CFAD V. Anacor, |PR201 5-01776 ANACOR EX. 2053 - “I/77
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2053 - 1/77
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`

`
`Onychomycosis
`the current approach to diagnosis and therapy
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2053 - 2/77
`
`

`
`Robert Baran, MD
`Nail Disease Center.
`Cannes. France
`
`Roderick Hay, MD
`Professor of Cutaneous Medicine
`StJohn's Institute of Dermatology
`StThomas· Hospital
`London. U.K.
`
`Eckart Haneke, MD
`Professor and Director
`Department of Dermatology
`Ferdinand Sauerbruch Hospital
`Wuppertal. Germany
`
`Antonella Tosti, MD
`Associate Professor of Dermatology
`Department of Dermatology
`University of Bologna
`Bologna. Italy
`
`Bianca Maria Piraccini, MD
`Department of Dermatology
`University of Bologna
`Bologna. Italy
`
`Although every effort has been made to ensure that drug
`doses and other Information are presented accurately
`1n this publication. the ult1mate responsibility rests With
`the prescnbing physic1an. Neither the publishers nor the
`authors can be held responsible for errors or for any
`consequences ans1ng from the use of information
`contained herein.
`
`©R. Baran 1999
`
`F1rst published in the United K1ngdom in 1999 by
`Martin Dunitz Ltd.
`The Livery House
`7-9 Pratt Street
`London NW 1 OAE
`
`R epri nted with correcnons 2001
`
`Graphic des1gn by Atelier Hohne. Grafelfing. Germany
`Pnnted and bound 1n Spa1n
`
`All nghts reserved. No part of th1s pubhcauon may be re(cid:173)
`produced. stored 1n a retneval system. or transm1t1ed. 1n any
`form or by any means. electromc. mechanical. photocopying.
`recording or otherWise. Without the pnor permiSSion of the
`publisher or 1n accordance w1th the prov1sions of the
`Copynght Act 19B8. or under the terms of any licence per(cid:173)
`mitting hm1ted copying ISSued by the Copynght L1cens1ng
`Agency. 90 Tottenham Court Road. London W1 P9 HE.
`A CIP catalogue record for this book IS available from the
`Bnt1sh Library
`ISBN 1-85317-767-9
`
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`
`

`
`Robert Baran
`Roderick Hay
`Eckart Haneke
`Antonella Tosti
`w ith the collaboration of Bianca Maria Piraccini
`
`Onychomycosis
`the current approach to diagnosis and therapy
`
`Martin Dunitz Ltd.
`Publishers
`
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`

`
`Contents
`
`Preface
`
`Epidemiology
`
`2
`
`3
`
`Anatomy of the normal nail
`
`Clinical patterns correlated
`with main routes of entry
`
`4
`
`Clinical differential diagnosis
`
`5
`Mycological examination
`5.1 The proper collection of samples:
`The "How" and "Where"
`5.2 Microscopic examination
`5.3 Culture
`5.4 Histopathological examination
`
`6
`
`Goals for the treatment of onychomycosis
`
`Mycological cure
`
`Clearance of the nail plate
`
`Clinical measurement and assessment
`
`of responses
`
`5 1
`
`6 1
`
`10 I
`
`I
`12 1
`
`20 1
`
`28
`
`28
`30
`31
`34 \
`
`40
`
`40 1
`41
`
`42 1
`
`Review of current antifungal therapy
`
`7
`7.1
`Topical treatment
`7.1.1 Transungual drug delivery systems
`7.1.2 Nail avulsion
`total surgical
`
`partial surgical
`
`chemical
`
`7.2 Systemic treatment w ith new antifungal drugs
`
`ltraconazole
`
`Fluconazole
`
`Terbinaf1ne
`7.3.1 Treatment in the elderly
`7.3.2
`in childhood
`7.3.3
`7.3.4
`in immunocompromised patients
`7.4 Rationale for a stepwise approach to therapy
`
`in pregnant women
`
`8
`Preventive measures
`8.1 Reasons for prevention
`8.1 .1 Genetic predisposition
`8.1.2 Reduced nail growth rate
`8.1 .3 Underlying disease
`8.2. Prevention
`
`Index
`
`44 1
`
`44 1
`
`~I
`:I
`
`50
`54
`54
`
`57 1
`59 ,
`63
`64
`64
`64
`66
`
`70
`70
`
`70 1
`
`~~ I
`
`71 I
`
`73 [
`
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`

`
`Preface
`
`This book is w ritten by clinicians for clinicians.
`In it the authors, w ho have an abiding interest
`in all fields of nail pathology, have focused on
`one of the commonest of nail disorders,
`onychomycosis. The stepwise approach provi(cid:173)
`des a basis for identifying the most appropriate
`cost-benefit considerations in the management
`of fungal nail infection. Consideration of the
`subject follows a logical path from clinical
`expression through laboratory diagnosis to
`therapy. The new classification of the clinical
`appearances reflects the underlying nail patho(cid:173)
`logy and provides a rational explanation for the
`pathogenesis and the response to treatment.
`Compared w ith the situat ion ten years ago,
`there is now a wide choice of treatment
`options for patients with onychomycosis from
`topical antifungal agents to nail surgery. The
`development of new treatment regimens.
`however, has had the greatest impact on the
`success of t herapy. This in turn has opened t he
`possibility of successful treatment to the
`majority of patients w ith fungal nail infections.
`particularly those caused by dermatophytes.
`The result has been a major increase in the
`numbers of pat ients with onychomycosis
`presenting for treatment. We hope that this
`book will provide an up to date review of this
`common clinical problem which will be of
`interest to a wide group of health professionals
`including dermatologists, general practitioners.
`practice nurses and chiropodists/ podiatrists.
`
`The authors
`
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`

`
`Epidemiology
`
`Onychomycoses are the most common of
`nail diseases. They occur worldwide. but with
`variable frequency depending on different
`climatic. professional and socio-economic
`conditions. One hundred years ago, they were
`considered to be very rare. affecting mainly
`those caring for children with tinea capitis. but
`their prevalence has increased dramatically
`during the last few decades (Table 1.1} [1].
`
`Table 1.1
`Proportion of onychomycoses to dermato(cid:173)
`mycoses (literature survey; from [1])
`
`City and year
`
`Paris
`
`1910
`
`Munich 1913-1922
`
`Berlin
`
`1919- 1934
`
`Munich 1938
`
`Hamburg 1938
`
`Hamburg 1949
`
`Munich 1951
`
`Berlin
`
`1951-1956
`
`Munich 1958
`
`Brussels 1980
`
`%
`
`0.2
`
`0.13
`
`2
`
`2.6
`
`2.8
`
`10
`
`8.4
`
`17.1
`
`11.1
`
`30
`
`Approximately 1.5% to 15% of persons pre(cid:173)
`senting to a dermatologist have onychomycosis
`[2. Klein. pers oral comm]. Other estimates
`suggest between 2% [3] and 23% [4]. There
`are considerable differences in the prevalence:
`a survey of 20.000 persons from North Malawi
`found no onychomycosis though there was a
`1.5 to 2.5% prevalence of dermatophytosis in
`this population [5): this is probably due to the
`fact that many of the people do not wear shoes.
`The frequency of onychomycosis in rural Zaire
`was 0.89%, but 4% of men and 2.8% of
`women in towns had fungal nail infections [6].
`Large scale studies from Europe. the Middle
`East and North America have revealed very
`high rates of fungal nail infections (Table 1.2).
`A prevalence of 27% was found in coal
`miners: heat. humidity and common shower
`facilities were held responsible for this high
`proportion [7]. In another study carried out
`1 0 years later. 327 out of 1000 people from
`the Ruhr area in Germany were found to have a
`dermatophyte infection of their nails [8].
`
`The frequency of onychomycosis increases with
`age. Although these infections are very rare in
`young children- two studies found 0.2 %,
`other studies have failed to find a single case
`and the latest revealed an overall prevalence of
`0.44% [16-20, 51 I- they are common in
`young adults and very common in the elderly
`[ 19]. Among adolescents, young males are
`more frequently affected than females; this is
`probably due to a higher frequency of nail
`damage due to sports and leisure activities
`amongst male adolescents. A recent survey
`among National Basketball Association and
`Women's National Basketball Association
`(WNBA) teams found 89% of the players
`suffered from onychomycosis during their
`career [19a]. A previous survey in Ohio, USA.
`showed that approximately 14% of the general
`population had fungal nail infection and 48% of
`people > 70 years [ 151.
`
`Eighteen to 40% of all nail diseases are due to
`fungal infections [21. 22) and approximately
`30% of all dermatomycoses are nail infections
`[2].
`
`By far the most common pathogens are
`dermatophytes. Virtually unknown in Western
`Europe at the beginning of the 20th century
`Trichophyton rubrum was probably introduced
`from West Africa or Asia and has become the
`most frequent pathogen in Western Europe,
`North America. and Asia causing 50% to 75%
`of all cases of onychomycosis [23. 24].
`T rubrum and T mentagrophytes together
`make up at least 80% of onychomycosis in
`Central Europe [25]. Yeasts can be cultured
`from 5% to 17% of cases w ith >70% of these
`being Candida a/bicans [26]. Non-dermato(cid:173)
`phyte moulds are considered pathogenic in
`less than 5% of cases [25. 27-30] and even
`this proportion is debatable [31]. Seytalidium
`dimidiatum. S. hyalinum and Scopulariopsis
`brevicaulis though are generally accepted as
`nail pathogens as well as some Aspergillus.
`Fusarium. Acremonium spp and Onychoco/a
`canadensis [32]. However. there are con(cid:173)
`siderable variations according to geographical
`location [33]: up to 50% of the onychomycosis
`cases among Thai conscripts were due to
`Scytalidium dimidiatum (Hendersonula
`toruloidea) [34]. In Saudi Arabia. most cases of
`onychomycosis were due to Candida albicans
`with 204 of 243 culturally positive cases of
`onychomycosis and 241 of 257 cases
`secondary to paronychia [35]. However in one
`study 60% of nails that had either been
`
`6
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`

`
`Table 1.2
`Prevalence of onychomycoses world -wide
`
`Country
`
`Year publ
`
`Prevalence [% ]
`
`Subjects examined
`
`Authors
`
`1965
`Germany
`1966
`Britain
`1966
`East Germany
`1972
`USA
`Germany - Ruhr area 1974
`1977
`Zaire (Congo)
`
`Great Britain
`Spain
`
`Greece
`
`Finland
`
`North Malawi
`Great Britain
`Ontario. Canada
`Ohio. USA
`Canada & USA
`
`1992
`1995
`
`1995
`
`1995
`
`1996
`1996
`1997
`1997
`1997
`
`27
`2
`13
`>15-20
`32.7
`0.9
`2.8
`4.0
`2.7
`2.6
`
`2.5
`11 .7
`8.4
`11 .3
`4.3
`13
`0
`11
`6.9
`14
`0.44
`
`Coal miners
`
`Estimate
`1 000 persons
`rural areas
`urban areas - female
`- male
`omnibus suNey
`computer-ass1sted
`telephone inteNiew system
`fingernails
`toenails
`all ages
`adults
`females
`males
`20.000 rural area
`1 00 diabetics
`
`general population
`2500 children and 50
`adolescents under 18 years
`
`7
`3
`4
`9
`8
`4
`6
`
`10
`11
`
`12
`
`19
`
`5
`13
`14
`15
`20
`
`negative on microscopy or had grown yeasts
`yielded dermatophytes after nail avulsion [36].
`This suggests t hat growth by contaminant
`fungi may obscure the presence of the true
`pathogen. Furthermore. a change in the pattern
`of fungal pathogens has also been noted
`during the last decade [37].
`
`Toenails are about seven times more frequently
`affected than fingernails. The reason for this is
`probably the growth rate which is about three
`times slower for toenails than fingernails [32].
`
`The enormous increase in the prevalence of
`onychomycosis has been attributed to various
`factors. Increased and prolonged exposure to
`fungal pathogens through communal bathing
`and showering facilities. health spas. saunas.
`and gyms. sports activities. wearing of
`occlusive footwear. ageing of the population.
`
`increasing numbers of diabetics. administration
`of immunosuppressive and cytotoxic drugs.
`and the AIDS epidemic are all thought to pre(cid:173)
`dispose to fungal nail infections [38. 39].
`However. a series of investigations from France
`showed that although the main fungal patho(cid:173)
`gen isolated from public sports facilities was
`T mentagrophvtes the fungi isolated from the
`feet of the users were mostly T rubrum [ 40].
`Another study from Wales also did not support
`the assumption that frequent use of public
`changing facilities is necessarily related to the
`transmission of fungal infection. Instead. the
`fact that a high proportion of parents was
`affected suggested that they might act as the
`source of infection [1 7]. Investigations of
`families from Italy. France and the USA suggest
`that susceptibility to fungal nail infections.
`particularly those due to T rubrum. might be
`inherited as an autosomal dominant trait [41 ].
`
`7
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`

`
`Epidemiology
`
`Damaged nails are more susceptible to
`onychomycoses (3, 42]. This is supported by
`the obseNation that dermatophytes can be
`grown from normal toenails and dermatophyte
`onycholysis of the big toenail may heal after
`correction of an underlying foot deformity
`[43. 44]. Tinea unguium was seen in 42 % of
`subjects with arterial circulatory disorders [45].
`Nail changes alone were seen in 8%. and nail
`and interdigital abnormalities in an additional
`22% of vascular disease patients (controls 4%
`and 0%. respectively). However. cultures were
`positive in only 9% of patients and 1 % of con(cid:173)
`trols [46] (Table 1.3). The role of diabetes melli(cid:173)
`tus is debatable [47]. There may not be an
`increased incidence of dermatophyte infections
`
`of the nail unit in diabetics but Candtda infec(cid:173)
`tions may be more prevalent [48]. However. for
`some authorities [49]. after controlling for age
`and sex. the risk ratio in 55 diabetic subjects for
`onychomycosis of the toes (present in 26.2%
`of the samples) was 2.77 times greater than
`that of normal individuals. The majority of
`organisms implicated in causing onycho(cid:173)
`mycosis were dermatophytes (88%). with
`Candida species in 3% and non-dermatophyte
`moulds accounting for 9% [49].
`
`Psoriasis and hereditary palmoplantar
`keratoses also appear to favour fungal nail
`infections (8, 50-52].
`
`Table 1.3
`Frequency of onychomycoses and importance of predisposing diseases
`
`Condition
`
`Abnormal toenails
`
`Number
`examined
`------
`72
`183
`
`Subungual hyperkeratoses
`
`Podiatric
`
`Impaired arterial circulation
`
`Venous insufficiency
`
`Diabetes mellitus
`
`Psoriasis
`
`Psoriasis
`
`Psoriasis
`
`Psoriasis
`
`Keratosis palmoplantaris
`Old age (> 70 yrs)
`
`168
`
`112
`
`100
`
`100
`
`100
`
`120
`
`78
`
`561
`(298
`(263
`
`8
`
`Onycho-
`mycosis[%)
`
`Reference
`
`3
`
`3
`
`3
`
`43
`
`34
`
`37
`
`42
`
`10 (30)
`
`12 to 26
`
`14
`16
`16
`
`35
`24
`15
`
`27
`23
`30
`
`13
`0.7
`27
`
`48
`
`45
`culture-proven (altered nails) 46
`13 &49
`
`dermatophytes
`Candtda spp
`moulds
`
`all fungi
`dermatophytes
`Candida albicans
`
`all nails in psoriatics
`normal appearing nails
`altered nails
`
`all nails
`normal appearing nails)
`clinically abnormal nails)
`
`8
`
`50
`
`51
`
`14
`
`52
`
`15
`
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`

`
`References
`
`1. Haneke E. Epidemiology and
`pathology of onychomycoses. In
`Nolt1ng S. Koning HC. eds. Onychomy(cid:173)
`coses Berlin. Spnnger. 1989:1-8
`2. Achten G. Wanet-Rouard J.
`OnychomycosiS (Mycology No 5).
`Brussels. Cilag: 1 981
`3. Walshe MM. English MP Fungi 1n
`nails Br J Dermatol 1966;
`78.198-207
`4. Seebacher C. Untersuchungen uber
`d1e Pilzflora kranker und gesunder
`Zehennagel. Mykosen 1966:
`11:893-902
`5. Ponn1nghaus JM. Clayton Y.
`Warndorff D The spectrum of derma(cid:173)
`tophytes in northern Malaw1 (Afnca).
`Mycoses 1996: 39:293-297
`6. Vanbreuseghem R. Prevalence des
`onychomycoses au za·,re paniculiere(cid:173)
`ment chez les coupeurs de canne a
`sucre. Ann Soc Belg Med Trop 1977:
`57:7-15
`7. G<itz H. Hantschke D Einblicke 1n
`d1e Ep1dem1olog'e der Dermatol(cid:173)
`mykosen 1m Kohlenbergbau. Hautarzt
`1965. 16:543
`8. G<itz H. Pat1n C. Hantschke D. Das
`Wachstum von Dermatophyten auf
`normalem und psoriatischem Nagel(cid:173)
`keratln. Mykosen 1974: 17:373-377
`9. Zaias N. OnychomycosiS. Arch
`Dermatol 1972: 105:263
`1 0. Robens DT. Prevalence of
`dermatophyte onychomycosis 1n the
`Un1ted Kingdom: results of an omm(cid:173)
`bus survey. Br J Dermatol 1992: 126
`Suppl 39:23-27
`11. Sa is G. Jucgla A. Peyri J. Pre(cid:173)
`valence of dermatophyte onychomy(cid:173)
`COSIS in Spain: a cross-sect1onal study
`Br J Dermatol 1995: 132:758-61
`I 2. Devllotou-Panagiotldou D. Koussl(cid:173)
`dou-Eremondi T. Badillet G. Dermato(cid:173)
`phytosis 1n nonhern Greece during the
`decade 1981-1990. Mycoses 1995;
`38:151-157
`13. Buxton PK. Milne UR. Prescott RJ.
`Proud foots MC: Stuart FM. The pre(cid:173)
`valence of dermatophyte 1nfect1on 1n
`well-controlled diabetiCS and the
`response to Trichophyton ant1gens.
`Br J Dermatol 1996: 134:900-903
`14. Gupta AK. Lynde CW. Jain HC.
`S1bbald RG. Elewski BE. Daniel CR Ill.
`Watteel GN. Summerbell RC. A h1gher
`prevalence of onychomycosiS 1n
`psoriatics compared with non-pso(cid:173)
`natiCS. a multicentre study. Br J
`Dermatol 1997; 136:786-789
`15. Elewski B & Chanf MA. Prevalence
`of onychomycoSIS 1n patients
`attendmg a dermatology cl1nic 1n
`nonheastern Oh1o for other condit1ons
`Arch Dermatol 1997; 133
`1172-1173
`16. Findlay GH. Vismar HF. Soph1anos
`T Spectrum of paed1atnc dermatology.
`Br J Dermatol 1974; 91 :379-387
`17. Philpot CM. Shuttlewonh D. Der(cid:173)
`matophyte onychomycoSIS in children.
`Clln Exp Dermatol1989; 14:203-205
`
`18. Khosravi AR. Aghamman MR.
`Mahmoud1 M. Dermatophytoses 1n
`Iran. Mycoses 1994; 37:43-48
`19. He1kkllii H. Stubb S The pre(cid:173)
`valence of onychomycosis in F1nland
`Br J Dermatol 1995; 133:699- 703
`19a. McNerney J. OnychomycOSIS 1n
`spec1al populations ISS02-05). JEADV
`2000; 14 (suppl 14). 83.
`20. Gupta AK. Sibbald RG. Lynde CD.
`Hull PR. Shear NH. de Doncker P.
`Dan1el CRIll. OnychomycosiS 1n
`children: prevalence and treatment
`strategies JAm Acad Dermatol 1997;
`36:395-402
`2 1. Langer H. Ep1demiolog1sche
`und klinische Untersuchungen be1
`Onychomykosen. Arch Kiln Exp
`Dermatol1957; 204.624
`22. Achten G. Wanet-Rouard J.
`Onychomycoses 1n the laboratory.
`Mykosen 1978; 23. Suppl 1.125
`23. Darde ML. Ep,dem1olog'e des
`dermatophyt1es. Ann Dermatol
`Venereol 1992: 119:99-100
`24. Manzano-Gayosso P. Mendez(cid:173)
`Tovar U. H~rnandez- Hernandez F.
`L6pez-Manlnez R Dermatophytoses
`1n Mex1co City. Mycoses 1994;
`37:49-52
`25. Clayton YM. Clin1cal and mycolo(cid:173)
`gical diagnostic aspects of onychomy(cid:173)
`coses and dermatomycoses. Clin Exp
`Dermatol 1992; 17: suppl 1 :37-40
`26. Cohen J. Scher RK. Pappert A.
`The nail and fungus infections.
`In Elewsk1 B. ed. Cutaneous Fungal
`lnfect1ons. New York. lgaku Sho1n.
`1992:106-123
`27. Summerbell RC. Kane J. Krajden S.
`Onychomycosis. t1nea ped1s. and tinea
`manuum caused by non-dermato(cid:173)
`phytiC filamentous fung1. Mycoses
`1989; 32:609-619
`28. Willemsen MD. Changing pattern
`in superficial 1nfect1ons: focus on
`onychomycOSIS. J Eur Acad Dermatol
`Venereal 1993; 2:S6- S11
`29. Williams HC The ep1dem1ology
`of onychomycosiS 1n Bnta1n. Br J
`Dermatol 1993; 129:101-109
`30. Greer DL. Et1ology of onycho(cid:173)
`mycosis: rev1ew of the literature.
`Issues 1n the modern management of
`onychomycosis. Monte Carlo 1993
`31. Ell1s DH. Watson AB. Marley JE.
`Williams TG. Non-dermatophytes 1n
`onychomycosis of the toena1ls. Br J
`Derma to I 1997. 136.490-493
`32. Haneke E. Fungal 1nfect1ons of the
`na1l. Sem Dermatol 1991 . 1 0: 41-53
`33. Elewsk1 BE. Hay RJ. Update on
`the management of onychomycosis.
`Highlights of the Third Annual
`International Summ1t of Cutaneous
`Ant1fungal Therapy Clin lnf D1s 1996;
`23:305-313
`34. Kotrawas R. Chongsathe1n S.
`Rojanavamch V. Buddhavudh1kara1 P.
`Vinyayadhakorn S Hendersonula
`toruloidea mfect1on 1n Tha1land. lnt J
`Dermatol 1988; 27:391-395
`35. AI-Sogair SM. Moawad MK.
`AI-Humaidan YM. Fungalmfectlon as
`a cause of skin d1sease 1n the Eastern
`Province of Saudi Arabia: prevailing
`fung1 and pattern of infectiOn
`Mycoses 1991. 34 :333-337
`
`36. Sz11i M. Sandor L. Comparative
`mycolog1cal stud1es from nails
`removed because of onychomyCOSIS
`(Hunganan). B<irgy6gy Venerol Szle
`1984; 60:175-177
`37. G1nter G. R1eger E. He1gl K.
`Propst E. Ste1gend~ Hauf1gke1t der
`Onychomykose - Andert s1ch das
`Erregerspektrum? Mycoses 1996: 39
`Suppl 1·118-122
`38. Barranco V New approaches to
`the d1agnosis and management of
`onychomycosis. lnt J Dermatol 1994;
`33:292-299
`39. Conant MA. The AIDS ep1dem1c
`J Am Acad Dermatol 1 994; 31
`Suppi:S47-S50
`40. FeUIIhade M. Pied et mycoses
`Aspects epidemiOIOglques Pled 1990:
`6:5-6
`4 1. Za1as N. Tosti A. Rebell G. Morelli
`R. Bardaw F. B1eley H. Za1ac M. Glick
`B. Paley B; Allevato M. Baran R.
`Autosomal dom1nant pattern of distal
`subungual onychomycOSIS caused by
`Tnchophyton rubrum J Am Acad
`Dermatol 1996; 34:302-304
`42. Male 0. Tappeiner J. Nagelver(cid:173)
`anderungen durch Schimmelpilze
`Dermatol Wschr 1965; 151-212
`43. Baran R. Bad1llet G. Un dermato(cid:173)
`phyte ungueal est-11 necessa1rement
`pathogene? Ann Dermatol Venererol
`1983; 110:629-631
`44. Baran R. Badillet G. Pnmary
`onycholysis of the b1g toenail: a review
`of 112 cases. Br J Dermatol 1982;
`106:529- 534
`45. Dahlke H. Zur Pathogenese der
`Tinea pedis. Insbesondere be1 pen(cid:173)
`pheren Durchblutungsst<irungen
`Mykosen 1971; 14:409-413
`46. Wienert V. Stemmer R.
`Onychomykosen be1 phlebolog1schen
`Patienten. Phlebol Proktol 1982:
`11:281-283
`47. Buxton PK, Milne UR. Prescott RJ
`et al .. The prevalence of dermatophyte
`1nfect1on 1n well-controlled diabetiCS
`and the response to Tnchophyton
`antigen. Br J Dermatol. 1996: 134.
`900-903
`48. R1ch P. Special patient populations.
`onychomycosiS in the d1abet1c pat1ent.
`JAm Acad Dermatol. 1996;
`35:S10-S12
`49. Gupta AK. Konmkof N. Mac
`Donald P et al. Prevalence and ep1·
`derm1ology of toenail onychomycosis
`in d1abetic subjects: a mult1centre
`survey. Br J Dermatol 1998: 139:
`665-671
`50. Feuerman E. Alteras I. Aryelly J.
`The 1ncidence of pathogenic fung1 1n
`psonatic na1ls. Castellama 1976;
`4:195-196
`5 1. Staberg B. Gammeltoft MD.
`Onsberg P. OnychomycosiS 1n pat1ents
`w1th psonas1s Acta Dermatol Venereol
`1983;63:436-438
`52. Nielsen PG. Faergemann J.
`Dermatophytes and keratin 1n patients
`w1th hereditary palmoplanta r kerato(cid:173)
`derma Acta Dermatol Venereol 1993;
`73:416-418
`
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`
`L
`
`Anatomy of the normal nail
`
`The nail unit lies immediately above the peri(cid:173)
`ostium of the distal phalanx and consists of a
`keratinized product. the nail plate. and four
`specialized epithelia : the proximal nail fold (or
`eponychium). the nail matrix. the nail bed and
`the hyponychium (Fig 2.1) (1. 2].
`
`The proximal part of the fingernails. especially
`the thumbs. shows a whitish. opaque. half(cid:173)
`moon-shaped area. the lunula. which is the
`visible portion of the nail matrix. The shape of
`the lunula determines the shape of the free
`edge of the nail plate.
`
`Nail plate
`
`The nail plate is a fully keratinized multilayered
`sheet of cornified cells. From the 15th week of
`embryonic life. nail plate production occurs
`cont inuously and thereafter almost uniformly
`throughout life [1]. The nail plate is almost
`rectangular in shape and translucent. It appears
`pink because of the blood vessels of the under(cid:173)
`lying nail bed. The nail plate adheres tightly to
`the nail bed. since the horny layer of the nail bed
`partially contributes to the formation of the ven(cid:173)
`tral nail plate [3]. The nail plate has a somewhat
`loose attachment. along its lateral borders [4].
`
`Fig 2.1
`Sagittal section
`through fingernail
`
`Transverse section
`throug h fi ngernail
`
`Proximally and laterally, the nail plate is
`surrounded by the proximal and lateral folds.
`whereas its distal margin is free. Detachment of
`the nail plate from the underlying tissues occurs
`at the hyponychium. which marks the separa(cid:173)
`tion of the nail from the digit. The nail plate's
`free edge appears white due the presence of
`air in the subungual space.This space frequent(cid:173)
`ly contains keratinous debris. especially in the
`toenails.
`
`10
`
`More than 90% of fingernails show a thin distal
`transverse white band. the onychocorneal
`band. which marks the most distal portion of
`firm attachment of the nail plate to the nail bed
`[5]. This area represents an important anatomi(cid:173)
`cal barrier against environmental and microbial
`hazards.
`
`In transverse sections. the nail plate consists
`of three portions: dorsal nail plate. intermediate
`nail plate and ventral nail plate [6]. The dorsal
`and intermediate portions of the nail plate are
`produced by the nail matrix and consist of hard
`keratins. The intermediate nail plate. w hich is
`produced by the distal matrix. represents 2iJ of
`the whole nail thickness. The ventral portion of
`the nail plate is produced by the nail bed and is
`formed by soft keratins. The thickness of this
`portion of the nail plate considerably increases
`in nail bed disorders.
`
`Nail matrix
`
`The nail matrix consists of a proliferative
`epithelium that keratinizes in the absence of a
`granular layer. Maturation and differentiation of
`nail matrix keratinocytes lead to the formation
`of the superficial and intermediate layers of the
`nail plate. The site of nail matrix keratinization
`can be recognized in histological sections as an
`eosinophilic band (keratogenous zone). In this
`area. nail matrix keratinocytes show nuclear
`fragmentation and condensation of cytoplasm.
`
`In longitudinal sections the matrix consists of
`a proximal (dorsal) and a distal (ventral) region.
`Proximal nail matrix keratinocytes give rise to
`the upper portion of the nail plate whereas
`distal nail matrix keratinocytes produce its inter(cid:173)
`mediate portion.
`
`The nail matrix epithelium contains melano(cid:173)
`cytes. Although nail matrix melanocytes are
`usually quiescent. they may start to produce
`melanin in a large number of physiological and
`pathological conditions. This is more common
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`
`in Black and Asian populations than 1n Caucasi(cid:173)
`ans. The nail growth rates range from 1 .8 to
`4.8 mm/ month in fingernails and 1 .3 to 1 .8
`mm/month in toenails. This gradually declines
`with age [7]. Complete replacement of a finger(cid:173)
`nail requires 4 to 6 months and that of a toenail
`12 to 18 months. Linear nail growth may also
`increase in some physiological and pathological
`circumstances and may be influenced by
`drugs. The triazole derivatives itraconazole [8)
`and fluconazole [9) have been reported to
`enhance nail growth. Terbinafine may also
`induce an increase of linear nail growth [1 0].
`
`Hyponychium
`
`The hyponychium is normally covered by the
`nail plate's free margin, but becomes visible in
`nail biters or when the nail plate is cut very
`short.
`
`Its epithelium is similar to that of plantar or volar
`skin and it keratinizes through the formation of
`a granular layer. Cornified hyponychial cells
`accumulate in the subungual space. especially
`in toenails.
`
`Nail bed
`
`Proximal nail fold
`
`The nail bed epithelium consists of several cell
`layers and extends from the lunula to the
`hyponychium. Nail bed keratinization occurs in
`the absence of a granular layer and gives rise
`to the ventral nail plate. This corresponds to
`about Ys of the terminal nail thickness and it can
`be recognized in histological sections because
`of its mild eosinophilia.
`
`The nail bed dermoepidermal architecture
`shows a distinctive arrangement w ith longi(cid:173)
`tudinal grooves and ridges extending from the
`lunula to the hyponychium. The nail bed
`capillaries run longitudinally along these nail
`bed grooves.
`
`The nail bed epithelium is so adherent to the
`nail plate that it remains attached to the under(cid:173)
`surface of the nail when this is avulsed.
`
`The proximal nail plate is surrounded and
`partially covered by the proximal nail fold.
`which overlies about a quarter of the nail plate.
`Adhesion between proximal nail fold and nail
`plate is tight due to the presence of the cuticle.
`which is firmly attached to the superficial nail
`plate. The cuticle. which is continuously formed
`by keratinization of the proximal nail plate.
`consists of a thin layer of orthokeratotic cells.
`
`The proximal nail fold consists of a dorsal
`portion that is anatomically similar to the skin
`of the dorsum of the digit and a ventral portion
`that continues proximally w ith the proximal
`matrix.
`
`References
`
`1. Za1as N. The nail 1n health and
`d1sease. 2nd ed. Appleton & Lange.
`Norwalk. 1990
`2. Baran R. Dawber RPR. D1sease
`of the nails and their management
`Blackwell. Oxford. 1994
`3. Johnson M. Cosma1sh JS. Shuster
`S Na1l IS produced by the normal nail
`bed a controversy resolved Br J
`Dermatol. 1991, 125:27-29
`
`4. Baran R. De Doncker P. Lateral edge
`Involvement 1nd1cates poor prognos1s
`for treat1ng onychomycosis w1th the
`new system1c anufungals. Acta Derm
`Venereal 1996. 73 : 82-83
`5. Sonnex TS. Gnfflths WAD. N1col
`WJ. The nature and s1gn1f1cance of the
`transverse w hite band of human na1ls.
`Sem1nars Dermatol. 1981. 10: 12- 1 6
`6. Forslind B. B1ophyS1Cal stud1es of
`the normal nail Acta Derm Venereal
`1970; 50 161-168.
`7. Bean WB. Na1l growth. Twenty-f1ve
`year's obseNation. Arch Intern Med
`1968, 122. 359-361
`
`8. De Doncker P. P1erard G. Acqwed
`nad beading 1n patients rece1ving
`1traconazole An mdicator of faster na1l
`growth ? A study us1ng opt1cal profdo(cid:173)
`metry. Clin Exp Derm. 1994, 19.
`404- 406.
`9. Shelley WB. Shelley ED. Ponra1t of a
`practice. Cutis 1992: 49. 386.
`10. Faergemann J. Anderson C. Hersle
`K et al. Double-blind. parallel-group
`cornpanson of terbinaf1ne and gnseo(cid:173)
`fulvln 1n the treatment of toena1l
`onychomycosis. J Am Acad Dermatol
`1995: 32: 750-753.
`
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`
`r )
`\.. )
`
`Clinical patterns correlated
`with main routes of entry
`
`Fig 3.1
`Distal lateral subung ual onychomycosis
`
`Fig 3.2
`DLSO due to T. rubrum
`
`Fig 3.3
`DLSO w ith onycholysis due to T. rubrum
`
`A fungus gains entry to the nail by four main
`routes. each resulting in different clinical
`patterns of infection [1-2]. These are :
`
`• Via the distal subungual area and the
`lateral nail groove (Fig 3.1) leading to distal
`lateral subungual onychomycosis (DLSO)
`(Fig 3.2). The fungus invades the horny layer of
`the hyponychium and/or the nail bed. then the
`undersurface of the nail plate which becomes
`opaque. This causes thickening of the horny
`layer raising the free edge of the nail plate with
`disruption of the normal nail plate-nail bed
`attachment. The disease spreads proximally
`against the stream of nail growth. Sometimes
`a yellow brown discoloration is observed.
`T. rubrum is the most common fungal invader.
`T. mentagrophytes var. interdigitale is much
`less common and Eptdermophyton floccosum
`is rare. In contrast to this form. DLSO may also
`appear as primary onycholysis with a minimum
`of hyperkeratosis especially in fingernails
`(Fig 3.3). Primary onycholysis may be associ(cid:173)
`ated w ith the presence of Candtda (Fig 3.4).
`Overriding of the toes and repeated micro(cid:173)
`trauma of the nail against the shoes may create
`an area of onycholysis favourable to the invasion
`of microorganisms. In such cases. mixed infec(cid:173)
`tion due to T rubrum and Pseudomonas is not
`exceptional (Fig 3.5).The clinical significance of
`nail invasion or colonization by fungi which are
`not normally pathogenic needs to be carefully
`considered in the light of laboratory findings.
`
`The nail bed infection in DLSO caused by
`T rubrum is the result of the fungus spreading
`from the plantar (Fig 3.6) [3] and palmar sur(cid:173)
`face of the feet and hands. a pattern seen in
`the one-hand/two-foot tinea syndrome
`(Fig 3.7) [4].
`
`T mentagrophytes var. mterdigitale produces
`a chronic syndrome with episodic pruritic
`vesicles in the skin of the plantar arch and in
`the toewebs w here scaling is also visible.
`Intermittent vesicles. scaling of the heel and
`thickening of the skin of the sole are often
`visible. This syndrome can also be observed in
`patients with superficial white onychomycosis
`caused by the same fungus. Organisms such
`as Scytaltdium dimidiatum which mimic the
`pattern of disease caused by dermatophytes
`produce the clinical pattern of DLSO but this is
`often associated with onycholysis and. some(cid:173)
`times. paronychia in fingernails (Fig 3.8).
`
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`
`Fig 3.4
`Candida onycholysis
`
`Fig 3.7
`One-hand/ two-foot syndrome
`
`Fig 3.5
`Mixed infection due to T. rubrum
`and Pseudomonas
`
`Fig 3.8
`DLSO due to Scyta/idium dimidiatum
`w ith associated paronychia
`
`Fig 3.6
`Tinea pedis
`
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`
`Clinical patterns correlated
`with main routes of entry
`
`• Via the dorsal surface of the nail plate
`(Fig 3.9). producing superticial onychomycosis
`(SO) (Fig 3.1 0). Superticial white onycho(cid:173)
`mycosis (SWO) is normally confined to the
`toenails. The causative organisms produce the
`clinical picture of small. w hite patches with
`distinct edges