affect Disord, 1998; 50(1):33–40. 21. Freinkel R.K. and Freinkel N. Hair growth and alopecia in hypothyroidism. Arch Dermatol, 1972; 106(3):349–52. 22. Silvestri A., Santonastaso P. and Paggiarin D. Alopecia areata during lithium therapy. A case report. Gen Hosp Psychiatr, 1988; 10(1):46–8. 23. Davis R., Peters D.H. and McTavish D. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs, 1994; 47(2): 332–72. 24. McKinney P.A., Finkenbine R.D. and DeVane C.L. Alopecia and mood stabilizer therapy. Ann Clin Psychiatr, 1996; 8(3):183–5. 25. Klotz U. and Schweizer C. Valproic acid in childhood epilepsy: anticonvulsive efficacy in relation to its plasma levels. Int J Clin Pharmacol Ther Toxicol, 1980; 18(10): 461–5.

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26. Henriksen O. and Johannessen S.I. Clinical and pharmacokinetic observations on sodium valproate—a 5-year follow-up study in 100 children with epilepsy. Acta Neurol Scand, 1982; 65(5):504–23. 27. Mattson R.H., Cramer J.A. and Collins J.F. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group [see comments]. New Engl J Med, 1992; 327(11):765–71. 28. Verity C.M., Hosking G. and Easter D.J. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group. Dev Med Child Neurol, 1995; 37(2):97–108. 29. Ikeda M., Maruyama K., Nobuhara Y., et al. Cytoprotective effects of 4,6-bis(1H-pyrazol-1yl)pyrimidine and related compounds on HCI.ethanol-induced gastric lesions in rats. Chem Pharm Bull (Tokyo), 1997; 45(3):549–51. 30. Suzuki T., Koizumi J., Moroji T., et al. Effects of long-term anticonvulsant therapy on copper, zinc, and magnesium in hair and serum of epileptics. Biol Psychiatr, 1992; 31(6):571–81. 31. Physician Desk Reference. 1999; Montvale, NJ: Medical Economics. 32. Bourgeois J. Two cases of hair loss after sertraline use. J Clin Psychopharmacol, 1996; 16(1):91–2. 33. McDougle C.J., Brodkin E.S., Naylor S.T., et al. Sertraline in adults with pervasive developmental disorders: a prospective open-label investigation. J Clin Psychopharmacol, 1998; 18(1):62–6. 34. Ogilvie A.D. Hair loss during fluoxetine treatment [letter]. Lancet, 1993; 342(8884): 1423.

35. Jenike M.A. Severe hair loss associated with fluoxetine use [letter]. Am J Psychiatr, 1991; 148(3):392. 36. Gupta S. and Major L.F. Hair loss associated with fluoxetine [letter]. Br J Psychiatr, 1991; 159:737–8. 37. Wong R.C. and Ellis C.N. Physiologic skin changes in pregnancy. J Am Acad Dermatol, 1984; 10(6):929–40. 38. Brodin M.B. Drug-related alopecia. Dermatol Clin, 1987; 5(3):571–9. 39. Smit A.J., Hoorntje S.J. and Donker A.J. Zinc deficiency during captopril treatment. Nephron, 1983; 34(3):196–7. 40. Leaker B. and Whitworth J.A. Alopecia associated with captopril treatment [letter]. Aust NZ J Med, 1984; 14(6):866. 41. Fraunfelder F.T., Meyer S.M. and Menacker S.J. Alopecia possibly secondary to topical ophthalmic beta-blockers [letter]. JAMA, 1990; 263(11):1493–4. 42. Tosti A., Misciali C., Bardazzi F., et al. Telogen effluvium due to recombinant interferon alpha-2b. Dermatology, 1992; 184(2):124–5. 43. Duvic M., Lemak N.A., Valero V., et al. A randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol, 1996; 35(1):74–8. 44. Goldhirsch A., Kiser J., Ross R., et al. [Prevention of cytostatic-related hair loss by hypothermia of a hairy scalp using a cooling cap]. Schweiz Med Wochenschr, 1982; 112(16):568–71. 45. Katsimbri P., Bamias A. and Pavlidis N. Prevention of chemotherapy-induced alopecia using an effective scalp cooling system. Eur J Cancer, 2000; 36(6):766–71. 46. Litt J. (ed.). Drug eruption reference manual. Millennium edn. 2000; New York: The Parthenon Publishing Group.

6 Telogen effluvium: acute and chronic

Telogen effluvium (TE) is discussed at length in Chapter 5 as it relates to medications. However, TE can occur as a result of a systemic disturbance. Metabolic imbalances, such as those described below, may cause an immediate anagen release (IAR) as described by Headington.1 Follicles that would normally complete a longer cycle by remaining in anagen prematurely enter telogen and are subsequently shed 2–3 months after the offending insult has been instituted.

Acute telogen effluvium secondary to a known cause Fever Fever can cause alopecia 8–10 weeks after the bout. It can be quite severe, is not total and is usually reversible. Fever, which augments metabolic demands, would probably impair the ability of the rapidly multiplying follicular matrix cells to proliferate normally.2 Endogenous pyrogens, such as interferons a and ?, may slow down matrix proliferation. 2 Interferons a and ? have been shown to decrease epithelial proliferation and to affect follicular matrix cells directly.3,4

Postpartum During pregnancy anagen is prolonged, and, as a result, percentages of anagen hairs increase during pregnancy from 84% in the first trimester to 94% in the final trimester.5,6 After parturition, there is a delayed anagen release, as described by Headington. 1 Follicles enter catagen and then telogen. Increased hair loss may occur 1–4 months after childbirth, and may continue for several months.7,8 There may be aggravating factors, such as psycho-physical trauma, blood loss, and low plasma protein. Full recovery is usual in 4–12 months.8,9 Loss is more marked in the frontal and temporal regions, but may be generalized (see Figure 6.1). It is never total. Telogen effluvium tends to be less severe in subsequent pregnancies.5

Crash dieting/hypo-proteinemia Acute voluntary starvation in young women is not uncommon, and must be questioned on taking history. Obese adolescents sometimes inflict on themselves a diet of salads and fruits lacking in protein. This also can lead to hair loss. Rooth and Carlstrom10 noted hair loss, edemas and weakness in 20 obese patients on a 200 calorie diet or on a total fast; but these changes were prevented by the addition of a small amount of protein.

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Figure 6.1 A 30-year-old female presenting with a one-month history of abrupt diffuse hair shedding commencing 6 weeks after the birth of her last child. (a) Side view, showing fronto-temporal thinning. (b) Top view, showing a widening of the central part.

Thyroid influences There is no consistent correlation between the degree and duration of hypothyroidism and the severity of hair loss.9 Diffuse alopecia may sometimes be the first or only cutaneous sign of hypothyroidism. The hair loss is diffuse. A thorough history regarding weight gain, cold tolerance, and energy level is important. Patients usually respond to thyroxine replacement11 unless the problem has been of very long duration and some follicles have atrophied. Severe thyrotoxicosis can also cause diffuse alopecia of the scalp.12

Iron deficiency Iron deficiency with or without anemia has been reported to be present in as many as 72%

of women with diffuse alopecia13. Iron deficiency even in the absence of anemia (low hemoglobin) has also been reported by Hard.14 Because androgenetic alopecia and iron deficiency are both common conditions in women, the two not infrequently occur together. It is possible that telogen effluvium from iron deficiency may unmask an underlying androgenetic alopecia.

Major interventions and prolonged anesthesias Blood loss and surgery with prolonged anesthesia may cause telogen effluvium15,16 (see Figure 6.2). Desai and Roaf17 report telogen effluvium in a patient after prolonged surgery, with regrowth after 4 months. This is clearly different from the patchy alopecia occurring after localized pressure from surgery.18

Telogen effluvium: acute and chronic

149

Figure 6.2 35-year-old female with a 6-week history of abrupt diffuse hair shedding commencing 8 weeks after bowel surgery. (a) Side view, showing marked thinning. (b) Top view, showing thinning of the central part. (c) Occipital view, displaying a significant widening of the parting.

Malignant disease, renal failure, hepatic disease and malabsorption Hodgkin’s disease may present with telogen effluvium as its first sign.19 This kind of hair loss is also referred to as ‘toxic telogen effluvium’.15 Scalp hair can become dry, brittle and sparse with chronic renal disease.20,21 There may thinning of body hair, including pubic or axillary hair. Hepatic disease has been reported to be associated with diffuse alopecia. Zaun 22 studied 53 patients who had either hepati-

tis, cirrhosis or fatty liver. He found increased telogen counts in 34 patients and evident hair loss in 11. The liver is the major site of amino acid inter-conversion. It has been suggested that disturbed liver metabolism of cystine and methionine may be related to alopecia.22 When sparse hair and growth retardation are associated with chronic frequent loose pale and bulky stools, malabsorption should be investigated. 9 Inflammatory bowel disease has been reported to be associated with hair loss, particularly with Crohn’s disease.23

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Hair Loss: principles of diagnosis and management of alopecia

Psychological stress, acute anxiety, and depression Acute anxiety or depression may cause a telogen effluvium.15. There is literature that does support the notion of psychogenic telogen effluvium,24,25 but the paucity of reports suggests that it is uncommon.2

Medications These are discussed extensively in Chapter 5.

Chronic telogen effluvium of unknown cause in the female patient

this to be a physiological phenomenon. A modern term for this condition, coined by Whiting, would be Chronic Telogen Effluvium (CTE).28,29 CTE is not uncommon. It is a form of diffuse hair loss affecting the entire scalp for which no obvious cause can be found. It usually affects women of 30 to 60 years of age who generally have a full head of hair prior to the onset of shedding. The onset is usually abrupt, with or without a recognizable initiating factor. The degree of shedding is usually severe in the early stages, and the hair may come out in handfuls. Females present with a diffuse thinning, reduction in pony tail diameter, increased parting widths over the entire scalp and increased telogen shedding, frequently with a positive pull test. CTE contrasts with classic acute telogen effluvium by its persistence and its tendency to fluctuate for a period of years. Patients are particularly troubled by

‘Woman is herself constantly doing something to her hair. She even carries a little mirror everywhere with her with the principal object of looking at her hair to see that it is all right. Obviously, it is a source of anxiety to her.’— CBerg, 195126

Frequently encountered in dermatological practice is the woman who presents with chronic diffuse hair loss of unknown cause. Women who present with this type of hair loss frequently are upset and want a satisfactory explanation for their problem. Diffuse cyclic hair loss in women was first described by Guy et al. in 1959.27 They describe a ‘not uncommon condition’ presenting with transitory episodes of shedding lasting several weeks with no apparent cause. The typical patient is a ‘vigorous otherwise healthy woman’ who presents with diffuse hair loss that is cyclic and reversible. They considered

Figure 6.3 A histological transverse section of chronic telogen effluvium, showing a disproportionate number of telogen hairs on transverse section (courtesy of Dr Magdalena Martinka).

Telogen effluvium: acute and chronic

the continuing hair loss, and fear total baldness. Repeated reassurance that the condition does not cause complete baldness is necessary. CTE does appear to be self-limiting in the long run. Scalp biopsies show an increase percentage of telogen hairs (see Figure 6.3). No apparent cause can be found. Trueb et al.30 feel that in approximately 30% of cases of chronic diffuse loss of scalp hair with a duration of at least 6 months no underlying abnormality can be found. Typically this occurs in women, starting abruptly without a recognizable initiating factor, and involving the entire scalp area in increased shedding of telogen hair. With the exception of bitemporal recession, hair thinning is usually discrete which contrasts to the intense emotional overtones brought about by this situation. This may initially lead to the differential diagnosis of psychogenic pseudoeffluvium. Owing to the synchronization of the hair cycle, the amount of shed hair here is greater than that in androgenetic alopecia, while miniaturized hairs are not a feature of the disorder. Overlap with androgenetic alopecia and/or psychogenic pseudo-effluvium is not uncommon. Scalp dysesthesia or a sensation of pain in the hair (trichodynia) is an accompanying symptom in a significant proportion of cases, and correlates better with emotional upset than with actual hair loss. In certain cases of CTE, laboratory testing may often show ferritin levels below the normal male reference range of 25–30 µg/l.31 The normal ferritin levels for men and women differ in most laboratories. Usually normal reference levels for women are considerably lower, as a large number of the ‘normal control’ group are menstruating women. Van Neste and Rushton feel that topping ferritin levels to at least the lower limit for men may correct this problem to a certain degree.31 These authors also feel that hemoglobin levels should be

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above the lower male range (greater than 13 g/ dl) to maintain the normal anagen to telogen ratio of 9:1. Nutritional supplements (except for iron when indicated) are not recommended. Sufficient nutrition is obtained in a normal diet. There is evidence that the taking of excessive and unnecessary supplements could actually induce telogen effluvium.31 For example, large amounts of zinc in supplements (> 25 mg/day) may affect iron absorption adversely.31 At the University of British Columbia Hair Clinic our approach to CTE is: (1) Confirm the diagnosis with a 4 mm scalp biopsy with transverse sectioning (see Figure 6.3). (2) Make sure you have ruled out any underlying cause of telogen effuvium. (3) Top up ferritin levels to greater than 30 µg/1. The patient should be monitored every 4–6 months with repeat ferritin levels until they have reached this threshold level. (4) Topical minoxidil 5% solution twice daily. We have found that topical minoxidil solution is beneficial in maintaining hairs in anagen and increasing conversion of hairs from telogen to anagen. Patients must be warned that initially there may increased shedding with topical minoxidil solution, as one must temporarily shed more telogen hairs to increase the eventual percentage of anagen hairs. We feel that it is likely that topping up ferritin levels will maximize the hair growth potential of topical minoxidil in those menstruating women with low ferritins. However, further studies with double-blinded placebo controls analyzing the single and combinational benefits of supplemental iron and topical minoxidil solution for CTE are needed. CTE is usually reversible. However, in those women who have a genetic predisposition to androgenetic alopecia (AGA), CTE may unmask their AGA, and hair will not necessarily grow back to the same density as before.

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References 1. Headington J.T. Telogen effluvium. New concepts and review. Arch Dermatol, 1993; 129(3):356–63. 2. Fiedler V. Diffuse alopecia: telogen hair loss. In Disorders of hair growth, ed. E.Olsen, pp. 241–252. 1993, McGraw-Hill, Inc.: New York. 3. Yaar M., Karassik R.L., Schnipper L.E. and Gilchrest B.A. Effects of alpha and beta interferons on cultured human keratinocytes. J Invest Dermatol, 1985; 85(1):70–4. 4. Tabibzadeh, S.S., P.G. Satyaswaroop and P.N.Rao. Antiproliferative effect of interferon-gamma in human endometrial epithelial cells in vitro: potential local growth modulatory role in endometrium. J Clin Endocrinol Metab, 1988; 67(1):131–8. 5. Pecoraro V. The normal trichogram of pregnant women. In Advances of biology of the skin, ed. W.Montagna, p. 203. 1969, Pergamon Press: Oxford. 6. Lynfield Y. Effect of pregnancy on the human hair cycle. J Invest Dermatol, 1960; 35: 323–7. 7. Schiff B. Study of postpartum alopecia. Arch Dermatol, 1963; 87:609. 8. Skelton J. Post partum alopecia. J Obstet Gynecol, 1966; 94:125. 9. Rook A. Diffuse alopecia: Endocrine, metabolic and chemical influences on the follicular cycle. In Diseases of the hair and scalp, ed. A.Rook, pp. 136–66. 1991, Blackwell Scientific Publications: Oxford. 10. Rooth G. and S.Carlstrom. Therapeutic fasting. Acta Med Scand 1970; 187(6): 455–63. 11. Freinkel R.K. and N.Freinkel. Hair growth and alopecia in hypothyroidism. Arch Dermatol, 1972; 106(3):349–52. 12. Williams R. Thyroid and adrenal interrelations with special reference to hypotrichosis and axillairis in thyrotoxicosis. J Clin Endocrinol Metab, 1947; 7:52.

13. Rushton D.H., Ramsay I.D., James K.C., et al. Biochemical and trichological characterization of diffuse alopecia in women. Br J Dermatol, 1990; 123(2):187–97. 14. Hard S. Non-anemic iron deficiency as an etiologic factor in diffuse loss of hair of the scalp in women. Acta Derm Venereol, 1963; 43:562–9. 15. Camacho F. Alopecias due to telogen effluvium. In Trichology: diseases of the pilosebaeous follicle, ed. F.Camacho, pp. 403–9. 1997, Aula Medica Group SA: Madrid. 16. Thompson J.S. Alopecia after ileal pouchanal anastomosis. Dis Colon Rectum, 1989; 32(6):457–65. 17. Desai S.P. and E.R.Roaf. Telogen effluvium after anesthesia and surgery. Anesth Analg, 1984; 63(1):83–4. 18. Abel R. Post operative (pressure) alopecia. Arch Dermatol, 1960; 81:34. 19. Klein A.W., R.I.Rudolph and J.J.Leyden. Telogen effluvium as a sign of Hodgkin disease. Arch Dermatol, 1973; 108(5):702–3. 20. Lubach D. [Dermatological changes in patients receiving long-term hemodialysis]. Hautarzt, 1980; 31(2):82–5. 21. Scoggins R. Cutaneous manifestations of hyperlipidemia and uraemia. Postgrad Med 1967; 41:357. 22. Zaun H. Wachstumsstorungen der kopfhaare als folge von hepatopathien. Arch Klin Exp Derm, 1969; 235:386–93. 23. Schattner A. and Y.Shanon. Crohn’s ileocolitis presenting as chronic diffuse hair loss. J R Soc Med, 1989; 82(5):303–4. 24. Kligman A. Pathologic dynamics of human hair loss. Arch Dermatol, 1961; 83:175–98. 25. Dahlin P.A., J.George and J.C.Nerette. Telogen effluvium: hair loss after spinal cord injury. Arch Phys Med Rehabil, 1984; 65(8): 485–6. 26. Berg C. The unconscious significance of hair. 1951, London: George Allen & Unwin Ltd. 27. Guy W. Diffuse cyclic hair loss in women. Arch Dermatol, 1959; 81:83–5.

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28. Whiting D.A. Chronic telogen effluvium. Dermatol Clin, 1996; 14(4):723–31. 29. Whiting D.A. Chronic telogen effluvium: increased scalp hair shedding in middleaged women. J Am Acad Dermatol, 1996; 35(6): 899–906.

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30. Trueb R.M. [Idiopathic chronic telogen effluvium in the woman]. Hautarzt, 2000; 51(12):899–905. 31. Van Neste D.J. and D.H.Rushton. Hair problems in women. Clin Dermatol, 1997; 15(1):113–25.

7 Cicatricial (scarring) alopecias

Introduction Cicatricial (scarring) alopecia represents a diverse group of diseases characterized by lack of follicular ostia (Figure 7.1) and irreversible alopecia. The terms cicatricial and scarring are used interchangeably. A basic knowledge of follicular anatomy is important in the understanding of scarring alopecias, because the location of the inflammatory infiltrate is crucial in determining irreversibility of alopecia. Follicular stem cells are located in the bulge area where the arrector pili muscle inserts into the follicles. These cells migrate down into the

hair follicle, and subsequently differentiate into the various layers of the hair follicle. As the hair cycles through anagen, catagen, and telogen, there is a permanent upper portion of the hair follicle and a non-permanent lower portion, (see Chapter 1, Figure 1.8). When the inflammation is located deep, in the vicinity of the non-permanent portion, a scarring alopecia is unlikely to develop. If the inflammation is located within the permanent portion, particularly around the stem cells of the bulge area and the infundibulum, then a cicatrizing alopecia is more likely to occur. Follicles can be saved from irreversible damage if this peribulge infiltrate can be controlled. Scarring alopecias are true trichologic emergencies.

Classification

Figure 7.1 Lack of follicular ostia is the hallmark sign of scarring hair loss.

Classification schemes for cicatrizing alopecias have been based upon clinical, histological or proposed pathogenic criteria.1,2 Clinically, scarring alopecias are categorized as either inflammatory or non-inflammatory. The non-infectious inflammatory scarring alopecias include chronic cutaneous lupus erythematosus (CCLE), lichen planopilaris (LPP) and folliculitis decalvans (FD). CCLE and LPP are characterized by keratotic follicular papules, while FD presents with pus-

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tules. The non-inflammatory scarring alopecias are pseudopelade of Brocq (PP) and follicular degeneration syndrome, developmental abnormalities, genetic disorders, and neoplastic infiltrates. A second scheme, based upon pathology, classifies the cicatrizing alopecias according to inflammatory infiltrate cell type: lymphocyte or neutrophil. The lymphocytic-mediated disorders include CCLE, LPP, and PP, while the neutrophilic mediated conditions include FD, dissecting cellulitis, and acne keloidalis. This pathologically based classification system assists the clinician both in therapeutic decision-making and in gaining a better patho-physiological understanding of these disorders. Scarring alopecias can also be classified as primary or secondary.3 Primary scarring alopecia is defined microscopically as preferential destruction of follicular epithelium and / or its associated adventitial dermis with relative sparing of the interfollicular reticular dermis. In primary scarring alopecias, the hair follicle is the primary target of destruction. CCLE, LPP, PP, and FD are primary alopecias. Secondary scarring alopecias result from events outside the follicular unit that impinge upon and eventually eradicate the follicle. In these cases, the hair follicle is simply an ‘innocent bystander’. Follicular destruction is not the primary event. Sarcoidosis and morphea are examples of secondary scarring alopecias. Sperling has coined the term central, centrifugal scarring alopecia (CCSA).4 This grouping includes pseudopelade, follicular degeneration syndrome, and folliculitis decalvans. These conditions are centered on the crown or vertex and progress in a roughly symmetrical pattern, with disease activity limited to the peripheral zone surrounding the alopecic zone.

The biopsy for cicatrizing alopecias A scalp biopsy is crucial in the diagnosis of a cicatrizing alopecia. First, a biopsy site is selected. This site should be representative of active disease (primary lesion), preferably with a positive pull test and a paucity of follicular orifices. A less cosmetically important site, such as the posterior scalp, is preferable. The area is marked with a red marker, and lidocane with epinephrine is infiltrated into the area. Ten minutes is then allowed to take advantage of the vasoconstrictive effect of the epinephrine. The hair in the biopsy site is clipped. The punch is placed parallel to the direction of the hairs and inserted to the depth of the bevel. The biopsy should include the subcutaneous fat, because this is the location of terminal anagen hair bulbs. Two 4 mm punch biopsies are performed. One is submitted for transverse sectioning and the other is divided in half and submitted for both direct immunofluorescence and longitudinal sectioning. Special stains, such as PAS and elastin, may also be requested. Pressure is then applied to the biopsy site with a cotton applicator that may be saturated with aluminium chloride. The biopsy site is then closed with a blue 4.0 nylon suture. The blue suture allows for easier recognition and differentiation from hair during suture removal 7 to 10 days later.

Lymphocytic-mediated cicatricial alopecias Clinical features The three most common lymphocytic-mediated cicatricizing alopecias are CCLE, LPP and PP.

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Figure 7.2 Chronic cutaneous lupus erythematosus of the scalp. (a) and (b). A 23-year-old female with painful erythematous atrophic plaques. (c). A 60-year-old female with frontal scalp involvement. (d). Follicular hyperkeratosis occurring centrally within a plaque of lupus erythematosus. CCLE accounts for 30 to 40% of patients with scarring alopecias and has a definite female predilection. Very few patients (< 10%) who present with CCLE ever progress to systemic LE. However, an ANA is recommended for all patients with CCLE. In a series of 86 patients with CCLE of a mean duration of 15.1 years, 35 per cent (30/86) had scarring alopecia.5 A published report6 of 89 patients with CCLE showed that 34% had scalp involve-

ment. More than half these patients had scalp involvement at the onset of the condition. In a smaller study by Callen, 7/17 patients (41%) with CCLE had cicatricial scalp involvement.7 In three out of the seven, the scalp was the most prominent finding.7 This common involvement of the scalp is intriguing, because the scalp is a relatively light-protected area. In 10% of patients with CCLE, scalp involvement may be the sole manifestation of LE.8 Age of

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onset of scalp CCLE is usually at between 20 and 60 years of age. Patients present with erythematous plaques of alopecia, atrophy, telangiectasia and follicular hyperkeratosis (Figure 7.2). Scalp lesions begin as erythematous papules or irregular small scaly plaques. These lesions slowly progress to large erythematous, edematous plaques. At this point patients may experience loss of hair. This initial alopecia induced by follicular inflammation is potentially reversible. A prominent thickened and adherent scale may develop, which when removed reveals keratinous plugs on its under-surface. These keratinous plugs are from the follicular openings, and represent follicular hyperkeratosis. Follicular hyperkeratosis is more active in the center of a plaque, a clue to help distinguish CCLE from LPP (Figure 7.2d). As the lesion expands, the central erythema fades and the surface flattens. Hypopigmentation and depigmentation begin to appear. Central atrophy and telangiectasia eventually become prominent, and scarring develops. With continued spread of the disease, large, white atrophic scarred alopecic plaques will predominate over their inflammatory precursors. There is also increased curliness of hairs in scarred areas, owing to torsional within the hair follicle. In addition, normal anagen hairs can easily be pulled out of the scalp, a characteristic feature of the scarring alopecias. The term lichen planopilaris was first introduced in 1895 by Pringle,9 who described the association of lichen planus with follicular keratotic lesions. In 1915, Graham-Little10 described folliculitis decalvans et atrophicans or follicular scalp lesions resulting in cicatricial alopecia associated with follicular keratotic lesions at other sites. These two presentations are now considered variants of lichen planus. A clinical triad of classic plaquetype lichen

planus, spinous or acuminate lesions, and alopecia of the scalp or other hairy areas has been described.11 It was felt 40 years ago that one had to have this triad to make a diagnosis of LPP. This view is limited, and fails to account for the majority of intermediate cases. There is a spectrum of LPP. Mehregan et al.12 showed that 50% of their series of 45 patients with scalp LPP had strictly scalp involvement only. Seven per cent had either axillary or groin involvement, 7% nail involvement, 27% mucous membrane involvement and 40% glabrous skin involvement. Clearly, patients with scalp lichen planus should be followed up to assess whether lichen planus develops elsewhere (Figures 7.3h, 7.3i and 7.3j). The whole skin surface, the oral mucosa and the nails must be examined. Of all patients who have lichen planus, a series of 807 patients showed that only 10 (< 1%) had scalp involvement.13 LPP accounts for 30–40% of scarring alopecias. It usually occurs between 30 and 70 years of age, and a female predominance (2:1) has been noted. LPP is usually an insidious process evolving over several years, with a predilection for areas of greater hair density, such as the occipital scalp in men with AGA (Figures 7.3b and 7.3c). Follicular hyperkeratosis is present at the periphery of the plaques, rather than centrally (Figures 7.3a), and ulcerations may even develop (Figure 7.3d). Pruritus and tenderness are often a prominent feature, and anagen hairs can be extracted with gentle hair-pulling. Lesions typical of lichen planus do not occur on the scalp. LPP may be very widespread, with its extent not clearly apparent unless the scalp is shaved (Figures 7.3e, 7.3f, 7.3g). Occasionally drugs such as gold14 or mepacrine (atabrine)15 can trigger scalp lichen planus and cause irreversible hair loss. Tufted folliculitis consisting of several hair shafts emerging from a single ostium can also

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Figure 7.3 Lichen planopilaris (LPP). (a) Follicular hyperkeratosis at the periphery of erythematous alopecic areas. (b) and (c) LPP affecting the spared areas of male androgenetic alopecia. (b) Showing active inflammation. (c) Burnt out LPP. (d) Ulcerative lesion of LPP of the scalp. (e) Extensive case of LPP at the back of the scalp.

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(f) and (g). Close-up after the head has been shaved, showing marked involvement of much of the scalp. (h), (i), (j). LPP in a 45-year-old male with scarring alopecia as well as acuminate lesions on the arms and lichen planus-like lesions in the groin. This fits well with GrahamLittle disease. (k). Tufting of hairs in LPP.

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Figure 7.4 Pseudopelade of Brocq (a). Scarring hair loss affecting central portion of the scalp. (b) A 5year-old with pseudopelade (Brocq). (c), (d), (e) An 8-year-old boy with scattered pseudopelade (Brocq).

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(f) and (g) PP progressing over 10 years in a 40-year-old male. (h) PP affecting the area spared by androgenetic alopecia. (i) PP affecting the area most affected by androgenetic alopecia and mimicking androgenetic alopecia. (j) pp affecting tne beard area.

Cicatricial (scarring) alopecias

occur in LPP (Figure 7.3k). Tufting is common as an endstage phenomenon in many scarring alopecias, and occurs because the infundibular epithelium of damaged follicles often heals so as to cause the formation of a common large infundibulum. This is known as polytrichia.16 There is a variant of LPP, post-menopausal frontal fibrosing alopecia.17–19 Kossard has described an entity occurring in postmenopausal women presenting with perifollicular erythema along the marginal hairline, producing a frontal fibrosing hair loss extending to the temporal and parietal hair margins. Eyebrow loss was described in 13/16 women.19 Histological findings were indistinguishable from LPP. In 1885, Brocq of Paris described what later became known as Pseudopelade19a. Pelade is the French word for alopecia areata (AA). Pseudopelade refers to ‘like alopecia areata but not alopecia areata’. In pseudopelade (Brocq), the follicular ostia are not present while in AA they are most certainly present. Brocq subsequently admitted that this term does confuse the Iiterature 19b,19c. Pseudopelade (Brocq) (which is referred to as PP in this text) is regarded by most as a condition in which destruction of follicles leading to permanent patchy baldness is not accompanied by any clinically evident inflammatory pathology. End-stage LPP or CCLE may mimic an early pseudopelade (Brocq) as discussed below. PP is an idiopathic disorder, usually of adulthood. However, PP in children has been described. This author has seen at least 3 cases in children under the age of 10 (Figures 7.4b-e). Braun-Falco et al. reported an incidence of 4/ 142 (4.35%) cases of PP under the age of 11 and nine patients (9.6%) in the age range of 11–20.20 PP presents with small, irregular, asymmetrical, ivory porcelain white patches devoid of follicular units. This has been classically described as ‘footprints in the snow’. There is

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controversy as to whether PP is a distinct entity or is effectively the same as end-stage CCLE or LLP.21 Detailed studies by Braun-Falco et al.20,22 strongly support the idea that pseudopelade can exist as a distinct entity. His group described 94/142 (66.2%) patients with PP without any previous underlying condition. PP is usually asymptomatic and without inflammation. Occasionally there may be erythema and mild pruritus. The parietal and vertex areas of the scalp are primarily involved (Figures 7.4a and 7.4b). Occasionally PP may affect the beard area and not just the scalp (Figure 7.4j).23 The course is extremely variable. In the majority of cases, extension of the process takes place only very slowly (Figures 7.4f and 7.4g). The course is often protracted and prolonged. Indeed, after 15– 20 years the patient may still be able to arrange his/her hair to conceal the patches effectively. However, in some cases, extension occurs more rapidly, and exceptionally there may be almost total baldness after 2 to 3 years. Occasionally the pattern of hair loss of PP can mimic androgenetic alopecia as described by Zinkernagel et al.,24 and the diagnosis of PP may be missed (Figure 7.4i). As with other cicatrizing alopecias, anagen hairs are easily extracted. A form of central centrifugal scarring alopecia in African-Americans, also known as follicular degeneration syndrome (FDS), overlaps significantly with PP with marked non-inflammatory cicatricial alopecia on the top of the scalp in black patients.25,26 Although initially thought to be a consequence of hair-care practices, it is now believed to represent an idiopathic disorder unrelated to trauma or hair cosmetics. Sperling believes the main etiology for FDS is that the inner root sheath desquamates prematurely far below the level of the isthmus not only in alopecic areas but even in non-inflamed follicles or the clinically normal scalp of affected individuals (Figure 7.5).

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Figure 7.5 Central centrifugal scarring alopecia (follicular degeneration syndrome) in African-Americans. (a) Black female with significant alopecia. (b) Close-up showing obliteration of follicular ostia. (c) Black male with significant alopecia. (d) Close-up of patient illustrating lack of follicular ostia.

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Figure 7.6 Algorithm for diagnosis of major non-infectious scarring alopecias.

Some clinical pearls can be helpful in establishing a diagnosis (Figure 7.6). First, if follicular hyperkeratosis is present, a central localization tends to occur in CCLE, while a peripheral distribution is seen in LPP. Second, the most likely diagnosis is PP if the scarring alopecia is non-inflammatory. Finally, if pustules are present, then FD is the most likely diagnosis.

Pathology The histopathology of CCLE reveals follicular vacuolar interface changes, a superficial and deep perivascular and periadnexal lymphocytic infiltrate, loss of sebaceous epithelium, and fibrosis (Figure 7.7). Perifollicular inflammation is most severe at the level of the infundibulum, and inflammatory cells may invade the follicular epithelium. The presence of a focally thinned epidermis, a thickened basement membrane zone and an increased dermal mucin helps support the diagnosis of CCLE. Pigment incontinence is present. Direct immunofluorescence demonstrates granular deposits of C3 of IgG distributed along the dermal-epidermal junction.1

Figure 7.7 Pathology of lupus erythematosus showing peri-adnexal and perivascular lymphocytic infiltration with follicular hyperkeratosis.

The lymphocytic infiltrate of LPP is lichenoid, with a characteristic perifollicular interface dermatitis (Figure 7.8). Other features include loss of sebaceous epithelium and marked perifollicular lamellar fibrosis. Inflammation affects the upper portion of the follicle, but may extend down the length of the follicle. Pigment incontinence is present.

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Figure 7.8 (a), (b) and (c). Pathology of lichen planopilaris displaying the characteristic follicular lymphocytic interface dermatitis. (Courtesy of Dr Magdalena Martinka.)

Figure 7.9 Numerous hairs exiting from one infundibulum which clinically appears as polytrichia or tufted folliculitis. (Courtesy of Dr Magdalena Martinka.)

Perivascular and peri-eccrine infiltrates are usually not present, as in LE. There may also be tufted folliculitis in the upper portion of the epidermis (Figure 7.9). Direct immunofluorescence may demonstrate grouped globular IgM cytoid bodies in follicular epithelium. The pathology of PP depends on disease duration. In the early stages, a peri-infundibular lymphocytic infiltrate is present beneath a normal epidermis. As PP progresses, the epidermis becomes atrophic, rete ridges vanish, and sebaceous glands and hair follicles are obliterated. Pigment incontinence is less evident than in LE or LPP. The end stage of PP is characterized by marked scarring and the absence of an inflammatory infiltrate. Direct immunofluoresence is negative. Special staining techniques may help in establishing a diagnosis of a scarring alopecia. Elastin staining demonstrated normal or abundant elastic tissue in PP, while in LE and LPP the quantity of elastin is significantly dimin-

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Figure 7.10 Algorithm for pathological assessment of major noninfectious scarring alopecias.

7.10 dividing entities into lymphocytic- versus neutrophilic-mediated. Folliculitis decalvans is neutrophilic-mediated (Figure 7.11), and will be described below.

Differential diagnosis

Figure 7.11 Neutrophilic infiltrate in folliculitis decalvans. (Courtesy of Dr Magdalena Martinka.) ished.27 Periodic acid Schiff staining in LE will demonstrate a thickened basement membrane zone and alcian blue stain or colloidal iron stains will show increased dermal acid mucopolysaccharides. An algorithmic approach to the pathology of scarring alopecias is presented in Figure

Scalp psoriasis has the presence of follicular ostia and the lack of follicular plugging and atrophy. However, there are reported cases of scarring alopecia in severe scalp psoriasis.28 Inflammatory changes in the infundibular area of the follicle in psoriasis may disrupt follicular stem cells and result in scarring alopecia. Tinea capitis can be scarring, but again there is no follicular plugging or atrophy. A potassium hydroxide preparation and/or culture will help confirm the diagnosis. Keratoacanthomas and squamous cell carcinomas can mimic hypertrophic lupus erythematosus. The lymphocytic scarring alopecias can certainly be difficult to tell apart from each other. Early CCLE and LLP can look quite similar. In addition, the co-existence of LPP and CCLE

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Figure 7.12 Algorithmic approach to treatment of lymphocytic-mediated scarring alopecias.

has been reported.29 Differentiating clinical and histopathological features of lymphocytic scarring alopecias are discussed above and are summarized in Figures 7.6 and 7.10.

Treatment The treatment of scarring alopecia depends on three variables: diagnosis, patient age, and disease severity. The severity is determined by the rapidity of the progression of the condition, the degree of inflammation, the severity of symptoms, and the extent of scalp involvement. The goals of treatment are to arrest the cicatrizing process, decrease follicular inflammation and prevent further fibrosis. At the University of British Columbia Hair Clinic the therapeutic strategy for patients with lymphocytic-mediated scarring alopecias is based upon the extent of the alopecia: groups with less than 10% scalp involvement and those with more than 10% scalp involvement are treated differently. This is summarized in algorithmic form in Figure 7.12.

Figure 7.13 Injecting intralesional cortisone into the surrounding hairy areas of scarring alopecia. Triamcinolone 10 mg/ml, injected with a volume of 0.1 ml/injection for 20 injections, can halt further spread of the condition and reduce symptoms of itch and burning. Injections are performed once monthly.

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Figure 7.14 Lupus erythematosus: the patient from Figure 7.2c, showing marked improvement after 1 year of hydroxychloroquine 200 mg twice daily, monthly intralesional corticosteroid injections and topical superpotent corticosteroid ointment twice daily.

Figure 7.15 Lichen planopilaris: the patient from Figure 7.3d with previous ulcerative LPP improved markedly with hydroxychloroquine, intralesional corticosteroid and topical corticosteroid.

If there is less than 10% scalp involvement, double therapy with topical and intralesional corticosteriods is initiated. Intralesional corticosteroid, 2 ml of 10 mg per ml, is administered to scarring areas once every four weeks (Figure 7.13), and an ultra-potent topical corticosteroid is applied twice daily. If the patient is not responding within eight weeks to this double therapy, then hydroxychloroquine, 200 mg twice a day,30 is added for a minimum of six months (Figures 7.14 and 7.15). If the alopecia is very severe, rapidly progressive, inflamed, and symptomatic, then prednisone is added at 1 mg per kilogram per day and tapered over two months. The prednisone provides bridge therapy, because of a delay in the therapeutic effects of hydroxychloroquine. If there is more than 10% scalp involvement, triple therapy is immediately initiated with intralesional steroid, ultra-potent topical

corticosteroid and hydroxychloroquine. If the alopecia is rapidly progressive, very inflamed and symptomatic, then a systemic steroid is also administered for eight to twelve weeks. If improvement is not noted after six months, than other treatments can be attempted. Isotretinoin,31–33 at doses of 1 mg per kg per day, can be initiated and then tapered once improvement is detected. Dapsone (100 mg/day)34–37 and thalidomide (100 mg/day)38–40 are other alternatives. Again, therapy is tapered once improvement is acheived. A pull test is conducted with each visit, and therapy is continued for six to twenty-four months until the pull test is negative. When a pull test is negative for over two years and alopecia is clinically stable, then scalp reduction and/or hair transplantation are further options. Premature transplantation may actually aggravate the condition. Increasing the number of hairs, which can serve as a primary target in scarring

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Figure 7.16 Folliculitis decalvans in a 30-year-old male. (a) Marked erythema and folliculitis. (b) After 6 months of isotretinoin 1 mg/kg/day, showing much improvement.

Figure 7.17 Folliculitis decalvans in a 17-year-old female, showing hair shafts embedded within the skin.

Figure 7.18 Tufted folliculitis in dissecting cellulitis, most evident after the scalp has been shaved.

alopecias, may cause the patient to become more symptomatic with increased inflammation, pruritus or burning if the condition is remotely still active. The use of topical minoxidil is controversial. Although there are no controlled trials for

topical minoxidil solution for scarring alopecias, many clinicians feel that topical minoxidil, by retaining unaffected hairs in anagen for a longer period of time, enables the overall density to be better than that of untreated individuals.41

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Figure 7.19 (a). Dissecting cellulitis of the scalp with characteristic boggy cysts. (b). Close-up of boggy cysts.

Neutrophil-mediated cicatricial alopecias The neutrophil-mediated cicatricial alopecias, such as FD, are considered an abnormal immune response to the normal scalp flora. Patients present with round patches of alopecia with overlying erosion, scale or crust. Follicular-based pustules develop in successive crops (Figure 7.16). Hair shafts are occasionally embedded within the scalp (Figure 7.17) Tufted folliculitis is a feature frequently seen in FD (Figure 7.18).42 In the early stages, the pathology demonstrates a neutrophilic folliculitis (Figure 7.11); however, as the disease progresses, fibrosis is prominent.43,44 Dissecting cellulitis can present as a boggy cystic inflammatory process (Figure 7.19).

The therapeutic strategy for the neutrophilmediated cicatrizing alopecias is targeted at anti-staphylococcal therapy with systemic erythromycin, cephalosporins, cloxacillin, rifampin and fusidic acid. There is some evidence that a combination of rifampin 300 mg twice daily and clindamycin 300 mg twice daily for twelve weeks affords more benefit than single-agent therapy.43 Systemic fusidic acid may also have some benefit.44 Topical therapy can also be added, such as topical fusidic acid.44 For severe dissecting folliculitis, high-dose isotretinoin for a prolonged course is recommended.45–49 Patients may be so symptomatic with discomfort, itch and burning, that controlling the inflammation for these individuals is more important than salvaging the hair. Laser-assisted hair removal50 may help for this subset of patients.

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Hair Loss: principles of diagnosis and management of alopecia

Conclusion The scarring alopecias are trichological emergencies. An accurate diagnosis is arrived at through a careful clinical and histo-pathological assessment. An aggressive multiplemodality therapeutic approach is often necessary to gain disease control.

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33. Green S.G. and W.W.Piette. Successful treatment of hypertrophic lupus erythematosus with isotretinoin. J Am Acad Dermatol, 1987; 17(2 Pt 2):364–8. 34. Singh Y.N., Adya C.M., Verma K.K., et al. Dapsone in cutaneous lesions of SLE: an open study. J Assoc Physicians India, 1992; 40(11): 735–6. 35. Lindskov R. and F.Reymann. Dapsone in the treatment of cutaneous lupus erythematosus. Dermatologica, 1986; 172(4):214–7. 36. Rothe M.J. and F.A.Kerdel. Treatment of cutaneous lupus erythematosus. Lupus, 1992; 1(6):351–6. 37. Duna G.F. and J.M.Cash. Treatment of refractory cutaneous lupus erythematosus. Rheum Dis Clin North Am, 1995; 21(1): 99– 115. 38. Holm A.L., Bowers K.E., McMeekin T.O. and Gaspari A.A. Chronic cutaneous lupus erythematosus treated with thalidomide. Arch Dermatol, 1993; 129(12):1548–50. 39. Knop J., Bonsmann G., Happle R., et al. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol, 1983; 108(4):461–6. 40. Hasper M.F. and A.H.Klokke. Thalidomide in the treatment of chronic discoid lupus erythematosus. Acta Derm Venereol, 1982; 62(4):321–4. 41. Dawber R. Update of minoxidil treatment of hair loss. In Hair and its disorders, biology, pathology, and management, ed. F.Camacho, pp. 167–76. 2000, London: Martin Dunitz Ltd. 42. Annessi G. Tufted folliculitis of the scalp: a distinctive clinicohistological variant of folliculitis decalvans [see comments]. Br J Dermatol, 1998; 138(5):799–805. 43. Powell J.J., R.P.Dawber and K.Gatter. Folliculitis decalvans including tufted folliculitis: clinical, histological and therapeutic findings. Br J Dermatol, 1999; 140(2):328–33. 44. Abeck D., H.C.Korting and O.Braun-Falco. Folliculitis decalvans. Long-lasting response to combined therapy with fusidic

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acid and zinc. Acta Derm Venereal, 1992; 72(2): 143–5. 45. Scerri L., H.C.Williams, and B.R.Allen. Dissecting cellulitis of the scalp: response to isotretinoin. Br J Dermatol, 1996; 134(6): 1105–8. 46. Plewig G., J.Nikolowski and H.H.Wolff. Action of isotretinoin in acne rosacea and gram-negative folliculitis. J Am Acad Dermatol, 1982; 6(4 Pt 2 Suppl): 766–85. 47. Shaffer N., R.C.Billick and H.Srolovitz. Perifolliculitis capitis abscedens et suffodiens. Resolution with combination therapy. Arch Dermatol, 1992; 128(10):1329–31.

48. Bachynsky T., O.M.Antonyshyn and J.B. Ross. Dissecting folliculitis of the scalp. A case report of combined treatment using tissue expansion, radical excision, and isotretinoin. J Dermatol Surg Oncol, 1992; 18(10):877–80. 49. Dubost-Brama A., Delaporte E., Alfandari S., et al. [Perifolliculitis capitis abscedens and suffidiens. Efficacy of isotretinoin]. Ann Dermatol Venereal, 1994; 121(4):328–30. 50. Chui C.T., Berger T.G., Price V.H. and Zachary C.B. Recalcitrant scarring follicular disorders treated by laser-assisted hair removal: a preliminary report. Dermatol Surg, 1999; 25(1):34–7.

Index Note: References to figures are indicated by ‘f’ and references to tables by ‘t’.

AA see alopecia areata acne 16, 47, 156 adrenoleukodystrophy, premature male AGA and 85 adriamycin (doxorubicin), alopecia and 137 AGA see androgenetic alopecia alkylating agents 138 alopecia assessment of patient with 1–18 causes of 10t DPCP treatment of 57f drug-induced 134–46 irreversible 155 reversible 139, 143 see also hair loss alopecia areata (AA) 9, 10, 16, 19–81, 163 AGA and 96–7 autoimmune disorders and 21 of beard 34, 36f clinical features of 28–36 cyclosporin in 66f cytokines and 24 differential diagnosis of 38–42, 40–1f Down’s syndrome and 20f, 21 emotional stress and 24 etiology of 19 extent of hair loss 30, 34f extracranial 35f genetic factors and 19–21 histopathology of 29f immunological factors and 21–4 intralesional corticosteroid injections for 44f nail changes and 39f nail dystrophy and 34, 39f neurological factors and 25 pathogenesis 23f pathology of 27–8 pattern of hair loss 30 prognosis of 36–7 systemic steroids and 46–7 telogen effluvium and 95–6 topical immunotherapy for 54–5f treatment of children with systemic steroids 47 treatment of 42–66

treatment plan 66–70 white hairs, vitiligo and 37f alopecia areata circumscripta 31–2f Alopecia Areata Investigational Assessment Guidelines 43 alopecia masking lotion 68 alopecia totalis (AT) 30, 34f, 42 alopecia universalis (AU) 30, 34f, 42 amitriptyline 143 amoxapine 143 ANA see antinuclear antibodies examination anagen effluvium 134, 136–8, 137f drug-induced 137t anagen (growing) hairs 6, 155 anagen phase, alkaline phosphatase activity and 3 anagen-telogen hair ratio 12, 27, 134 androgen blockade 102–4, 114 androgen receptor blockers (ARP inhibitors) 104–5 androgen receptor proteins (ARP) 85 androgenetic alopecia (AGA) 10t, 16, 83–119, 151, 158 differential diagnosis 38 history 9 iron deficiency and 148 miniaturization of hairs 27 surgical management of 121–33 treatment in men 109–12 treatment in women 108–9 vellus hairs in 6–8 in women 16, 88, 89f, 91f, 134 anemia, iron deficiency 16 anesthesias, telogen effluvium and prolonged 148 angiogenesis, tretinoin and 108 animal models, AA and non-AA 25–7 anthralin 43, 48, 49–51, 68, 69 anti-coagulants, hair loss and 139 anti-psychotics/anxiolytics 143 anti-thyroid drugs, telogen effluvium and 139 antidepressants, tricyclic/tetracyclic 143 antihypertensive agents 143 antinuclear antibodies (ANA) examination 16, 157 antitumor antibiotics 138 anxiety, telogen effluvium and acute 150

176

Index

arrector pili muscle 5, 98, 155 atherogenesis 88 autoeczematization 64 autoimmune diseases 21, 23 autoimmune polyglandular syndrome 21, 22 autoimmunity, clues for 21–4 baldness coronary heart disease and 87 drugs and 134 patterns in population 85 prostate cancer and 88 beard, alopecia areata of 34, 36f Beau’s lines 34 beta-blockers 143 betamethasone dipropionate 43, 48 biologic response modifiers 101, 105–8, 114 bitemporal recession 91, 151 bleomycin 137 body, alopecia areata of 34 body hair, thinning of 149 bulge area, stem cells of 5, 155 buspirone 143 busulfan 138 C3H/HeJ mice 25, 26 calcitonin gene-related peptide 25 captopril 143 carbamazepine, alopecia and 142–3 carbimazole 139 cardiovascular disease 87 carmustine 138 castling, DPCP and 52 catagen 134, 136, 155 catagen hairs 6, 27, 98 catagen-telogen hair ratio 101 cell-mediated immunity 22–4 cellulitis 156 central centrifugal scarring alopecia (CCSA) 156, 164f cephalosporins 171 chemotherapy 134 children anthralin and 49 hair loss in 9 systemic steroid treatment in 47 therapeutic modality choices for 69 topical therapies for 67 chlorambucil 137 chlormethamine 137 cholesterol-lowering agents 144

chondroitin sulfate 3 chromosome 8p 12 26 chronic cutaneous lupus erythematosus (CCLE) 155, 156, 157 histopathology of 165 vs LPP 158, 167 chronic telogen effluvium (CTE) 150, 151 cicatricial (scarring) alopecias 10t, 16, 17, 155–72 algorithm for diagnosis for 165f inflammatory 155 lymphocytic 167 pathology algorithm 167f cimetidine, alopecia induced by 136 circumscript alopecia 32f circumscript alopecia areata 38 clindamycin 171 clobetasol propionate 68 clofibrate 144 clonazepam 143 cloxacillin 171 colchicine 138 corticosteroids 43–7, 69 cortisone, injection of intralesional 168f coumarins 139 Cox proportional hazards model 87 Crohn’s disease 149 cyclophosphamide 137, 138 cyclosporin 65–6 cyproterone acetate (CPA) 101, 104–5, 108 cysts, boggy 171f cytarabine 137 cytochrome P450 aromatase enzyme 86 cytokines, alopecia areata and 24 cytomegalovirus (CMV) infection 24 cytosine arabinoside 138 cytostatic drugs 136–8 dacarbazine 138 dactinomycin 137 dapsone 169 daunorubicin 137 dehydroepiandrosterone sulfate (DHEAS) test 16, 98, 108 delayed anagen release (DAR) 138 delayed telogen release (DTR) 138 depression 9, 150 dermal acid mucopolysaccharides 167 dermographism, severe 64 despiramine 143 dexamethasone 43

Index

diabetes mellitus 22 dibromoketone 53 diffuse alopecia 16, 143, 148 diffuse alopecia areata 30, 33f diffuse cyclic hair loss, in women 150 dihydrotestosterone 85 dinitrochlorobenzene (DNCB) 51–2 diphenylcyclopropenone (DPCP) 26, 51, 52–64, delayed response 59f eczematous eruptions from 60–1 f pigmentary changes with 62f treatment of eyebrows with 60f unilateral treatment with 59f discoid lupus erythematosus (DLE) 10t, 16, 17 divalproex 142 dopaquinone 6 Down’s syndrome, alopecia areata and 20f, 21 doxepin 143 doxorubicin (adriamycin), alopecia and 137 drug-induced alopecia 134–46 anagen effluvium 137f, 145 lichenoid eruption of scalp 134 telogen effluvium 139t, 140t, 141t Dundee experimental bald rat (DEBR) 25 dyslipidemia 88 dysmorphobia 9 dystrophic anagen hairs, positive pull test 96 dystrophic hairs, counts of 12 dystrophy, checking for presence of 15 eczema, DPCP and 64 elastin staining 156, 166 eosinophils 27 epidermal growth factors (EGF) 105 erythema 163, 170f erythema multiforme 64 estrogen, AGA and 105 eumelanin 6 exclamation point hairs 32f eyebrows dermatography of 69 injection with triamcinolone 45f loss of 163 treatment with DPCP 64 facial edema 130 facial hypertrichosis 107 ferritin, levels of 98, 151 fever, alopecia and 147

177

finasteride 101, 102–4, 109, 133 hair transplants and 130 and minoxidil combination therapy 110 fluocinolone 43 fluorouracil 137 fluoxetine 143 follicular bundles, with miniaturized hairs 99f follicular degeneration syndrome (FDS) 156, 163, 164f follicular hyperkeratosis 58, 158, 165 follicular ostia 10, 88, 155 follicular scalp lesions 158 follicular stem-cell gene therapy 114 follicular stem-cells 155 folliculitis, tufted 166, 170f, 171 folliculitis decalvans (FD) 155, 156, 167, 170f, 171 fronto-parietal/fronto-temporal recession 90 fusidic acid 171 gastric parietal cell antibodies 22 gene replacement therapy 70 gold, hair loss and 158 graft hair preparation 126 Graham-Little disease 160f hair density and distribution of 10 dryness of 139 thinning of 86 hair anatomy 1–8 hair color, loss of 144 hair cortex 4, 5, 136 hair counts 13, 103 hair cycling, on human scalp 6 hair follicles 1–2 cellular components of 24 growth inhibitors 24 layers of 3f non-permanent and permanent segments 7 hair grafts, planting of 129 hair loss 9, 158 pattern in a family 95f prevention of 101, 113 severity of 148 see also alopecia hair matrix cell mitosis 136 hair removal, laser-assisted 171 hair shafts 2, 6 abnormalities of 15 quality of 10, 11f

178

Index

hair shedding 9, 12 abrupt diffuse 148f, 149f physiological 6 hair thinning 9, 89, 151 hair transplants 101, 108, 110, 121–2f, 169 complication of donor area 126 finasteride and 130 male 113f, 132f minoxidil and 130 multiple-bladed knife for 123f positioning of hairline 126–8 recipient area 126–30 removal of donor strips 124f hair weights, study of 103 hair-growth promoters 101 hair-specific antibodies 23 hairpieces 69, 101 hairs light-microscopic examination of 13–16 miniaturization of 27, 83 halcinonide 43 haloperidol 143 Henle’s layer 2, 4, 5 hen’s egg test 53 heparin 139 hepatic disease 149 hirsutism 16, 87, 108 Hodgkin’s disease 149 hormone modifiers 101, 102–5 Hox genes 26–7 human leukocyte antigens (HLA) 19–21 Huxley’s layer 2, 4, 5 hyaluronic acid 3 hydroxycarbamide 137 hydroxychloroquine 169 hydroxyurea 138 hyper-androgenism 16, 87, 98, 108 hyper-insulinemia 88 hyperpigmentation 64 hypertension 47, 88 hyperthryoidism 9 hypertrichosis 108 hypertrophic lupus erythematosus 167 hypo-proteinemia 147 hypopigmentation 64, 158 hypopituitarism 85 hypothyroidism 9, 136, 140, 148 iatrogenic hypothyroidism 139 ICAM-1 27

ichthyosis 144 ifosfamide 138 imipramine 143 immediate anagen release 138, 147 immediate telogen release 138 immunosuppressive therapy, responsiveness to 21 inflammatory bowel disease 149 infundibulum 1, 5, 155, 163 inner root sheath (IRS) 2, 4, 5 insulin-resistance-associated disorders 88 interferons 143 intracellular androgen metabolism, AGA and 85 intralesional corticosteroids 67, 69, 169 intramuscular corticosteroid therapy 47 iodine, telogen effluvium and 139 iron deficiency 16, 148 isotretinoin 169, 171 isthmus 1, 5 Kaplan-Meier survival analysis 53 keloids 125 keratin 4 keratinization, disturbed 136, 144 keratinocytes, abnormal 24 keratoacanthomas 167 keratotic follicular papules 155 leflunomide 26 lichen planopilaris (LPP) 155, 156, 158–63, 159– 60f, 169f cicatricial alopecia 10t pathology of 166f peripheral distribution 165 lichen planus 17, 22, 158 lichenoid eruption 136 lithium 140–2 Ludwig pattern, stages of 89 Ludwig Stage I pattern, in teenagers 95f Ludwig Stage III, women with 108 Ludwig Stages I–III 90f lupus erythematosus 22, 158, 169f chronic cutaneous scalp 157f luteinizing hormone-releasing hormone (LH-RH) 105 lymphadenopathy 62f, 64 lymphocytic-mediated cicatricial (scarring) alopecias 156–70 treatment algorithm 168f M phase drugs 138

Index

McKusick Mendelian Inheritance in Man (MIM) 83 Major Histocompatibility Complex (MHC) 19 malignant diseases 149 maprotiline 143 mechlormethamine 137 medulla 2, 4 melanin 3, 6 melanocytes 6, 24–5 melphalan 18, 138 men AGA treatment options 101 frontal hairline recession 89 vertex balding in 87 mepacrine (atabrine), hair loss and 158 6-mercaptopurine 138 mesenchymal-derived dermal papilla 86 methotrexate 137, 138 methylprednisolone 47 methylthiouracil 139 mice, hairless 26 micro-grafting 132 Microsporum canis 42 mini-grafting 132 miniaturized hairs 88, 93 minoxidil (Rogaine) 43, 47–8, 101, 105–8, 109 and hair transplants 130 hypertrichosis of the face and 107f topical 133, 170 use of betamethasone dipropionate and 48f monoamine oxide inhibitors 143 morphea 156 mouse teratogenicity test 53 myasthenia gravis 22 nail dystrophy, alopecia areata and 34, 37 National Alopecia Areata Foundation (NAAF) 19, 70 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 19 neutrophil-mediated cicatricial alopecias 171 nitrosoureas 138 non-cicatricial (non-scarring) alopecias 10f, 16, 17f non-inflammatory cicatrizing alopecias 155 nortriptyline 143 Norwood-Hamilton classification 92, 109 Norwood-Hamilton pattern 90, 94f Norwood-Hamilton Stage III 92f Norwood-Hamilton Stage III and IV 103 Norwood-Hamilton Stage VII 94f Norwood-Hamilton Stages IV–VI 93f

179

obesity 47, 88 olanzapine 143 onychorrhexis 34 ophiasis 33f, 37, 58f ophiasis inversus (sisapho) 30, 33f oral contraceptives 143 oral cyclosporine 22 outer root sheath (ORS) 2, 5 papular atrichia 85 paroxetine 143 PAS stain 156 patchy alopecia areata 30, 33f, 42 patient, history of 9 patient expectations, therapy and 113–14 peri-infundibular lymphocytic infiltrate 166 perifollicular interface dermatitis 165 pernicious anemia 22 pheomelanin 6 photochemotherapy (PUVA) 64–5, 70 squaric acid dibutyl ester and 52 phototrichogram method 103 pigment incontinence 165 cis-platin 138 polymyalgia rheumatica 22 polytrichia 163 polytrichia folliculitis 166f post-menopausal frontal fibrosing alopecia 163 postpartum hair loss 138, 147 prednisolone, pulsed oral 47 pressure-induced alopecia (PIA) 38, 42 procarbazine 138 Propecia 102, 104 propylthiouracil 139 prostate cancer, AGA and incidents of 88 protriptyline 143 pruritus 158, 163 pseudopelade (PP) 38, 156, 161f, 163, 166 psycho-physical trauma 147 psychogenic pseudoeffluvium 151 psychopharmacologic medications 140–3 pull-tests 10, 11f, 93, 156, 169 pulse therapy, intravenous methylprednisolone 47 pustules 156 PUVA therapy see photochemotherapy pyrogens, endogenous 147 quail-chick model 86 5α-reductase 85

180

Index

renal failure 149 respiridone 143 reticular alopecia areata 30, 33f Retin-A 108 rifampin 171 Rogaine see Minoxidil S phase-specific drugs 138 SAHA (seborrhea, alopecia, hirsutism, acne) syndrome 87 Salmonella typhimurium 51 sarcoidosis 156 scalp cellulitis of 171f physiology of 1–8 scalp biopsies 14–15f, 16, 134, 151, 156 scalp irritation, minoxidil and 10 scalp lesions 158 scalp prostheses 68f scalp psoriasis 167 scalp reduction 169 scarring alopecia see cicatricial alopecia sebaceous epithelium, loss of 165 seborrheic dermatitis 100 serotonin reuptake inhibitors 143 sertraline 143 serum ferritin, evaluation of 16 sex hormone binding globulin (SHBG) 105 short-contact therapy 49 shortened anagen (SA) 138 sisapho 30, 33f skin diseases, alopecia and severe 136 Smyth chicken model 25 soriatane 144 spironolactone 101, 105, 108 squamous cell carcinomas 167 squaric acid dibutyl ester (SADBE) 26, 51, 52 steroid-metabolizing enzymes 85 steroids systemic 22, 46–7 topical, intralesional and systemic 43 stress alopecia areata and emotional 24 telogen effluvium and psychological 150 striae, systemic steroids and 47 substance P (SP) expression 24, 25 support groups 69 suprabulbar area 1, 4f syphilitic alopecia 27, 28 systemic diseases 136

systemic erythromycin 171 targeted follicular gene therapy 114 telangiectasia 158 telogen effluvium 9, 10t, 16, 96f, 142f acute and chronic 147–53 alopecia areata and 27, 28, 95 differential diagnosis 38, 134 drug-induced 139–44 pathology of 28 types of 138–9 in women 86 telogen hairs 6, 27, 98, 155 cross-section of 8f positive pull test 96 temporal triangular alopecia (TTA) 42 terminal-vellus hair ratio 27, 134 testosterone 85 thalidomide 169 thallium, hair loss and 144 thiotepa 137, 138 thyroid dysfunction 16 thyroid function assessment 140 thyroid influences 21, 148 thyroid screening 9 thyroid stimulating hormone test (TSH) 98 thyrotoxicosis 139, 140 tinea capitis 9, 10t, 38, 167 topical immunotherapy 43, 51–64, 69 topical ophthalmic beta-blockers 143 trachyonychia 34 traction alopecia 10t, 38 trazodone 143 tretinoin (all-trans-retinoic acid) 108 triamcinolone acetonide 45 triamcinolone hexacetonide 45 triangular temporal alopecia 38 trichodynia 151 trichogram/pluck test 12 trichologic anatomy 1–8 trichomalacia 28 trichotillomania 9, 27, 28, 38 triparanol 144 tufting, cicatricial alopecias and 163 tyrosine 6 ulcerative colitis 22 valproic acid (VPA) 142 vasopressin 138

Index

vellus hairs 6, 98, 99f vellus-like hairs 7f vertex pattern balding 87 vertex thinning 90 vinblastine 137, 138 vincristine 137, 138 vitiligo 63f, 64

women AGA in 88, 89f, 91f finasteride and 104 hair loss in 86 hair transplantation in 131–2 treatment of AGA in 101, 108–9 Woods light examination 42 zolpidem 143

181