Shari R. Lipner, MD, PhD

Patients frequently present to dermatologists with nail disorders as their chief concern. Alternatively, nail conditions may be encountered by the examining physician as an incidental finding that may be a clue to underlying systemic disease. Competence in the diagnosis and treatment of nail diseases can drastically improve patient quality of life and can be lifesaving,¹ but many dermatologists find management of nail diseases challenging.² Bridging this educational gap begins with dermatology resident and medical student education. In a collaboration with dermatology educators, the American Academy of Dermatology (AAD) prepared a free online core curriculum for medical students that covers the essential concepts of dermatology. We sought to determine the integration of nail education in the AAD Basic Dermatology Curriculum.

Methods

A cross-sectional study of the AAD Basic Dermatology Curriculum was conducted to determine nail disease content. The curriculum modules were downloaded in June 2018,³ and mentions of nails were recorded and evaluated for overall quantities and relevant content. References to nail procedures and diagnostic techniques including nail biopsies, fungal cultures, microscopy on nail scrapings, nail clippings, and nail-related cancers also were assessed in the analysis.

Results

Of 342 patients discussed in cases and quizzes, nails were mentioned for 19 patients (89 times total)(Table 1). Additionally, there were 2 mentions each of nail clippings and nail tumors, 0 mentions of nail biopsies, and 1 mention each of fungal cultures and microscopy on nail scrapings (Table 1). Of the 40 modules, nails were mentioned in 12 modules (Table 2) and 6 introductions to the modules (Table 1). There were no mentions of the terms nails, subungual, or onychomycosis in the learning objectives.³

Comment

Our study demonstrates a paucity of content relevant to nails in the AAD Basic Dermatology Curriculum. Medical students are missing an important opportunity to learn about diagnosis and management of nail conditions and may incorrectly conclude that nail expertise is not essential to becoming a competent board-certified dermatologist.

Particularly concerning is the exclusion of nail examinations in the skin exam module addressing full-body skin examinations (0 mentions in 31 slides). This curriculum may negatively influence medical students and may then follow at the resident level, with a study reporting that 50.3% (69/137) of residents examine nails only when the patient brings it to their attention.⁴

Most concerning was the inadequate coverage of nail unit melanoma in the melanoma module (1 mention in 53 slides). Furthermore, the ABCDE—asymmetry, border, color, diameter, and evolving—mnemonic for cutaneous melanoma was covered in 6 slides in this module, and the ABCDEF—family history added—mnemonic for nail unit melanoma was completely excluded. Not surprisingly, resident knowledge of melanonychia diagnosis is deficient, with a prior study demonstrating that 62% (88/142) of residents were not confident diagnosing and managing patients with melanonychia, and only 88% (125/142) of residents were aware of the nail melanoma mnemonic.⁴

Similarly, nail biopsy for melanonychia diagnosis was excluded from the curriculum, whereas skin biopsy was thoroughly discussed in the context of a cutaneous melanoma diagnosis. This deficient teaching may track to the dermatology resident curriculum, as a survey of third-year dermatology residents (N=240) showed that 58% performed 10 or fewer nail procedures, and one-third of residents felt incompetent in nail surgery.⁵

We acknowledge that the AAD Basic Dermatology Curriculum is simply an introduction to dermatology. However, given that dermatologists are among the major specialists who care for nail patients, we advocate for more content on nail diseases in this curriculum. Nails can easily be incorporated into existing modules, and a new module specifically dedicated to nail disease should be added. Moreover, we envision that our findings will positively reflect on competence in treating nail disease for dermatology residents.

Patients frequently present to dermatologists with nail disorders as their chief concern. Alternatively, nail conditions may be encountered by the examining physician as an incidental finding that may be a clue to underlying systemic disease. Competence in the diagnosis and treatment of nail diseases can drastically improve patient quality of life and can be lifesaving,¹ but many dermatologists find management of nail diseases challenging.² Bridging this educational gap begins with dermatology resident and medical student education. In a collaboration with dermatology educators, the American Academy of Dermatology (AAD) prepared a free online core curriculum for medical students that covers the essential concepts of dermatology. We sought to determine the integration of nail education in the AAD Basic Dermatology Curriculum.

Methods

A cross-sectional study of the AAD Basic Dermatology Curriculum was conducted to determine nail disease content. The curriculum modules were downloaded in June 2018,³ and mentions of nails were recorded and evaluated for overall quantities and relevant content. References to nail procedures and diagnostic techniques including nail biopsies, fungal cultures, microscopy on nail scrapings, nail clippings, and nail-related cancers also were assessed in the analysis.

Results

Of 342 patients discussed in cases and quizzes, nails were mentioned for 19 patients (89 times total)(Table 1). Additionally, there were 2 mentions each of nail clippings and nail tumors, 0 mentions of nail biopsies, and 1 mention each of fungal cultures and microscopy on nail scrapings (Table 1). Of the 40 modules, nails were mentioned in 12 modules (Table 2) and 6 introductions to the modules (Table 1). There were no mentions of the terms nails, subungual, or onychomycosis in the learning objectives.³

Comment

Our study demonstrates a paucity of content relevant to nails in the AAD Basic Dermatology Curriculum. Medical students are missing an important opportunity to learn about diagnosis and management of nail conditions and may incorrectly conclude that nail expertise is not essential to becoming a competent board-certified dermatologist.

Particularly concerning is the exclusion of nail examinations in the skin exam module addressing full-body skin examinations (0 mentions in 31 slides). This curriculum may negatively influence medical students and may then follow at the resident level, with a study reporting that 50.3% (69/137) of residents examine nails only when the patient brings it to their attention.⁴

Most concerning was the inadequate coverage of nail unit melanoma in the melanoma module (1 mention in 53 slides). Furthermore, the ABCDE—asymmetry, border, color, diameter, and evolving—mnemonic for cutaneous melanoma was covered in 6 slides in this module, and the ABCDEF—family history added—mnemonic for nail unit melanoma was completely excluded. Not surprisingly, resident knowledge of melanonychia diagnosis is deficient, with a prior study demonstrating that 62% (88/142) of residents were not confident diagnosing and managing patients with melanonychia, and only 88% (125/142) of residents were aware of the nail melanoma mnemonic.⁴

Similarly, nail biopsy for melanonychia diagnosis was excluded from the curriculum, whereas skin biopsy was thoroughly discussed in the context of a cutaneous melanoma diagnosis. This deficient teaching may track to the dermatology resident curriculum, as a survey of third-year dermatology residents (N=240) showed that 58% performed 10 or fewer nail procedures, and one-third of residents felt incompetent in nail surgery.⁵

We acknowledge that the AAD Basic Dermatology Curriculum is simply an introduction to dermatology. However, given that dermatologists are among the major specialists who care for nail patients, we advocate for more content on nail diseases in this curriculum. Nails can easily be incorporated into existing modules, and a new module specifically dedicated to nail disease should be added. Moreover, we envision that our findings will positively reflect on competence in treating nail disease for dermatology residents.

Patients frequently present to dermatologists with nail disorders as their chief concern. Alternatively, nail conditions may be encountered by the examining physician as an incidental finding that may be a clue to underlying systemic disease. Competence in the diagnosis and treatment of nail diseases can drastically improve patient quality of life and can be lifesaving,¹ but many dermatologists find management of nail diseases challenging.² Bridging this educational gap begins with dermatology resident and medical student education. In a collaboration with dermatology educators, the American Academy of Dermatology (AAD) prepared a free online core curriculum for medical students that covers the essential concepts of dermatology. We sought to determine the integration of nail education in the AAD Basic Dermatology Curriculum.

Methods

A cross-sectional study of the AAD Basic Dermatology Curriculum was conducted to determine nail disease content. The curriculum modules were downloaded in June 2018,³ and mentions of nails were recorded and evaluated for overall quantities and relevant content. References to nail procedures and diagnostic techniques including nail biopsies, fungal cultures, microscopy on nail scrapings, nail clippings, and nail-related cancers also were assessed in the analysis.

Results

Of 342 patients discussed in cases and quizzes, nails were mentioned for 19 patients (89 times total)(Table 1). Additionally, there were 2 mentions each of nail clippings and nail tumors, 0 mentions of nail biopsies, and 1 mention each of fungal cultures and microscopy on nail scrapings (Table 1). Of the 40 modules, nails were mentioned in 12 modules (Table 2) and 6 introductions to the modules (Table 1). There were no mentions of the terms nails, subungual, or onychomycosis in the learning objectives.³

Comment

Our study demonstrates a paucity of content relevant to nails in the AAD Basic Dermatology Curriculum. Medical students are missing an important opportunity to learn about diagnosis and management of nail conditions and may incorrectly conclude that nail expertise is not essential to becoming a competent board-certified dermatologist.

Particularly concerning is the exclusion of nail examinations in the skin exam module addressing full-body skin examinations (0 mentions in 31 slides). This curriculum may negatively influence medical students and may then follow at the resident level, with a study reporting that 50.3% (69/137) of residents examine nails only when the patient brings it to their attention.⁴

Most concerning was the inadequate coverage of nail unit melanoma in the melanoma module (1 mention in 53 slides). Furthermore, the ABCDE—asymmetry, border, color, diameter, and evolving—mnemonic for cutaneous melanoma was covered in 6 slides in this module, and the ABCDEF—family history added—mnemonic for nail unit melanoma was completely excluded. Not surprisingly, resident knowledge of melanonychia diagnosis is deficient, with a prior study demonstrating that 62% (88/142) of residents were not confident diagnosing and managing patients with melanonychia, and only 88% (125/142) of residents were aware of the nail melanoma mnemonic.⁴

Similarly, nail biopsy for melanonychia diagnosis was excluded from the curriculum, whereas skin biopsy was thoroughly discussed in the context of a cutaneous melanoma diagnosis. This deficient teaching may track to the dermatology resident curriculum, as a survey of third-year dermatology residents (N=240) showed that 58% performed 10 or fewer nail procedures, and one-third of residents felt incompetent in nail surgery.⁵

We acknowledge that the AAD Basic Dermatology Curriculum is simply an introduction to dermatology. However, given that dermatologists are among the major specialists who care for nail patients, we advocate for more content on nail diseases in this curriculum. Nails can easily be incorporated into existing modules, and a new module specifically dedicated to nail disease should be added. Moreover, we envision that our findings will positively reflect on competence in treating nail disease for dermatology residents.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Onychomycosis is a fungal infection of the nail unit due to dermatophytes, yeasts, and nondermatophyte molds (NDMs). It accounts for approximately 50% of all nail disorders seen in clinical practice and is estimated to affect 10% to 12% of the US population.^1,2 Oral medications approved by the US Food and Drug Administration (FDA) include terbinafine and itraconazole, which have demonstrated good efficacy in treating onychomycosis but are associated with potential drug-drug interactions and systemic side effects.^3,4 Although liver failure associated with these drugs is rare,⁵ many patients are anxious about systemic adverse events and therefore prefer to use topical therapies for onychomycosis.

Many patients desire topical therapy but not every patient is an appropriate candidate. Patients who will likely respond well to topical therapy include those with superficial onychomycosis, distal lateral subungual onychomycosis that involves less than 50% of the nail plate surface area (without matrix involvement and a nail plate thickness less than 2 mm), and only up to 3 or 4 nails affected.⁶ In patients who have contraindications to oral therapy, topical therapy may be the only treatment option. To maximize efficacy of FDA-approved topical agents for onychomycosis therapy, patient education is of utmost importance. Failure to properly counsel the patient on proper medication application may result in decreased antifungal efficacy; poor patient compliance due to lack of improvement; and progression of disease, leading to increased onychodystrophy and pain.

Before initiating therapy, patients should be counseled that treatment with topical drugs is long, requiring daily application of the medication for 6 months for fingernails and 12 months for toenails, based on average nail growth rates (2–3 mm per month for fingernails; 1 mm per month for toenails).⁷ Patients also are advised to avoid nail polish application during the course of therapy, as clinical trials were performed without nail polish and the true efficacy with nail polish is unknown.^8-10 Because patients who have had onychomycosis for shorter durations generally have better cure rates than those who have disease for longer durations, it is prudent to initiate topical therapy as early as possible.^11,12 Treating the feet with an antifungal while treating the nails for onychomycosis further enhances efficacy.^13,14 There are 3 FDA-approved topical therapies for onychomycosis: ciclopirox nail lacquer 8%, efinaconazole solution 10%, and tavaborole solution 5%.^15-17

Ciclopirox is a hydroxypyridone with broad-spectrum antimicrobial activity against dermatophytes, NDMs, yeasts, and bacteria. Its mechanism of action is to chelate polyvalent cations, such as Fe³⁺, and inhibit fungal metal-dependent enzymes responsible for the degradation of toxic metabolites.¹⁵ Ciclopirox nail lacquer 8% was FDA approved for the treatment of onychomycosis in 1999, making it the first topical approved for this purpose. Its indication is for immunocompetent patients with mild to moderate onychomycosis (Trichophyton rubrum) without lunula involvement, with mycologic cure rates of 29% to 36% and complete cure rates of 5.5% to 8.5% (toenails).¹⁵ It is the only FDA-approved topical treatment for both fingernails and toenails. Using a brush applicator, it is applied daily to the nail plate and its undersurface, hyponychium, and 5 mm of the surrounding skin. It is important to counsel the patient to remove the lacquer from the nail plate weekly because failure to do so will result in accumulation of numerous layers of medication, such that the active drug cannot reach the site of infection (Figures 1 and 2). The nail plate also should be trimmed and filed weekly by the patient, with monthly clipping/debridement by a physician recommended.^6,15

Efinaconazole is a triazole with antifungal activity against dermatophytes, NDMs, and Candida species. Its mechanism of action is inhibition of lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, which is a component of the fungal cell membrane. Efinaconazole solution 10% was FDA approved in June 2014 for the treatment of toenail onychomycosis due to T rubrum and Trichophyton mentagrophytes, with package insert mycologic cure rates of 53.4% to 55.2% and complete cure rates of 15.2% to 17.8%.^9,16 It is applied with a brush applicator to the nail plate, as well as its undersurface, nail folds, and hyponychium. Two drops are recommended for the great toenail and one drop for all other toenails, and no removal of the solution or debridement is required.^6,16

Tavaborole is a benzoxaborole with antifungal activity against dermatophytes, NDMs, and yeasts. Its mechanism of action is inhibition of fungal aminoacyl transfer RNA synthetase, thus impeding protein synthesis.¹⁸ Tavaborole solution 5% was FDA approved in July 2014 for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes, with mycologic cure rates of 31.1% and 35.9% and complete cure rates of 6.5% and 9.1%, respectively.^11,17 It is applied with a glass pointed-tip dropper to the nail plate, such that the entire nail is covered as well as under the nail tip. No removal of the solution or debridement is required.¹⁷

Topical therapies for onychomycosis require long treatment durations, thus excellent compliance and adherence to the treatment protocol are vital to maximize efficacy. Dermatologists who prescribe ciclopirox nail lacquer 8% should counsel patients to remove the lacquer with alcohol weekly, such that the antifungal penetrates the nail plate to reach the site of infection. Monthly debridement also must be clarified before initiating therapy. With all topical therapy for onychomycosis, it is important to treat early, treat concurrently for tinea pedis, and avoid use of nail polish so that patients have the best possible cure rates.

Onychomycosis is a fungal infection of the nail unit due to dermatophytes, yeasts, and nondermatophyte molds (NDMs). It accounts for approximately 50% of all nail disorders seen in clinical practice and is estimated to affect 10% to 12% of the US population.^1,2 Oral medications approved by the US Food and Drug Administration (FDA) include terbinafine and itraconazole, which have demonstrated good efficacy in treating onychomycosis but are associated with potential drug-drug interactions and systemic side effects.^3,4 Although liver failure associated with these drugs is rare,⁵ many patients are anxious about systemic adverse events and therefore prefer to use topical therapies for onychomycosis.

Many patients desire topical therapy but not every patient is an appropriate candidate. Patients who will likely respond well to topical therapy include those with superficial onychomycosis, distal lateral subungual onychomycosis that involves less than 50% of the nail plate surface area (without matrix involvement and a nail plate thickness less than 2 mm), and only up to 3 or 4 nails affected.⁶ In patients who have contraindications to oral therapy, topical therapy may be the only treatment option. To maximize efficacy of FDA-approved topical agents for onychomycosis therapy, patient education is of utmost importance. Failure to properly counsel the patient on proper medication application may result in decreased antifungal efficacy; poor patient compliance due to lack of improvement; and progression of disease, leading to increased onychodystrophy and pain.

Before initiating therapy, patients should be counseled that treatment with topical drugs is long, requiring daily application of the medication for 6 months for fingernails and 12 months for toenails, based on average nail growth rates (2–3 mm per month for fingernails; 1 mm per month for toenails).⁷ Patients also are advised to avoid nail polish application during the course of therapy, as clinical trials were performed without nail polish and the true efficacy with nail polish is unknown.^8-10 Because patients who have had onychomycosis for shorter durations generally have better cure rates than those who have disease for longer durations, it is prudent to initiate topical therapy as early as possible.^11,12 Treating the feet with an antifungal while treating the nails for onychomycosis further enhances efficacy.^13,14 There are 3 FDA-approved topical therapies for onychomycosis: ciclopirox nail lacquer 8%, efinaconazole solution 10%, and tavaborole solution 5%.^15-17

Ciclopirox is a hydroxypyridone with broad-spectrum antimicrobial activity against dermatophytes, NDMs, yeasts, and bacteria. Its mechanism of action is to chelate polyvalent cations, such as Fe³⁺, and inhibit fungal metal-dependent enzymes responsible for the degradation of toxic metabolites.¹⁵ Ciclopirox nail lacquer 8% was FDA approved for the treatment of onychomycosis in 1999, making it the first topical approved for this purpose. Its indication is for immunocompetent patients with mild to moderate onychomycosis (Trichophyton rubrum) without lunula involvement, with mycologic cure rates of 29% to 36% and complete cure rates of 5.5% to 8.5% (toenails).¹⁵ It is the only FDA-approved topical treatment for both fingernails and toenails. Using a brush applicator, it is applied daily to the nail plate and its undersurface, hyponychium, and 5 mm of the surrounding skin. It is important to counsel the patient to remove the lacquer from the nail plate weekly because failure to do so will result in accumulation of numerous layers of medication, such that the active drug cannot reach the site of infection (Figures 1 and 2). The nail plate also should be trimmed and filed weekly by the patient, with monthly clipping/debridement by a physician recommended.^6,15

Efinaconazole is a triazole with antifungal activity against dermatophytes, NDMs, and Candida species. Its mechanism of action is inhibition of lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, which is a component of the fungal cell membrane. Efinaconazole solution 10% was FDA approved in June 2014 for the treatment of toenail onychomycosis due to T rubrum and Trichophyton mentagrophytes, with package insert mycologic cure rates of 53.4% to 55.2% and complete cure rates of 15.2% to 17.8%.^9,16 It is applied with a brush applicator to the nail plate, as well as its undersurface, nail folds, and hyponychium. Two drops are recommended for the great toenail and one drop for all other toenails, and no removal of the solution or debridement is required.^6,16

Tavaborole is a benzoxaborole with antifungal activity against dermatophytes, NDMs, and yeasts. Its mechanism of action is inhibition of fungal aminoacyl transfer RNA synthetase, thus impeding protein synthesis.¹⁸ Tavaborole solution 5% was FDA approved in July 2014 for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes, with mycologic cure rates of 31.1% and 35.9% and complete cure rates of 6.5% and 9.1%, respectively.^11,17 It is applied with a glass pointed-tip dropper to the nail plate, such that the entire nail is covered as well as under the nail tip. No removal of the solution or debridement is required.¹⁷

Topical therapies for onychomycosis require long treatment durations, thus excellent compliance and adherence to the treatment protocol are vital to maximize efficacy. Dermatologists who prescribe ciclopirox nail lacquer 8% should counsel patients to remove the lacquer with alcohol weekly, such that the antifungal penetrates the nail plate to reach the site of infection. Monthly debridement also must be clarified before initiating therapy. With all topical therapy for onychomycosis, it is important to treat early, treat concurrently for tinea pedis, and avoid use of nail polish so that patients have the best possible cure rates.

Onychomycosis is a fungal infection of the nail unit due to dermatophytes, yeasts, and nondermatophyte molds (NDMs). It accounts for approximately 50% of all nail disorders seen in clinical practice and is estimated to affect 10% to 12% of the US population.^1,2 Oral medications approved by the US Food and Drug Administration (FDA) include terbinafine and itraconazole, which have demonstrated good efficacy in treating onychomycosis but are associated with potential drug-drug interactions and systemic side effects.^3,4 Although liver failure associated with these drugs is rare,⁵ many patients are anxious about systemic adverse events and therefore prefer to use topical therapies for onychomycosis.

Many patients desire topical therapy but not every patient is an appropriate candidate. Patients who will likely respond well to topical therapy include those with superficial onychomycosis, distal lateral subungual onychomycosis that involves less than 50% of the nail plate surface area (without matrix involvement and a nail plate thickness less than 2 mm), and only up to 3 or 4 nails affected.⁶ In patients who have contraindications to oral therapy, topical therapy may be the only treatment option. To maximize efficacy of FDA-approved topical agents for onychomycosis therapy, patient education is of utmost importance. Failure to properly counsel the patient on proper medication application may result in decreased antifungal efficacy; poor patient compliance due to lack of improvement; and progression of disease, leading to increased onychodystrophy and pain.

Before initiating therapy, patients should be counseled that treatment with topical drugs is long, requiring daily application of the medication for 6 months for fingernails and 12 months for toenails, based on average nail growth rates (2–3 mm per month for fingernails; 1 mm per month for toenails).⁷ Patients also are advised to avoid nail polish application during the course of therapy, as clinical trials were performed without nail polish and the true efficacy with nail polish is unknown.^8-10 Because patients who have had onychomycosis for shorter durations generally have better cure rates than those who have disease for longer durations, it is prudent to initiate topical therapy as early as possible.^11,12 Treating the feet with an antifungal while treating the nails for onychomycosis further enhances efficacy.^13,14 There are 3 FDA-approved topical therapies for onychomycosis: ciclopirox nail lacquer 8%, efinaconazole solution 10%, and tavaborole solution 5%.^15-17

Ciclopirox is a hydroxypyridone with broad-spectrum antimicrobial activity against dermatophytes, NDMs, yeasts, and bacteria. Its mechanism of action is to chelate polyvalent cations, such as Fe³⁺, and inhibit fungal metal-dependent enzymes responsible for the degradation of toxic metabolites.¹⁵ Ciclopirox nail lacquer 8% was FDA approved for the treatment of onychomycosis in 1999, making it the first topical approved for this purpose. Its indication is for immunocompetent patients with mild to moderate onychomycosis (Trichophyton rubrum) without lunula involvement, with mycologic cure rates of 29% to 36% and complete cure rates of 5.5% to 8.5% (toenails).¹⁵ It is the only FDA-approved topical treatment for both fingernails and toenails. Using a brush applicator, it is applied daily to the nail plate and its undersurface, hyponychium, and 5 mm of the surrounding skin. It is important to counsel the patient to remove the lacquer from the nail plate weekly because failure to do so will result in accumulation of numerous layers of medication, such that the active drug cannot reach the site of infection (Figures 1 and 2). The nail plate also should be trimmed and filed weekly by the patient, with monthly clipping/debridement by a physician recommended.^6,15

Efinaconazole is a triazole with antifungal activity against dermatophytes, NDMs, and Candida species. Its mechanism of action is inhibition of lanosterol 14α-demethylase, an enzyme involved in the biosynthesis of ergosterol, which is a component of the fungal cell membrane. Efinaconazole solution 10% was FDA approved in June 2014 for the treatment of toenail onychomycosis due to T rubrum and Trichophyton mentagrophytes, with package insert mycologic cure rates of 53.4% to 55.2% and complete cure rates of 15.2% to 17.8%.^9,16 It is applied with a brush applicator to the nail plate, as well as its undersurface, nail folds, and hyponychium. Two drops are recommended for the great toenail and one drop for all other toenails, and no removal of the solution or debridement is required.^6,16

Tavaborole is a benzoxaborole with antifungal activity against dermatophytes, NDMs, and yeasts. Its mechanism of action is inhibition of fungal aminoacyl transfer RNA synthetase, thus impeding protein synthesis.¹⁸ Tavaborole solution 5% was FDA approved in July 2014 for the treatment of toenail onychomycosis due to T rubrum and T mentagrophytes, with mycologic cure rates of 31.1% and 35.9% and complete cure rates of 6.5% and 9.1%, respectively.^11,17 It is applied with a glass pointed-tip dropper to the nail plate, such that the entire nail is covered as well as under the nail tip. No removal of the solution or debridement is required.¹⁷

Topical therapies for onychomycosis require long treatment durations, thus excellent compliance and adherence to the treatment protocol are vital to maximize efficacy. Dermatologists who prescribe ciclopirox nail lacquer 8% should counsel patients to remove the lacquer with alcohol weekly, such that the antifungal penetrates the nail plate to reach the site of infection. Monthly debridement also must be clarified before initiating therapy. With all topical therapy for onychomycosis, it is important to treat early, treat concurrently for tinea pedis, and avoid use of nail polish so that patients have the best possible cure rates.

What does your patient need to know at the first visit?

Risk factors for onychomycosis include prior trauma, history of tinea pedis, sports activities, frequenting gyms and pools, hyperhidrosis, advancing age, diabetes mellitus, immunosuppression, smoking, and family history of onychomycosis. Toenails are involved more frequently than fingernails, and typical physical examination findings are distal and lateral nail plate onycholysis with subungual hyperkeratosis. In more severe cases, there may be nail plate thickening, crumbling, yellowing, and involvement of the nail matrix.

Because other nail conditions may resemble onychomycosis, it is imperative to confirm the diagnosis using histopathology, direct microscopy, fungal culture, and/or polymerase chain reaction on nail plate clippings or subungual debris. 

What are your go-to treatments? What are the side effects?

After laboratory confirmation, assess the patient for the severity of the infection based on the surface area of nail plate affected, nail plate thickness, involvement of the nail matrix, and number of nails affected. United States Food and Drug Administration-approved oral and topical antifungals are used first line for the treatment of onychomycosis. Devices such as lasers are approved by the US Food and Drug Administration for temporary cosmetic improvement in the appearance of the nail without eradicating the fungus.

Oral antifungals such as terbinafine, itraconazole, and fluconazole (off label) are indicated for patients with severe disease. Patients with mild to moderate disease may benefit from oral or topical antifungals such as efinaconazole, tavaborole, or ciclopirox.

I recommend terbinafine to many of my patients due to its high complete and mycological cure rates, short list of drug-drug interactions, and low incidence of side effects. Adverse reactions are uncommon, with the most common being gastrointestinal upset. While liver injury has been reported, it is exceedingly rare. Itraconazole has many important drug interactions and is contraindicated in patients with congestive heart failure. With topical antifungals, side effects are uncommon, but dermatitis, ingrown nails, and vesicles may occur.

How do you keep patients compliant with treatment?

Patients on a 3-month course of daily oral terbinafine or itraconazole for toenail onychomycosis are typically highly compliant. Compliance for patients on oral fluconazole (off label) is generally more challenging because it is dosed weekly until the nail grows out (1-1.5 years for toenails). To circumvent missed fluconazole doses, I recommend that the patient schedule quarterly visits with me and also to set a cell phone alarm as a weekly reminder to take the medication.

Because topical medications are prescribed for the toenails for a year-long course (with avoidance of nail polish during this period), I prescribe topical antifungals only to highly motivated patients. In addition, because topical antifungals are retained in the nail plate for at least several days after a month-long application, I tell my patients that if they have a big event to attend that they can take a vacation from the topical antifungal, get a pedicure, and then resume treatment after the event. 

What do you do if they refuse treatment?

In 2018, we have many options to treat onychomycosis effectively, and therapy is individualized based on the patient's severity of disease, infecting organism(s), comorbidities, concomitant medications, and preferences. If the patient's fungal nail infection is asymptomatic and not aesthetically bothersome, he/she may opt for observation rather than treatment. If the decision is observation, I recommend use of a topical antifungal on the feet and web spaces to prevent worsening of onychomycosis. 

Suggested Readings

Gupta AK, Versteeg SG. A critical review of improvement rates for laser therapy used to treat toenail onychomycosis. J Eur Acad Dermatol Venereol. 2017;31:1111-1118.

Lipner SR, Scher RK. Long-standing onychodystrophy in a young woman. JAMA. 2016;316:1915-1916.

Lipner SR, Scher RK. Onychomycosis--a small step for quality of care. Curr Med Res Opin. 2016;32:865-867.

Lipner SR, Scher RK. Onychomycosis: current and investigational therapies. Cutis. 2014;94:E21-E24.

What does your patient need to know at the first visit?

Risk factors for onychomycosis include prior trauma, history of tinea pedis, sports activities, frequenting gyms and pools, hyperhidrosis, advancing age, diabetes mellitus, immunosuppression, smoking, and family history of onychomycosis. Toenails are involved more frequently than fingernails, and typical physical examination findings are distal and lateral nail plate onycholysis with subungual hyperkeratosis. In more severe cases, there may be nail plate thickening, crumbling, yellowing, and involvement of the nail matrix.

Because other nail conditions may resemble onychomycosis, it is imperative to confirm the diagnosis using histopathology, direct microscopy, fungal culture, and/or polymerase chain reaction on nail plate clippings or subungual debris. 

What are your go-to treatments? What are the side effects?

After laboratory confirmation, assess the patient for the severity of the infection based on the surface area of nail plate affected, nail plate thickness, involvement of the nail matrix, and number of nails affected. United States Food and Drug Administration-approved oral and topical antifungals are used first line for the treatment of onychomycosis. Devices such as lasers are approved by the US Food and Drug Administration for temporary cosmetic improvement in the appearance of the nail without eradicating the fungus.

Oral antifungals such as terbinafine, itraconazole, and fluconazole (off label) are indicated for patients with severe disease. Patients with mild to moderate disease may benefit from oral or topical antifungals such as efinaconazole, tavaborole, or ciclopirox.

I recommend terbinafine to many of my patients due to its high complete and mycological cure rates, short list of drug-drug interactions, and low incidence of side effects. Adverse reactions are uncommon, with the most common being gastrointestinal upset. While liver injury has been reported, it is exceedingly rare. Itraconazole has many important drug interactions and is contraindicated in patients with congestive heart failure. With topical antifungals, side effects are uncommon, but dermatitis, ingrown nails, and vesicles may occur.

How do you keep patients compliant with treatment?

Patients on a 3-month course of daily oral terbinafine or itraconazole for toenail onychomycosis are typically highly compliant. Compliance for patients on oral fluconazole (off label) is generally more challenging because it is dosed weekly until the nail grows out (1-1.5 years for toenails). To circumvent missed fluconazole doses, I recommend that the patient schedule quarterly visits with me and also to set a cell phone alarm as a weekly reminder to take the medication.

Because topical medications are prescribed for the toenails for a year-long course (with avoidance of nail polish during this period), I prescribe topical antifungals only to highly motivated patients. In addition, because topical antifungals are retained in the nail plate for at least several days after a month-long application, I tell my patients that if they have a big event to attend that they can take a vacation from the topical antifungal, get a pedicure, and then resume treatment after the event. 

What do you do if they refuse treatment?

In 2018, we have many options to treat onychomycosis effectively, and therapy is individualized based on the patient's severity of disease, infecting organism(s), comorbidities, concomitant medications, and preferences. If the patient's fungal nail infection is asymptomatic and not aesthetically bothersome, he/she may opt for observation rather than treatment. If the decision is observation, I recommend use of a topical antifungal on the feet and web spaces to prevent worsening of onychomycosis. 

Suggested Readings

Gupta AK, Versteeg SG. A critical review of improvement rates for laser therapy used to treat toenail onychomycosis. J Eur Acad Dermatol Venereol. 2017;31:1111-1118.

Lipner SR, Scher RK. Long-standing onychodystrophy in a young woman. JAMA. 2016;316:1915-1916.

Lipner SR, Scher RK. Onychomycosis--a small step for quality of care. Curr Med Res Opin. 2016;32:865-867.

Lipner SR, Scher RK. Onychomycosis: current and investigational therapies. Cutis. 2014;94:E21-E24.

What does your patient need to know at the first visit?

Risk factors for onychomycosis include prior trauma, history of tinea pedis, sports activities, frequenting gyms and pools, hyperhidrosis, advancing age, diabetes mellitus, immunosuppression, smoking, and family history of onychomycosis. Toenails are involved more frequently than fingernails, and typical physical examination findings are distal and lateral nail plate onycholysis with subungual hyperkeratosis. In more severe cases, there may be nail plate thickening, crumbling, yellowing, and involvement of the nail matrix.

Because other nail conditions may resemble onychomycosis, it is imperative to confirm the diagnosis using histopathology, direct microscopy, fungal culture, and/or polymerase chain reaction on nail plate clippings or subungual debris. 

What are your go-to treatments? What are the side effects?

After laboratory confirmation, assess the patient for the severity of the infection based on the surface area of nail plate affected, nail plate thickness, involvement of the nail matrix, and number of nails affected. United States Food and Drug Administration-approved oral and topical antifungals are used first line for the treatment of onychomycosis. Devices such as lasers are approved by the US Food and Drug Administration for temporary cosmetic improvement in the appearance of the nail without eradicating the fungus.

Oral antifungals such as terbinafine, itraconazole, and fluconazole (off label) are indicated for patients with severe disease. Patients with mild to moderate disease may benefit from oral or topical antifungals such as efinaconazole, tavaborole, or ciclopirox.

I recommend terbinafine to many of my patients due to its high complete and mycological cure rates, short list of drug-drug interactions, and low incidence of side effects. Adverse reactions are uncommon, with the most common being gastrointestinal upset. While liver injury has been reported, it is exceedingly rare. Itraconazole has many important drug interactions and is contraindicated in patients with congestive heart failure. With topical antifungals, side effects are uncommon, but dermatitis, ingrown nails, and vesicles may occur.

How do you keep patients compliant with treatment?

Patients on a 3-month course of daily oral terbinafine or itraconazole for toenail onychomycosis are typically highly compliant. Compliance for patients on oral fluconazole (off label) is generally more challenging because it is dosed weekly until the nail grows out (1-1.5 years for toenails). To circumvent missed fluconazole doses, I recommend that the patient schedule quarterly visits with me and also to set a cell phone alarm as a weekly reminder to take the medication.

Because topical medications are prescribed for the toenails for a year-long course (with avoidance of nail polish during this period), I prescribe topical antifungals only to highly motivated patients. In addition, because topical antifungals are retained in the nail plate for at least several days after a month-long application, I tell my patients that if they have a big event to attend that they can take a vacation from the topical antifungal, get a pedicure, and then resume treatment after the event. 

What do you do if they refuse treatment?

In 2018, we have many options to treat onychomycosis effectively, and therapy is individualized based on the patient's severity of disease, infecting organism(s), comorbidities, concomitant medications, and preferences. If the patient's fungal nail infection is asymptomatic and not aesthetically bothersome, he/she may opt for observation rather than treatment. If the decision is observation, I recommend use of a topical antifungal on the feet and web spaces to prevent worsening of onychomycosis. 

Suggested Readings

Gupta AK, Versteeg SG. A critical review of improvement rates for laser therapy used to treat toenail onychomycosis. J Eur Acad Dermatol Venereol. 2017;31:1111-1118.

Lipner SR, Scher RK. Long-standing onychodystrophy in a young woman. JAMA. 2016;316:1915-1916.

Lipner SR, Scher RK. Onychomycosis--a small step for quality of care. Curr Med Res Opin. 2016;32:865-867.

Lipner SR, Scher RK. Onychomycosis: current and investigational therapies. Cutis. 2014;94:E21-E24.

Nail surgery is an important part of dermatologic training and clinical practice, both for diagnosis and treatment of nail disorders as well as benign and malignant nail tumors. Patient comfort is essential prior to the procedure and while administering local anesthetics. Effective anesthesia facilitates nail unit biopsies, excisions, and other surgical nail procedures. Pain management immediately following the procedure and during the postoperative period are equally important.

Patients who undergo nail surgery may experience anxiety due to fear of a cancer diagnosis, pain during the surgery, or disfigurement from the procedure. This anxiety may lead to increased blood pressure, a decreased pain threshold, and mental and physical discomfort.¹ A detailed explanation of the procedure itself as well as expectations following the surgery are helpful in diminishing these fears. Administration of a fast-acting benzodiazepine also may be helpful in these patients to decrease anxiety prior to the procedure.²

Attaining adequate anesthesia requires an understanding of digital anatomy, particularly innervation. Innervation of the digits is supplied by the volar and dorsal nerves, which divide into 3 branches at the distal interphalangeal joint, innervating the nail bed, the digital tip, and the pulp.³ Pacinian and Ruffini corpuscles and free-ended nociceptors activate nerve fibers that transmit pain impulses.^4,5 Local anesthetics block pain transmission by impeding voltage-gated sodium channels located at free nerve endings. Pain from anesthesia may be due to both needle insertion and fluid infiltration.

Simple measures can maximize patient comfort during digital anesthesia. Both audiovisual distraction and interpersonal interaction can help to put the patient at ease.^6,7 Application of topical anesthetic cream (1–2 hours prior to the procedure under occlusion),⁸ ice (at least 6 minutes),⁹ or an ethyl chloride spray can be applied to the nail folds prior to needle insertion to alleviate injection pain, but these methods do little for infiltration pain. Use of an ethyl chloride spray may be the preferred technique due to the rapidity of the analgesic effects (Figure).¹⁰ A vibrating massager also can be applied in close proximity to the site of needle insertion.¹¹

Proper anesthetic preparation and technique also can minimize pain during injection. Because lidocaine 1% is acidic (pH, 6.09), buffering with sodium bicarbonate 8.4% can result in decreased injection pain and faster onset of action.^6,12 Warming the anesthetic using a water bath, incubator, or autoclave can decrease pain without degradation of lidocaine or epinephrine.¹³ At a minimum, 30-gauge needles are preferred to minimize pain from needle insertion. Use of 33-gauge needles has shown benefit for injecting the face and scalp and may prove to be helpful injecting sensitive areas such as the digits.¹⁴ A slow injection technique is more comfortable for the patient, as rapid injection causes tissue distention.¹¹

The ideal anesthetic for nail surgery would have a fast onset and a long duration of action, which would allow for shorter operation time as well as alleviation of pain postprocedure and some degree of vasoconstriction to help maintain a bloodless field. Lidocaine has the fastest time of onset (<1–3 minutes) but a short duration of action (30–120 minutes) and a vasodilatory effect. Bupivacaine takes 2 to 5 minutes to take effect and has a long duration of action (120–240 minutes) but a risk for cardiotoxicity. Ropivacaine is the preferred anesthetic by some nail surgeons because of its intermediate time of onset (1–15 minutes), long duration of action (120–360 minutes), and the benefit of some vasoconstriction.^5,15 The addition of epinephrine has 2 main advantages: vasoconstriction and prolongation of anesthetic effects; the latter may help to alleviate postoperative pain. If there are no contraindications to its use (ie, severe hypertension, Raynaud phenomenon), it can be used safely in digital anesthesia without risk for ischemia or infarction.¹¹

Digital anesthesia can be achieved by infiltration or using nerve blocks. One major difference between these 2 approaches is the time of onset of anesthesia, with the former being nearly instantaneous and the latter taking up to 15 minutes.¹⁶ There also usually is more prolonged pain at the site of needle insertion with nerve blocks compared to infiltration. The type of nail surgery being performed, the digit involved, and surgeon preference will determine the anesthetic method of choice.¹⁷

Pain management immediately following the procedure and for several days after is essential. Use of a longer-acting anesthetic, such as bupivacaine or ropivacaine, will provide anesthesia for several hours. A well-padded dressing serves to absorb blood and protect the nail and distal digit from trauma, as even minor trauma can exacerbate pain and bleeding. The patient should be instructed to apply ice to the surgical site and keep the ipsilateral extremity elevated for the next 2 days to reduce edema and pain.¹⁵ Written instructions are helpful, as anxiety during and after the procedure may limit the patient’s understanding and recollection of the verbal postoperative instructions. To maximize readability of the information, the National Institutes of Health and American Medical Association recommend that the instructions be written at a fourth- to sixth-grade reading level.^18,19

A single dose of ibuprofen (400 mg) or acetaminophen (500 mg to 1 g) immediately before or after the procedure can reduce opioid use and postoperative pain.²⁰ Gabapentin (300–1200 mg) given 1 to 2 hours before surgery may be considered in patients who are at high risk for postsurgical pain.²¹ Acetaminophen or nonsteroidal anti-inflammatory drugs (eg, ibuprofen [200–400 mg]) administered every 4 to 6 hours provides considerable pain reduction postprocedure. Nonsteroidal anti-inflammatory drugs may be superior to acetaminophen for pain control²² and carry a low risk for postoperative bleeding.²³ Additionally, a combination of acetaminophen with a nonsteroidal anti-inflammatory drug for 3 doses may be more effective than either drug alone.²⁴ Some patients may require an opioid combination, such as codeine plus acetaminophen, for a short time (up to 3 days) for pain relief following surgery. Excessive pain or pain lasting than more than 3 days is not normal or expected; in these cases, patients should return to the office to rule out ischemia or infection.

It is important to implement pain-minimizing strategies for nail surgeries. Because many of these approaches are derived from other surgical specialties, well-controlled clinical trials in patients undergoing nail surgery will be necessary to improve outcomes.

Nail surgery is an important part of dermatologic training and clinical practice, both for diagnosis and treatment of nail disorders as well as benign and malignant nail tumors. Patient comfort is essential prior to the procedure and while administering local anesthetics. Effective anesthesia facilitates nail unit biopsies, excisions, and other surgical nail procedures. Pain management immediately following the procedure and during the postoperative period are equally important.

Patients who undergo nail surgery may experience anxiety due to fear of a cancer diagnosis, pain during the surgery, or disfigurement from the procedure. This anxiety may lead to increased blood pressure, a decreased pain threshold, and mental and physical discomfort.¹ A detailed explanation of the procedure itself as well as expectations following the surgery are helpful in diminishing these fears. Administration of a fast-acting benzodiazepine also may be helpful in these patients to decrease anxiety prior to the procedure.²

Attaining adequate anesthesia requires an understanding of digital anatomy, particularly innervation. Innervation of the digits is supplied by the volar and dorsal nerves, which divide into 3 branches at the distal interphalangeal joint, innervating the nail bed, the digital tip, and the pulp.³ Pacinian and Ruffini corpuscles and free-ended nociceptors activate nerve fibers that transmit pain impulses.^4,5 Local anesthetics block pain transmission by impeding voltage-gated sodium channels located at free nerve endings. Pain from anesthesia may be due to both needle insertion and fluid infiltration.

Simple measures can maximize patient comfort during digital anesthesia. Both audiovisual distraction and interpersonal interaction can help to put the patient at ease.^6,7 Application of topical anesthetic cream (1–2 hours prior to the procedure under occlusion),⁸ ice (at least 6 minutes),⁹ or an ethyl chloride spray can be applied to the nail folds prior to needle insertion to alleviate injection pain, but these methods do little for infiltration pain. Use of an ethyl chloride spray may be the preferred technique due to the rapidity of the analgesic effects (Figure).¹⁰ A vibrating massager also can be applied in close proximity to the site of needle insertion.¹¹

Proper anesthetic preparation and technique also can minimize pain during injection. Because lidocaine 1% is acidic (pH, 6.09), buffering with sodium bicarbonate 8.4% can result in decreased injection pain and faster onset of action.^6,12 Warming the anesthetic using a water bath, incubator, or autoclave can decrease pain without degradation of lidocaine or epinephrine.¹³ At a minimum, 30-gauge needles are preferred to minimize pain from needle insertion. Use of 33-gauge needles has shown benefit for injecting the face and scalp and may prove to be helpful injecting sensitive areas such as the digits.¹⁴ A slow injection technique is more comfortable for the patient, as rapid injection causes tissue distention.¹¹

The ideal anesthetic for nail surgery would have a fast onset and a long duration of action, which would allow for shorter operation time as well as alleviation of pain postprocedure and some degree of vasoconstriction to help maintain a bloodless field. Lidocaine has the fastest time of onset (<1–3 minutes) but a short duration of action (30–120 minutes) and a vasodilatory effect. Bupivacaine takes 2 to 5 minutes to take effect and has a long duration of action (120–240 minutes) but a risk for cardiotoxicity. Ropivacaine is the preferred anesthetic by some nail surgeons because of its intermediate time of onset (1–15 minutes), long duration of action (120–360 minutes), and the benefit of some vasoconstriction.^5,15 The addition of epinephrine has 2 main advantages: vasoconstriction and prolongation of anesthetic effects; the latter may help to alleviate postoperative pain. If there are no contraindications to its use (ie, severe hypertension, Raynaud phenomenon), it can be used safely in digital anesthesia without risk for ischemia or infarction.¹¹

Digital anesthesia can be achieved by infiltration or using nerve blocks. One major difference between these 2 approaches is the time of onset of anesthesia, with the former being nearly instantaneous and the latter taking up to 15 minutes.¹⁶ There also usually is more prolonged pain at the site of needle insertion with nerve blocks compared to infiltration. The type of nail surgery being performed, the digit involved, and surgeon preference will determine the anesthetic method of choice.¹⁷

Pain management immediately following the procedure and for several days after is essential. Use of a longer-acting anesthetic, such as bupivacaine or ropivacaine, will provide anesthesia for several hours. A well-padded dressing serves to absorb blood and protect the nail and distal digit from trauma, as even minor trauma can exacerbate pain and bleeding. The patient should be instructed to apply ice to the surgical site and keep the ipsilateral extremity elevated for the next 2 days to reduce edema and pain.¹⁵ Written instructions are helpful, as anxiety during and after the procedure may limit the patient’s understanding and recollection of the verbal postoperative instructions. To maximize readability of the information, the National Institutes of Health and American Medical Association recommend that the instructions be written at a fourth- to sixth-grade reading level.^18,19

A single dose of ibuprofen (400 mg) or acetaminophen (500 mg to 1 g) immediately before or after the procedure can reduce opioid use and postoperative pain.²⁰ Gabapentin (300–1200 mg) given 1 to 2 hours before surgery may be considered in patients who are at high risk for postsurgical pain.²¹ Acetaminophen or nonsteroidal anti-inflammatory drugs (eg, ibuprofen [200–400 mg]) administered every 4 to 6 hours provides considerable pain reduction postprocedure. Nonsteroidal anti-inflammatory drugs may be superior to acetaminophen for pain control²² and carry a low risk for postoperative bleeding.²³ Additionally, a combination of acetaminophen with a nonsteroidal anti-inflammatory drug for 3 doses may be more effective than either drug alone.²⁴ Some patients may require an opioid combination, such as codeine plus acetaminophen, for a short time (up to 3 days) for pain relief following surgery. Excessive pain or pain lasting than more than 3 days is not normal or expected; in these cases, patients should return to the office to rule out ischemia or infection.

It is important to implement pain-minimizing strategies for nail surgeries. Because many of these approaches are derived from other surgical specialties, well-controlled clinical trials in patients undergoing nail surgery will be necessary to improve outcomes.

Nail surgery is an important part of dermatologic training and clinical practice, both for diagnosis and treatment of nail disorders as well as benign and malignant nail tumors. Patient comfort is essential prior to the procedure and while administering local anesthetics. Effective anesthesia facilitates nail unit biopsies, excisions, and other surgical nail procedures. Pain management immediately following the procedure and during the postoperative period are equally important.

Patients who undergo nail surgery may experience anxiety due to fear of a cancer diagnosis, pain during the surgery, or disfigurement from the procedure. This anxiety may lead to increased blood pressure, a decreased pain threshold, and mental and physical discomfort.¹ A detailed explanation of the procedure itself as well as expectations following the surgery are helpful in diminishing these fears. Administration of a fast-acting benzodiazepine also may be helpful in these patients to decrease anxiety prior to the procedure.²

Attaining adequate anesthesia requires an understanding of digital anatomy, particularly innervation. Innervation of the digits is supplied by the volar and dorsal nerves, which divide into 3 branches at the distal interphalangeal joint, innervating the nail bed, the digital tip, and the pulp.³ Pacinian and Ruffini corpuscles and free-ended nociceptors activate nerve fibers that transmit pain impulses.^4,5 Local anesthetics block pain transmission by impeding voltage-gated sodium channels located at free nerve endings. Pain from anesthesia may be due to both needle insertion and fluid infiltration.

Simple measures can maximize patient comfort during digital anesthesia. Both audiovisual distraction and interpersonal interaction can help to put the patient at ease.^6,7 Application of topical anesthetic cream (1–2 hours prior to the procedure under occlusion),⁸ ice (at least 6 minutes),⁹ or an ethyl chloride spray can be applied to the nail folds prior to needle insertion to alleviate injection pain, but these methods do little for infiltration pain. Use of an ethyl chloride spray may be the preferred technique due to the rapidity of the analgesic effects (Figure).¹⁰ A vibrating massager also can be applied in close proximity to the site of needle insertion.¹¹

Proper anesthetic preparation and technique also can minimize pain during injection. Because lidocaine 1% is acidic (pH, 6.09), buffering with sodium bicarbonate 8.4% can result in decreased injection pain and faster onset of action.^6,12 Warming the anesthetic using a water bath, incubator, or autoclave can decrease pain without degradation of lidocaine or epinephrine.¹³ At a minimum, 30-gauge needles are preferred to minimize pain from needle insertion. Use of 33-gauge needles has shown benefit for injecting the face and scalp and may prove to be helpful injecting sensitive areas such as the digits.¹⁴ A slow injection technique is more comfortable for the patient, as rapid injection causes tissue distention.¹¹

The ideal anesthetic for nail surgery would have a fast onset and a long duration of action, which would allow for shorter operation time as well as alleviation of pain postprocedure and some degree of vasoconstriction to help maintain a bloodless field. Lidocaine has the fastest time of onset (<1–3 minutes) but a short duration of action (30–120 minutes) and a vasodilatory effect. Bupivacaine takes 2 to 5 minutes to take effect and has a long duration of action (120–240 minutes) but a risk for cardiotoxicity. Ropivacaine is the preferred anesthetic by some nail surgeons because of its intermediate time of onset (1–15 minutes), long duration of action (120–360 minutes), and the benefit of some vasoconstriction.^5,15 The addition of epinephrine has 2 main advantages: vasoconstriction and prolongation of anesthetic effects; the latter may help to alleviate postoperative pain. If there are no contraindications to its use (ie, severe hypertension, Raynaud phenomenon), it can be used safely in digital anesthesia without risk for ischemia or infarction.¹¹

Digital anesthesia can be achieved by infiltration or using nerve blocks. One major difference between these 2 approaches is the time of onset of anesthesia, with the former being nearly instantaneous and the latter taking up to 15 minutes.¹⁶ There also usually is more prolonged pain at the site of needle insertion with nerve blocks compared to infiltration. The type of nail surgery being performed, the digit involved, and surgeon preference will determine the anesthetic method of choice.¹⁷

Pain management immediately following the procedure and for several days after is essential. Use of a longer-acting anesthetic, such as bupivacaine or ropivacaine, will provide anesthesia for several hours. A well-padded dressing serves to absorb blood and protect the nail and distal digit from trauma, as even minor trauma can exacerbate pain and bleeding. The patient should be instructed to apply ice to the surgical site and keep the ipsilateral extremity elevated for the next 2 days to reduce edema and pain.¹⁵ Written instructions are helpful, as anxiety during and after the procedure may limit the patient’s understanding and recollection of the verbal postoperative instructions. To maximize readability of the information, the National Institutes of Health and American Medical Association recommend that the instructions be written at a fourth- to sixth-grade reading level.^18,19

A single dose of ibuprofen (400 mg) or acetaminophen (500 mg to 1 g) immediately before or after the procedure can reduce opioid use and postoperative pain.²⁰ Gabapentin (300–1200 mg) given 1 to 2 hours before surgery may be considered in patients who are at high risk for postsurgical pain.²¹ Acetaminophen or nonsteroidal anti-inflammatory drugs (eg, ibuprofen [200–400 mg]) administered every 4 to 6 hours provides considerable pain reduction postprocedure. Nonsteroidal anti-inflammatory drugs may be superior to acetaminophen for pain control²² and carry a low risk for postoperative bleeding.²³ Additionally, a combination of acetaminophen with a nonsteroidal anti-inflammatory drug for 3 doses may be more effective than either drug alone.²⁴ Some patients may require an opioid combination, such as codeine plus acetaminophen, for a short time (up to 3 days) for pain relief following surgery. Excessive pain or pain lasting than more than 3 days is not normal or expected; in these cases, patients should return to the office to rule out ischemia or infection.

It is important to implement pain-minimizing strategies for nail surgeries. Because many of these approaches are derived from other surgical specialties, well-controlled clinical trials in patients undergoing nail surgery will be necessary to improve outcomes.

Practice Gap

Early diagnosis of nail psoriasis is challenging because nail changes, including pitting, subungual hyperkeratosis, crumbling, oil spots, salmon patches, onycholysis, and splinter hemorrhages, may be subtle and nonspecific. Furthermore, 5% to 10% of psoriasis patients do not have skin findings, making the diagnosis of nail psoriasis even more difficult. Psoriatic arthritis (PsA) is more common in patients with nail psoriasis than in those with cutaneous psoriasis, and early joint damage may be asymptomatic.¹ Both nail psoriasis and PsA may progress rapidly, leading to functional impairment with poor quality of life.²

Diagnostic Tool

A 36-year-old man presented with a 4-year history of abnormal fingernails. He denied nail pain but stated that the nails felt sensitive at times and it was difficult to pick up small objects. His medical history was notable for type 2 diabetes mellitus, hypertension, and attention deficit disorder. He denied joint pain or skin rash.

Physical examination revealed pitting and onycholysis of the fingernails (Figure, A) without involvement of the toenails. A nail clipping was negative for fungus but revealed an incompletely keratinized nail plate with subungual parakeratotic scale, consistent with nail psoriasis. A radiograph showed erosive changes of the third finger of the right hand that were compatible with PsA (Figure, B).

Practice Implications

A nail clipping may be performed to diagnose nail psoriasis. Imaging and/or referral to a rheumatologist should be performed in all patients with isolated nail psoriasis to evaluate for early arthritic changes. If present, appropriate therapy is initiated to prevent further joint damage. In patients with nail psoriasis with or without associated joint pain, dermatologists should consider using radiograph imaging to screen patients for PsA.

Practice Gap

Early diagnosis of nail psoriasis is challenging because nail changes, including pitting, subungual hyperkeratosis, crumbling, oil spots, salmon patches, onycholysis, and splinter hemorrhages, may be subtle and nonspecific. Furthermore, 5% to 10% of psoriasis patients do not have skin findings, making the diagnosis of nail psoriasis even more difficult. Psoriatic arthritis (PsA) is more common in patients with nail psoriasis than in those with cutaneous psoriasis, and early joint damage may be asymptomatic.¹ Both nail psoriasis and PsA may progress rapidly, leading to functional impairment with poor quality of life.²

Diagnostic Tool

A 36-year-old man presented with a 4-year history of abnormal fingernails. He denied nail pain but stated that the nails felt sensitive at times and it was difficult to pick up small objects. His medical history was notable for type 2 diabetes mellitus, hypertension, and attention deficit disorder. He denied joint pain or skin rash.

Physical examination revealed pitting and onycholysis of the fingernails (Figure, A) without involvement of the toenails. A nail clipping was negative for fungus but revealed an incompletely keratinized nail plate with subungual parakeratotic scale, consistent with nail psoriasis. A radiograph showed erosive changes of the third finger of the right hand that were compatible with PsA (Figure, B).

Practice Implications

A nail clipping may be performed to diagnose nail psoriasis. Imaging and/or referral to a rheumatologist should be performed in all patients with isolated nail psoriasis to evaluate for early arthritic changes. If present, appropriate therapy is initiated to prevent further joint damage. In patients with nail psoriasis with or without associated joint pain, dermatologists should consider using radiograph imaging to screen patients for PsA.

Practice Gap

Early diagnosis of nail psoriasis is challenging because nail changes, including pitting, subungual hyperkeratosis, crumbling, oil spots, salmon patches, onycholysis, and splinter hemorrhages, may be subtle and nonspecific. Furthermore, 5% to 10% of psoriasis patients do not have skin findings, making the diagnosis of nail psoriasis even more difficult. Psoriatic arthritis (PsA) is more common in patients with nail psoriasis than in those with cutaneous psoriasis, and early joint damage may be asymptomatic.¹ Both nail psoriasis and PsA may progress rapidly, leading to functional impairment with poor quality of life.²

Diagnostic Tool

A 36-year-old man presented with a 4-year history of abnormal fingernails. He denied nail pain but stated that the nails felt sensitive at times and it was difficult to pick up small objects. His medical history was notable for type 2 diabetes mellitus, hypertension, and attention deficit disorder. He denied joint pain or skin rash.

Physical examination revealed pitting and onycholysis of the fingernails (Figure, A) without involvement of the toenails. A nail clipping was negative for fungus but revealed an incompletely keratinized nail plate with subungual parakeratotic scale, consistent with nail psoriasis. A radiograph showed erosive changes of the third finger of the right hand that were compatible with PsA (Figure, B).

Practice Implications

A nail clipping may be performed to diagnose nail psoriasis. Imaging and/or referral to a rheumatologist should be performed in all patients with isolated nail psoriasis to evaluate for early arthritic changes. If present, appropriate therapy is initiated to prevent further joint damage. In patients with nail psoriasis with or without associated joint pain, dermatologists should consider using radiograph imaging to screen patients for PsA.

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.¹ Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.² It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.³ Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.⁴ Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.⁵

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.⁶ This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.⁷ Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.⁶

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.⁸ In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.⁹ Patients also may present with aesthetic concerns that may impact their quality of life.¹⁰

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.¹¹ Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.¹² Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.¹³ For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.¹³

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.¹⁴Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.¹⁵ In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.¹⁶ Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.¹⁷ Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.¹⁸

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.¹⁹ Tea tree oil has been shown to be an effective treatment of tinea pedis,²⁰ and it is widely used in Australia as well as in Europe and North America.²¹ Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro^22-28 and in clinical trials.^29,30

In Vitro Data

Because TTO is composed of more than 100 active components,²³ the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.²² The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.²⁴ Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,²⁴ which are the 2 most common etiologies of onychomycosis.⁵ In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.²⁵ Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.³¹

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.⁵ In C albicans, TTO causes altered permeability of plasma membranes,³² dose-dependent alteration of respiration,³³ decreased glucose-induced acidification of media surrounding fungi,³² and reversible inhibition of germ tube formation.^19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.²⁹ Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.²⁹

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.³⁰ Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.³⁰

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.³⁵ The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.³⁵ Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,^36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.^36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.⁴⁰

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.³⁶ The in vitro activity of thymol, a component of TCS, was tested against Candida species.³⁷ The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.³⁷ It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.³⁸

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.³⁶ Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.³⁶

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.⁴⁰ The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.⁴⁰

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.⁴¹ Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.^42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.^45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.^49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.⁴⁶ In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.⁴⁷ In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.⁴²

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.⁴⁹ Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.⁴⁹

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.⁵⁰ The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.⁵⁰

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.^51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.⁵³ Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.^54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.⁵⁷ Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.^53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,⁵⁹ was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.⁵⁴ It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.⁵⁵ In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.⁵⁶

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).⁵⁸ Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).⁵⁸ A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.⁵⁸

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.⁵³ One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.⁵³

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O₃) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.⁶⁰ It was originally shown to have antibacterial properties in vitro,⁶¹ and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.^62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.⁶⁵ The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.⁶⁵

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.⁶² Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.⁶⁴

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.⁶⁵ Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.⁶⁵

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.²⁹ Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.³⁰ Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.⁴⁰ Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.⁴⁹ No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.⁴⁹ In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.⁵⁰ A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,⁵⁸ AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.⁵³

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.⁶⁵ Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.¹ Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.² It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.³ Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.⁴ Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.⁵

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.⁶ This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.⁷ Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.⁶

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.⁸ In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.⁹ Patients also may present with aesthetic concerns that may impact their quality of life.¹⁰

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.¹¹ Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.¹² Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.¹³ For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.¹³

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.¹⁴Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.¹⁵ In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.¹⁶ Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.¹⁷ Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.¹⁸

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.¹⁹ Tea tree oil has been shown to be an effective treatment of tinea pedis,²⁰ and it is widely used in Australia as well as in Europe and North America.²¹ Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro^22-28 and in clinical trials.^29,30

In Vitro Data

Because TTO is composed of more than 100 active components,²³ the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.²² The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.²⁴ Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,²⁴ which are the 2 most common etiologies of onychomycosis.⁵ In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.²⁵ Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.³¹

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.⁵ In C albicans, TTO causes altered permeability of plasma membranes,³² dose-dependent alteration of respiration,³³ decreased glucose-induced acidification of media surrounding fungi,³² and reversible inhibition of germ tube formation.^19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.²⁹ Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.²⁹

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.³⁰ Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.³⁰

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.³⁵ The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.³⁵ Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,^36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.^36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.⁴⁰

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.³⁶ The in vitro activity of thymol, a component of TCS, was tested against Candida species.³⁷ The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.³⁷ It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.³⁸

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.³⁶ Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.³⁶

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.⁴⁰ The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.⁴⁰

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.⁴¹ Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.^42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.^45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.^49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.⁴⁶ In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.⁴⁷ In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.⁴²

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.⁴⁹ Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.⁴⁹

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.⁵⁰ The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.⁵⁰

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.^51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.⁵³ Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.^54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.⁵⁷ Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.^53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,⁵⁹ was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.⁵⁴ It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.⁵⁵ In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.⁵⁶

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).⁵⁸ Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).⁵⁸ A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.⁵⁸

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.⁵³ One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.⁵³

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O₃) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.⁶⁰ It was originally shown to have antibacterial properties in vitro,⁶¹ and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.^62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.⁶⁵ The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.⁶⁵

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.⁶² Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.⁶⁴

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.⁶⁵ Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.⁶⁵

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.²⁹ Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.³⁰ Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.⁴⁰ Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.⁴⁹ No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.⁴⁹ In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.⁵⁰ A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,⁵⁸ AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.⁵³

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.⁶⁵ Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.¹ Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.² It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.³ Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.⁴ Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.⁵

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.⁶ This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.⁷ Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.⁶

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.⁸ In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.⁹ Patients also may present with aesthetic concerns that may impact their quality of life.¹⁰

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.¹¹ Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.¹² Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.¹³ For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.¹³

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.¹⁴Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.¹⁵ In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.¹⁶ Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.¹⁷ Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.¹⁸

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.¹⁹ Tea tree oil has been shown to be an effective treatment of tinea pedis,²⁰ and it is widely used in Australia as well as in Europe and North America.²¹ Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro^22-28 and in clinical trials.^29,30

In Vitro Data

Because TTO is composed of more than 100 active components,²³ the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.²² The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.²⁴ Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,²⁴ which are the 2 most common etiologies of onychomycosis.⁵ In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.²⁵ Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.³¹

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.⁵ In C albicans, TTO causes altered permeability of plasma membranes,³² dose-dependent alteration of respiration,³³ decreased glucose-induced acidification of media surrounding fungi,³² and reversible inhibition of germ tube formation.^19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.²⁹ Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.²⁹

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.³⁰ Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.³⁰

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.³⁵ The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.³⁵ Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,^36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.^36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.⁴⁰

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.³⁶ The in vitro activity of thymol, a component of TCS, was tested against Candida species.³⁷ The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.³⁷ It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.³⁸

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.³⁶ Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.³⁶

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.⁴⁰ The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.⁴⁰

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.⁴¹ Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.^42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.^45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.^49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.⁴⁶ In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.⁴⁷ In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.⁴²

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.⁴⁹ Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.⁴⁹

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.⁵⁰ The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.⁵⁰

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.^51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.⁵³ Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.^54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.⁵⁷ Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.^53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,⁵⁹ was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.⁵⁴ It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.⁵⁵ In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.⁵⁶

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).⁵⁸ Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).⁵⁸ A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.⁵⁸

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.⁵³ One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.⁵³

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O₃) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.⁶⁰ It was originally shown to have antibacterial properties in vitro,⁶¹ and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.^62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.⁶⁵ The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.⁶⁵

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.⁶² Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.⁶⁴

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.⁶⁵ Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.⁶⁵

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.²⁹ Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.³⁰ Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.⁴⁰ Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.⁴⁹ No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.⁴⁹ In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.⁵⁰ A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,⁵⁸ AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.⁵³

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.⁶⁵ Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Historically, a variety of tools have been used to alter one’s appearance for cultural or religious purposes or to conform to standards of beauty. As a defining feature of the face, the lips provide a unique opportunity for facial aesthetic enhancement. There has been a paradigm shift in medicine favoring preventative health and a desire to slow and even reverse the aging process.¹ Acknowledging that product technology, skill sets, and cultural ideals continually evolve, this article highlights perioral anatomy, explains aging of the lower face, and reviews techniques to achieve perioral rejuvenation through volume restoration and muscle control.

Perioral Anatomy

The layers of the lips include the epidermis, subcutaneous tissue, orbicularis oris muscle fibers, and mucosa. The upper lip extends from the base of the nose to the mucosa inferiorly and to the nasolabial folds laterally. The curvilinear lower lip extends from the mucosa to the mandible inferiorly and to the oral commissures laterally.² Circumferential at the vermilion-cutaneous junction, a raised area of pale skin known as the white roll accentuates the vermilion border and provides an important landmark during lip augmentation.³ At the upper lip, this elevation of the vermilion joins at a V-shaped depression centrally to form the Cupid’s bow. The cutaneous upper lip has 2 raised vertical pillars known as the philtral columns, which are formed from decussating fibers of the orbicularis oris muscle.² The resultant midline depression is the philtrum. These defining features of the upper lip are to be preserved during augmentation procedures (Figure 1).⁴

The superior and inferior labial arteries, both branches of the facial artery, supply the upper and lower lip, respectively. The anastomotic arch of the superior labial artery is susceptible to injury from deep injection of the upper lip between the muscle layer and mucosa; therefore, caution must be exercised in this area.⁵ Injections into the vermilion and lower lip can be safely performed with less concern for vascular compromise. The vermilion derives its red color from the translucency of capillaries in the superficial papillae.² The capillary plexus at the papillae and rich sensory nerve network render the lip a highly vascular and sensitive structure.

Aging of the Lower Face

Subcutaneous fat atrophy, loss of elasticity, gravitational forces, and remodeling of the skeletal foundation all contribute to aging of the lower face. Starting as early as the third decade of life, intrinsic factors including hormonal changes and genetically determined processes produce alterations in skin quality and structure. Similarly, extrinsic aging through environmental influences, namely exposure to UV radiation and smoking, accelerate the loss of skin integrity.⁶

The decreased laxity of the skin in combination with repeated contraction of the orbicularis oris muscle results in perioral rhytides.⁷ For women in particular, vertically oriented perioral rhytides develop above the vermilion; terminal hair follicles, thicker skin, and a greater density of subcutaneous fat are presumptive protective factors for males.⁸ With time, the cutaneous portion of the upper lip lengthens and there is redistribution of volume with effacement of the upper lip vermilion.⁹ Additionally, the demarcation of the vermilion becomes blurred secondary to pallor, flattening of the philtral columns, and loss of projection of the Cupid’s bow.¹⁰

Downturning of the oral commissures is observed secondary to a combination of gravity, bone resorption, and soft tissue volume loss. Hyperactivity of the depressor anguli oris muscle exacerbates the mesolabial folds, producing marionette lines and a saddened expression.⁷ With ongoing volume loss and ligament laxity, tissue redistributes near the jaws and chin, giving rise to jowls. Similarly, perioral volume loss and descent of the malar fat-pad deepen the nasolabial folds in the aging midface.⁶

The main objective of perioral rejuvenation is to reinstate a harmonious refreshed look to the lower face; however, aesthetic analysis should occur within the context of the face as a whole, as the lips should complement the surrounding perioral cosmetic unit and overall skeletal foundation of the face. To accomplish this goal, the dermatologist’s armamentarium contains a broad variety of approaches including restriction of muscle movement, volume restoration, and surface contouring.

Volume Restoration

Treatment Options

In 2015, hyaluronic acid (HA) fillers constituted 80% of all injectable soft-tissue fillers, an 8% increase from 2014.¹¹ Hyaluronic acid has achieved immense popularity as a temporary dermal filler given its biocompatibility, longevity, and reversibility via hyaluronidase.¹²

Hyaluronic acid is a naturally occurring glycosaminoglycan that comprises the connective tissue matrix. The molecular composition affords HA its hydrophilic property, which augments dermal volume.⁷ Endogenous HA has a short half-life, and chemical modification by a cross-linking process extends longevity by 6 to 12 months. The various HA fillers are distinguished by method of purification, size of molecules, concentration and degree of cross-linking, and viscosity.^7,13,14 These differences dictate overall clinical performance such as flow properties, longevity, and stability. As a general rule, a high-viscosity product is more appropriate for deeper augmentation; fillers with low viscosity are more appropriate for correction of shallow defects.¹ Table 1 lists the HA fillers that are currently approved by the US Food and Drug Administration for lip augmentation and/or perioral rhytides in adults 21 years and older.^15-17

Randomized controlled trials comparing the efficacy, longevity, and tolerability of different HA products are lacking in the literature and, where present, have strong industry influence.^18,19 The advent of assessment scales has provided an objective evaluation of perioral and lip augmentation, facilitating comparisons between products in both clinical research and practice.²⁰

Semipermanent biostimulatory dermal fillers such as calcium hydroxylapatite and poly-L-lactic acid are not recommended for lip augmentation due to an increased incidence of submucosal nodule formation.^6,14,21 Likewise, permanent fillers are not recommended given their irreversibility and risk of nodule formation around the lips.^14,22 Nonetheless, liquid silicone (purified polydimethylsiloxane) administered via a microdroplet technique (0.01 mL of silicone at a time, no more than 1 cc per lip per session) has been used off label as a permanent filling agent for lip augmentation with limited complications.²³ Regardless, trepidations about its use with respect to reported risks continue to limit its application.²²

Similarly, surgical lip implants such as expanded polytetrafluoroethylene is an option for a subset of patients desiring permanent enhancement but are less commonly utilized given the side-effect profile, irreversibility, and relatively invasive nature of the procedure.²² Lastly, autologous fat transfer has been used in correction of the nasolabial and mesolabial folds as well as in lip augmentation; however, irregular surface contours and unpredictable longevity secondary to postinjection resorption (20%–90%) has limited its popularity.^3,14,21

HA Injection Technique

With respect to HA fillers in the perioral area, numerous approaches have been described.^10,22 The techniques in Table 2 provide a foundation for lip rejuvenation.

Several injection techniques exist, including serial puncture, linear threading, cross-hatching, and fanning in a retrograde or anterograde manner.²⁴ A blunt microcannula (27 gauge, 38 mm) may be used in place of sharp needles and offers the benefit of increased patient comfort, reduced edema and ecchymosis, and shortened recovery period.^25,26 Gentle massage of the product after injection can assist with an even contour. Lastly, a key determinant of successful outcomes is using an adequate volume of HA filler (1–2 mL for shaping the vermilion border and volumizing the lips).²⁷ Figure 2 highlights a clinical example of HA filler for lip augmentation.

Fortunately, most complications encountered with HA lip augmentation are mild and transient. The most commonly observed side effects include injection-site reactions such as pain, erythema, and edema. Similarly, most adverse effects are related to injection technique. All HA fillers are prone to the Tyndall effect, a consequence of too superficial an injection plane. Patients with history of recurrent herpes simplex virus infections should receive prophylactic antiviral therapy.¹²

Muscle Control

An emerging concept in rejuvenation of the lower face recognizes not only restoration of volume but also control of muscle movement. Local injection of botulinum toxin type A induces relaxation of hyperfunctional facial muscles through temporary inhibition of neurotransmitter release.⁶ The potential for paralysis of the oral cavity may limit the application of botulinum toxin type A in that region.⁷ Nonetheless, the off-label potential of botulinum toxin type A has expanded to include several targets in the lower face. The orbicularis oris muscle is targeted to soften perioral rhytides. Conservative dosing (1–2 U per lip quadrant or approximately 5 U total) and superficial injection is emphasized in this area.²⁷ Similarly, the depressor anguli oris muscle is targeted by injection of 4 U bilaterally to soften the marionette lines. In the chin area, the mentalis muscle can be targeted by injection of 2 U deep into each belly of the muscle to reduce the mental crease and dimpling.²⁸ Combination treatment with dermal filler and neurotoxin demonstrates effects that last longer than either modality alone without additional adverse events.²⁹ With combination therapy, guidelines suggest treating with filler first.²⁷

Conclusion

A greater understanding of the extrinsic and intrinsic factors that contribute to the structural and surface changes of the aging face coupled with a preference for minimally invasive procedures has revolutionized the dermatologist’s approach to perioral rejuvenation. Serving as a focal point of the face, the lips and perioral skin are well poised to benefit from this paradigm shift. A multifaceted approach utilizing dermal fillers and neurotoxins may be most appropriate and has demonstrated optimal outcomes in facial aesthetics.

Inspection of the fingernails and toenails should be part of a complete physical examination. A basic understanding of nail anatomy and recognition of several basic types of nail lines and bands allow the clinician to properly diagnose and treat the nail disease, to recognize possible underlying systemic diseases, and to know when to refer the patient to a dermatologist for specialized evaluation and biopsy.

In this review, we delineate the three basic types of nail lines­—white lines (leukonychia striata), brown-black lines (longitudinal melanonychia), and red lines (longitudinal erythronychia)—and the differential diagnosis for each type. We also discuss grooves in the nail plate, or Beau lines.

BASIC NAIL ANATOMY

A fundamental understanding of the anatomy of the nail unit is necessary to understand the origin of nail diseases and underlying pathologic conditions.

The nail unit includes the nail matrix, the lunula, the nail fold, the nail plate, and the nail bed. The nail matrix extends from under the proximal nail fold to the half-moon-shaped area (ie, the lunula) and is responsible for nail plate production. The nail bed lies under the nail plate and on top of the distal phalanx and extends from the lunula to just proximal to the free edge of the nail; its rich blood supply gives it its reddish color.

Nails grow slowly, and this should be kept in mind during the examination. Regrowth of a fingernail takes at least 6 months, and regrowth of a toenail may take 12 to 18 months. Therefore, a defect in the nail plate may reveal an injury that occurred—or a condition that began—several months before.¹

NAIL EXAMINATION ESSENTIALS

A complete examination includes all 20 nail units and the periungual skin. Patients should be instructed to remove nail polish from all nails, as it may camouflage dystrophy or disease of the nail. Photography and careful measurement help document changes over time.

LEUKONYCHIA STRIATA: WHITE NAIL LINES

White nail lines or leukonychia is classified as true or apparent, depending on whether the origin is in the nail matrix or the nail bed.

In true leukonychia, there is abnormal keratinization of the underlying nail matrix, resulting in parakeratosis within the nail plate and an opaque appearance on examination.² The white discoloration is unaffected by pressure, and the opacity moves distally as the nail grows out, which can be documented by serial photography on subsequent visits.

Apparent leukonychia involves abnormal nail bed vasculature, which changes the translucency of the nail plate. The whiteness disappears with pressure, is unaffected by nail growth, and will likely show no change on later visits with serial photography.³

True leukonychia

Leukonychia striata, a subtype of true leuko­nychia, is characterized by transverse or longitudinal bands. It is most often associated with microtrauma, such as from a manicure.⁴ Lines due to trauma are typically more apparent in the central part of the nail plate; they spare the lateral portion and lie parallel to the edge of the proximal nail fold.⁵

Onychomycosis. White longitudinal bands may also be seen in onychomycosis, a fungal infection of the nail accounting for up to 50% of all cases of nail disease. The infection may present as irregular dense longitudinal white or yellowish bands or “spikes” on the nail plate with associated hyperkeratosis, known as a dermatophytoma (Figure 1).

If a fungal infection is suspected, a potassium hydroxide stain can be performed on the subungual debris, which is then examined with direct microscopy.⁶ Alternatively, the physician can send a nail plate clipping in a 10% buffered formalin container with a request for a fungal stain such as periodic acid-Schiff.⁷ Microscopic examination of a dermatophytoma shows a dense mass of dermatophyte hyphae, otherwise known as a fungal abscess.⁸

The physician can play an important role in diagnosis because clinical findings suggestive of a dermatophytoma are associated with a poor response to antifungal therapy.⁹

Inherited diseases. White longitudinal bands are also an important clue to the rare autosomal dominant genodermatoses Hailey-Hailey disease (from mutations of the ATP2A2 gene) and Darier disease (from mutations of the ATP2C1 gene). Patients with Hailey-Hailey disease may have nails with multiple parallel longitudinal white stripes of variable width originating in the lunula and most prominent on the thumbs.^10–12 These patients also have recurrent vesicular eruptions in flexural skin areas, such as the groin, axilla, neck, and periumbilical area causing significant morbidity.

Patients with Darier disease may have nails with alternating red and white longitudinal streaks, described as “candy-cane,”¹³ as well as wedge-shaped distal subungual keratosis accompanied by flat keratotic papules on the proximal nail fold.¹⁴ These nail changes are reported in 92% to 95% of patients with Darier disease.^15,16 Patients typically have skin findings characterized by keratotic papules and plaques predominantly in seborrheic areas and palmoplantar pits, as well as secondary infections and malodor causing significant morbidity.¹⁵ Therefore, knowing the characteristic nail findings in these diseases may lead to more rapid diagnosis and treatment.

Mees lines. Leukonychia striata can present as transverse white lines, commonly known as Mees lines. They are 1- to 2-mm wide horizontal parallel white bands that span the width of the nail plate, usually affecting all fingernails.¹⁷ They are not a common finding and are most often associated with arsenic poisoning. They can also be used to identify the time of poisoning, since they tend to appear 2 months after the initial insult.

Mees lines are also associated with acute systemic stresses, such as acute renal failure, heart failure, ulcerative colitis, breast cancer, infections such as measles and tuberculosis, and systemic lupus erythematosus, and with exposure to toxic metals such as thallium.³

Apparent leukonychia

Apparent leukonychia can alert the physician to systemic diseases, infections, drug side effects, and nutrient deficiencies. Specific nail findings include Muehrcke lines, “half-and-half” nails, and Terry nails.

Muehrcke lines are paired white transverse bands that span the width of the nail bed and run parallel to the distal lunula. They were first described in the fingernails of patients with severe hypoalbuminemia, some of whom also had nephrotic syndrome, which resolved with normalization of the serum albumin level. Muehrcke lines have since been reported in patients with liver disease, malnutrition, chemotherapy, organ transplant, human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome.^3,18 They are associated with periods of metabolic stress, ie, when the body’s capacity to synthesize proteins is diminished.¹⁹

Half-and-half nails, or Lindsay nails, are characterized by a white band proximally, a pink or red-brown band distally, and a sharp demarcation between the two (Figure 2). They were originally described in association with chronic renal disease,²⁰ and surprisingly, they resolve with kidney transplant but not with hemodialysis treatment or improvement in hemoglobin or albumin levels.^21–23 Half-and-half nails have been reported with Kawasaki disease, hepatic cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra.^3,24,25 They should be distinguished from Terry nails, which are characterized by leukonychia involving more than 80% of the total nail length.²⁶

Terry nails were originally reported in association with hepatic cirrhosis, usually secondary to alcoholism²⁷ but have since been found with heart failure, type 2 diabetes mellitus, pulmonary tuberculosis, reactive arthritis, older age, Hansen disease, and peripheral vascular disease.^3,26,28,29

LONGITUDINAL MELANONYCHIA: VERTICAL BROWN-BLACK NAIL LINES

Longitudinal melanonychia is the presence of black-brown vertical lines in the nail plate. They have a variety of causes, including blood from trauma; bacterial, fungal, or HIV infection; drug therapy (eg, from minocycline); endocrine disorders (Addison disease); exogenous pigmentation; or excess melanin production within the nail matrix.^30–32 They may also be a sign of a benign condition such as benign melanocytic activation, lentigines, or nevi, or a malignant condition such as melanoma (Figure 3).^33,34

When to suspect melanoma and refer

Although melanoma is less commonly associated with brown-black vertical nail lines, awareness of melanoma-associated longitudinal melanonychia reduces the likelihood of delayed diagnosis and improves patient outcomes.³⁵ Also, it is important to remember that although nail melanoma is more common in the 5th and 6th decades of life, it can occur at any age, even in children.³⁶

Findings that raise suspicion of nail melanoma (Table 1)^33,37 and that should prompt referral to a dermatologist who specializes in nails include the following:

• A personal or family history of melanoma
• Involvement of a “high-risk” digit (thumb, index finger, great toe),^30,31,38 although nail melanoma can occur in any digit
• Any new vertical brown-black nail pigmentation in a fair-skinned patient
• Only one nail affected: involvement of more than one nail is common in people with darker skin, and nearly all patients with darker skin exhibit longitudinal melanonychia by age 50³¹
• Changes in the band such as darkening, widening, and bleeding
• A bandwidth greater than 6 mm³³
• A band that is wider proximally than distally³⁴
• Nonuniform color of the line
• Indistinct lateral borders
• Associated with pigmentation of the nail fold (the Hutchinson sign, representing subungual melanoma),^31,39 nail plate dystrophy, bleeding, or ulceration.³³

While these features may help distinguish benign from malignant causes of longitudinal melanonychia, the clinical examination alone may not provide a definitive diagnosis. Delayed diagnosis of nail melanoma carries a high mortality rate; the internist can promote early diagnosis by recognizing the risk factors and clinical signs and referring the patient to a dermatologist for further evaluation with nail biopsy.

LONGITUDINAL ERYTHRONYCHIA: VERTICAL RED NAIL LINES

Longitudinal erythronychia—the presence of one or more linear red bands in the nail unit—can be localized (involving only one nail) or polydactylous (involving more than one nail). The localized form is usually due to a neoplastic process, whereas involvement of more than one nail may indicate an underlying regional or systemic disease.¹³Table 2 lists indications for referral to a nail specialist.

General features on examination

Clinical examination reveals one or more linear, pink-red streaks extending from the proximal nail fold to the distal free edge of the nail plate (Figure 4). The width of the band typically ranges from less than 1 mm to 3 mm.⁴⁰ Other features may include splinter hemorrhages within a red band, a semitransparent distal matrix, distal V-shaped chipping, splitting, onycholysis of the nail plate, and reactive distal nail bed and hyponychial hyperkeratosis. These features can be visible to the naked eye but may be better viewed with a magnifying glass, a 7× loupe, or a dermatoscope.¹³

Localized longitudinal erythronychia is usually seen in middle-aged individuals and is most commonly found on the thumbnail, followed by the index finger.^41,42 The condition may be asymptomatic, but the patient may present with pain or with concern that the split end of the nail catches on fabrics or small objects.⁴²

Glomus tumor

Intense, pulsatile pain with sensitivity to cold and tenderness to palpation is highly suggestive of glomus tumor,⁴³ a benign neoplasm that originates from a neuromyoarterial glomus body. Glomus bodies are located throughout the body but are more highly concentrated in the fingertips, especially beneath the nails, and they regulate skin circulation. Therefore, the nail unit is the most common site for glomus tumor.^44,45 A characteristic feature of subungual glomus tumor is demonstration of tenderness after pin-point palpation of the suspected tumor (positive Love sign).⁴⁵ While it is typical for glomus tumor to affect only one nail, multiple tumors are associated with neurofibromatosis type 1.⁴⁶ Confirmation of this diagnosis requires referral to a dermatologist.

Other causes of localized red nail lines

Onychopapilloma, a benign idiopathic tumor, is the most common cause of localized longitudinal erythronychia. Unlike glomus tumor, it is usually asymptomatic.^42,47 Less common benign conditions are warts, warty dyskeratoma, benign vascular proliferation, a solitary lesion of lichen planus, hemiplegia, and postsurgical scarring of the nail matrix. In some cases, the lines are idiopathic.^42,43

Malignant diseases that can present as localized longitudinal erythronychia include invasive squamous cell carcinoma, squamous cell carcinoma in situ (Bowen disease), and, less frequently, amelanotic melanoma in situ, malignant melanoma, and basal cell carcinoma.⁴² Squamous cell carcinoma in situ most commonly presents in the 5th decade of life and is the malignancy most commonly associated with localized longitudinal erythronychia. Clinically, there is also often nail dystrophy, such as distal subungual keratosis or onycholysis.⁴³

Patients with asymptomatic, stable localized longitudinal erythronychia may be followed closely with photography and measurements. However, any new lesion or a change in an existing lesion should prompt referral to a dermatologist for biopsy.¹³

Red streaks on more than one nail

Polydactylous longitudinal erythronychia usually presents in adults as red streaks on multiple nails and, depending on the presence or absence of symptoms (eg, pain, splitting), may be the patient’s chief complaint or an incidental finding noted by the astute clinician. Often, it is associated with systemic disease, most commonly lichen planus or Darier disease.

Lichen planus is a papulosquamous skin disease with nail involvement in 10% of patients and permanent nail dystrophy in 4%. Common nail findings include thinning, longitudinal ridging, and fissuring, as well as scarring of the nail matrix resulting in pterygium. Linear red streaks may accompany these more typical nail findings.¹³ Patients with Darier disease present with alternating red and white linear bands on multiple nails as in leukonychia striata.

Less frequently, polydactylous longitudinal erythronychia is associated with primary and systemic amyloidosis, hemiplegia, graft-vs-host disease, acantholytic epidermolysis bullosa, acantholytic dyskeratotic epidermal nevus, acrokeratosis verruciformis of Hopf, or pseudobulbar syndrome, or is idiopathic.^13,42,48 Therefore, the physician evaluating a patient with these nail findings should focus on a workup for regional or systemic disease or refer the patient to a dermatologist who specializes in nails.

BEAU LINES

Beau lines are a common finding in clinical practice. They are not true lines, but transverse grooves in the nail plate that arise from the temporary suppression of nail growth within the nail matrix that can occur during periods of acute or chronic stress or systemic illness (Figure 5).⁴⁹

The precipitating event may be local trauma or paronychia, chemotherapeutic agents cytotoxic to the nail matrix, or the abrupt onset of systemic disease.^18,50 The grooves have also been associated with rheumatic fever, malaria, pemphigus, Raynaud disease, and myocardial infarction, as well as following deep-sea dives.^51–53 The distance of a Beau line from the proximal nail fold can provide an estimate of the time of the acute stress, based on an average growth rate of 3 mm per month for fingernails and 1 mm per month for toenails.⁴⁹

Inspection of the fingernails and toenails should be part of a complete physical examination. A basic understanding of nail anatomy and recognition of several basic types of nail lines and bands allow the clinician to properly diagnose and treat the nail disease, to recognize possible underlying systemic diseases, and to know when to refer the patient to a dermatologist for specialized evaluation and biopsy.

In this review, we delineate the three basic types of nail lines­—white lines (leukonychia striata), brown-black lines (longitudinal melanonychia), and red lines (longitudinal erythronychia)—and the differential diagnosis for each type. We also discuss grooves in the nail plate, or Beau lines.

BASIC NAIL ANATOMY

A fundamental understanding of the anatomy of the nail unit is necessary to understand the origin of nail diseases and underlying pathologic conditions.

The nail unit includes the nail matrix, the lunula, the nail fold, the nail plate, and the nail bed. The nail matrix extends from under the proximal nail fold to the half-moon-shaped area (ie, the lunula) and is responsible for nail plate production. The nail bed lies under the nail plate and on top of the distal phalanx and extends from the lunula to just proximal to the free edge of the nail; its rich blood supply gives it its reddish color.

Nails grow slowly, and this should be kept in mind during the examination. Regrowth of a fingernail takes at least 6 months, and regrowth of a toenail may take 12 to 18 months. Therefore, a defect in the nail plate may reveal an injury that occurred—or a condition that began—several months before.¹

NAIL EXAMINATION ESSENTIALS

A complete examination includes all 20 nail units and the periungual skin. Patients should be instructed to remove nail polish from all nails, as it may camouflage dystrophy or disease of the nail. Photography and careful measurement help document changes over time.

LEUKONYCHIA STRIATA: WHITE NAIL LINES

White nail lines or leukonychia is classified as true or apparent, depending on whether the origin is in the nail matrix or the nail bed.

In true leukonychia, there is abnormal keratinization of the underlying nail matrix, resulting in parakeratosis within the nail plate and an opaque appearance on examination.² The white discoloration is unaffected by pressure, and the opacity moves distally as the nail grows out, which can be documented by serial photography on subsequent visits.

Apparent leukonychia involves abnormal nail bed vasculature, which changes the translucency of the nail plate. The whiteness disappears with pressure, is unaffected by nail growth, and will likely show no change on later visits with serial photography.³

True leukonychia

Leukonychia striata, a subtype of true leuko­nychia, is characterized by transverse or longitudinal bands. It is most often associated with microtrauma, such as from a manicure.⁴ Lines due to trauma are typically more apparent in the central part of the nail plate; they spare the lateral portion and lie parallel to the edge of the proximal nail fold.⁵

Onychomycosis. White longitudinal bands may also be seen in onychomycosis, a fungal infection of the nail accounting for up to 50% of all cases of nail disease. The infection may present as irregular dense longitudinal white or yellowish bands or “spikes” on the nail plate with associated hyperkeratosis, known as a dermatophytoma (Figure 1).

If a fungal infection is suspected, a potassium hydroxide stain can be performed on the subungual debris, which is then examined with direct microscopy.⁶ Alternatively, the physician can send a nail plate clipping in a 10% buffered formalin container with a request for a fungal stain such as periodic acid-Schiff.⁷ Microscopic examination of a dermatophytoma shows a dense mass of dermatophyte hyphae, otherwise known as a fungal abscess.⁸

The physician can play an important role in diagnosis because clinical findings suggestive of a dermatophytoma are associated with a poor response to antifungal therapy.⁹

Inherited diseases. White longitudinal bands are also an important clue to the rare autosomal dominant genodermatoses Hailey-Hailey disease (from mutations of the ATP2A2 gene) and Darier disease (from mutations of the ATP2C1 gene). Patients with Hailey-Hailey disease may have nails with multiple parallel longitudinal white stripes of variable width originating in the lunula and most prominent on the thumbs.^10–12 These patients also have recurrent vesicular eruptions in flexural skin areas, such as the groin, axilla, neck, and periumbilical area causing significant morbidity.

Patients with Darier disease may have nails with alternating red and white longitudinal streaks, described as “candy-cane,”¹³ as well as wedge-shaped distal subungual keratosis accompanied by flat keratotic papules on the proximal nail fold.¹⁴ These nail changes are reported in 92% to 95% of patients with Darier disease.^15,16 Patients typically have skin findings characterized by keratotic papules and plaques predominantly in seborrheic areas and palmoplantar pits, as well as secondary infections and malodor causing significant morbidity.¹⁵ Therefore, knowing the characteristic nail findings in these diseases may lead to more rapid diagnosis and treatment.

Mees lines. Leukonychia striata can present as transverse white lines, commonly known as Mees lines. They are 1- to 2-mm wide horizontal parallel white bands that span the width of the nail plate, usually affecting all fingernails.¹⁷ They are not a common finding and are most often associated with arsenic poisoning. They can also be used to identify the time of poisoning, since they tend to appear 2 months after the initial insult.

Mees lines are also associated with acute systemic stresses, such as acute renal failure, heart failure, ulcerative colitis, breast cancer, infections such as measles and tuberculosis, and systemic lupus erythematosus, and with exposure to toxic metals such as thallium.³

Apparent leukonychia

Apparent leukonychia can alert the physician to systemic diseases, infections, drug side effects, and nutrient deficiencies. Specific nail findings include Muehrcke lines, “half-and-half” nails, and Terry nails.

Muehrcke lines are paired white transverse bands that span the width of the nail bed and run parallel to the distal lunula. They were first described in the fingernails of patients with severe hypoalbuminemia, some of whom also had nephrotic syndrome, which resolved with normalization of the serum albumin level. Muehrcke lines have since been reported in patients with liver disease, malnutrition, chemotherapy, organ transplant, human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome.^3,18 They are associated with periods of metabolic stress, ie, when the body’s capacity to synthesize proteins is diminished.¹⁹

Half-and-half nails, or Lindsay nails, are characterized by a white band proximally, a pink or red-brown band distally, and a sharp demarcation between the two (Figure 2). They were originally described in association with chronic renal disease,²⁰ and surprisingly, they resolve with kidney transplant but not with hemodialysis treatment or improvement in hemoglobin or albumin levels.^21–23 Half-and-half nails have been reported with Kawasaki disease, hepatic cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra.^3,24,25 They should be distinguished from Terry nails, which are characterized by leukonychia involving more than 80% of the total nail length.²⁶

Terry nails were originally reported in association with hepatic cirrhosis, usually secondary to alcoholism²⁷ but have since been found with heart failure, type 2 diabetes mellitus, pulmonary tuberculosis, reactive arthritis, older age, Hansen disease, and peripheral vascular disease.^3,26,28,29

LONGITUDINAL MELANONYCHIA: VERTICAL BROWN-BLACK NAIL LINES

Longitudinal melanonychia is the presence of black-brown vertical lines in the nail plate. They have a variety of causes, including blood from trauma; bacterial, fungal, or HIV infection; drug therapy (eg, from minocycline); endocrine disorders (Addison disease); exogenous pigmentation; or excess melanin production within the nail matrix.^30–32 They may also be a sign of a benign condition such as benign melanocytic activation, lentigines, or nevi, or a malignant condition such as melanoma (Figure 3).^33,34

When to suspect melanoma and refer

Although melanoma is less commonly associated with brown-black vertical nail lines, awareness of melanoma-associated longitudinal melanonychia reduces the likelihood of delayed diagnosis and improves patient outcomes.³⁵ Also, it is important to remember that although nail melanoma is more common in the 5th and 6th decades of life, it can occur at any age, even in children.³⁶

Findings that raise suspicion of nail melanoma (Table 1)^33,37 and that should prompt referral to a dermatologist who specializes in nails include the following:

• A personal or family history of melanoma
• Involvement of a “high-risk” digit (thumb, index finger, great toe),^30,31,38 although nail melanoma can occur in any digit
• Any new vertical brown-black nail pigmentation in a fair-skinned patient
• Only one nail affected: involvement of more than one nail is common in people with darker skin, and nearly all patients with darker skin exhibit longitudinal melanonychia by age 50³¹
• Changes in the band such as darkening, widening, and bleeding
• A bandwidth greater than 6 mm³³
• A band that is wider proximally than distally³⁴
• Nonuniform color of the line
• Indistinct lateral borders
• Associated with pigmentation of the nail fold (the Hutchinson sign, representing subungual melanoma),^31,39 nail plate dystrophy, bleeding, or ulceration.³³

While these features may help distinguish benign from malignant causes of longitudinal melanonychia, the clinical examination alone may not provide a definitive diagnosis. Delayed diagnosis of nail melanoma carries a high mortality rate; the internist can promote early diagnosis by recognizing the risk factors and clinical signs and referring the patient to a dermatologist for further evaluation with nail biopsy.

LONGITUDINAL ERYTHRONYCHIA: VERTICAL RED NAIL LINES

Longitudinal erythronychia—the presence of one or more linear red bands in the nail unit—can be localized (involving only one nail) or polydactylous (involving more than one nail). The localized form is usually due to a neoplastic process, whereas involvement of more than one nail may indicate an underlying regional or systemic disease.¹³Table 2 lists indications for referral to a nail specialist.

General features on examination

Clinical examination reveals one or more linear, pink-red streaks extending from the proximal nail fold to the distal free edge of the nail plate (Figure 4). The width of the band typically ranges from less than 1 mm to 3 mm.⁴⁰ Other features may include splinter hemorrhages within a red band, a semitransparent distal matrix, distal V-shaped chipping, splitting, onycholysis of the nail plate, and reactive distal nail bed and hyponychial hyperkeratosis. These features can be visible to the naked eye but may be better viewed with a magnifying glass, a 7× loupe, or a dermatoscope.¹³

Localized longitudinal erythronychia is usually seen in middle-aged individuals and is most commonly found on the thumbnail, followed by the index finger.^41,42 The condition may be asymptomatic, but the patient may present with pain or with concern that the split end of the nail catches on fabrics or small objects.⁴²

Glomus tumor

Intense, pulsatile pain with sensitivity to cold and tenderness to palpation is highly suggestive of glomus tumor,⁴³ a benign neoplasm that originates from a neuromyoarterial glomus body. Glomus bodies are located throughout the body but are more highly concentrated in the fingertips, especially beneath the nails, and they regulate skin circulation. Therefore, the nail unit is the most common site for glomus tumor.^44,45 A characteristic feature of subungual glomus tumor is demonstration of tenderness after pin-point palpation of the suspected tumor (positive Love sign).⁴⁵ While it is typical for glomus tumor to affect only one nail, multiple tumors are associated with neurofibromatosis type 1.⁴⁶ Confirmation of this diagnosis requires referral to a dermatologist.

Other causes of localized red nail lines

Onychopapilloma, a benign idiopathic tumor, is the most common cause of localized longitudinal erythronychia. Unlike glomus tumor, it is usually asymptomatic.^42,47 Less common benign conditions are warts, warty dyskeratoma, benign vascular proliferation, a solitary lesion of lichen planus, hemiplegia, and postsurgical scarring of the nail matrix. In some cases, the lines are idiopathic.^42,43

Malignant diseases that can present as localized longitudinal erythronychia include invasive squamous cell carcinoma, squamous cell carcinoma in situ (Bowen disease), and, less frequently, amelanotic melanoma in situ, malignant melanoma, and basal cell carcinoma.⁴² Squamous cell carcinoma in situ most commonly presents in the 5th decade of life and is the malignancy most commonly associated with localized longitudinal erythronychia. Clinically, there is also often nail dystrophy, such as distal subungual keratosis or onycholysis.⁴³

Patients with asymptomatic, stable localized longitudinal erythronychia may be followed closely with photography and measurements. However, any new lesion or a change in an existing lesion should prompt referral to a dermatologist for biopsy.¹³

Red streaks on more than one nail

Polydactylous longitudinal erythronychia usually presents in adults as red streaks on multiple nails and, depending on the presence or absence of symptoms (eg, pain, splitting), may be the patient’s chief complaint or an incidental finding noted by the astute clinician. Often, it is associated with systemic disease, most commonly lichen planus or Darier disease.

Lichen planus is a papulosquamous skin disease with nail involvement in 10% of patients and permanent nail dystrophy in 4%. Common nail findings include thinning, longitudinal ridging, and fissuring, as well as scarring of the nail matrix resulting in pterygium. Linear red streaks may accompany these more typical nail findings.¹³ Patients with Darier disease present with alternating red and white linear bands on multiple nails as in leukonychia striata.

Less frequently, polydactylous longitudinal erythronychia is associated with primary and systemic amyloidosis, hemiplegia, graft-vs-host disease, acantholytic epidermolysis bullosa, acantholytic dyskeratotic epidermal nevus, acrokeratosis verruciformis of Hopf, or pseudobulbar syndrome, or is idiopathic.^13,42,48 Therefore, the physician evaluating a patient with these nail findings should focus on a workup for regional or systemic disease or refer the patient to a dermatologist who specializes in nails.

BEAU LINES

Beau lines are a common finding in clinical practice. They are not true lines, but transverse grooves in the nail plate that arise from the temporary suppression of nail growth within the nail matrix that can occur during periods of acute or chronic stress or systemic illness (Figure 5).⁴⁹

The precipitating event may be local trauma or paronychia, chemotherapeutic agents cytotoxic to the nail matrix, or the abrupt onset of systemic disease.^18,50 The grooves have also been associated with rheumatic fever, malaria, pemphigus, Raynaud disease, and myocardial infarction, as well as following deep-sea dives.^51–53 The distance of a Beau line from the proximal nail fold can provide an estimate of the time of the acute stress, based on an average growth rate of 3 mm per month for fingernails and 1 mm per month for toenails.⁴⁹

Inspection of the fingernails and toenails should be part of a complete physical examination. A basic understanding of nail anatomy and recognition of several basic types of nail lines and bands allow the clinician to properly diagnose and treat the nail disease, to recognize possible underlying systemic diseases, and to know when to refer the patient to a dermatologist for specialized evaluation and biopsy.

In this review, we delineate the three basic types of nail lines­—white lines (leukonychia striata), brown-black lines (longitudinal melanonychia), and red lines (longitudinal erythronychia)—and the differential diagnosis for each type. We also discuss grooves in the nail plate, or Beau lines.

BASIC NAIL ANATOMY

A fundamental understanding of the anatomy of the nail unit is necessary to understand the origin of nail diseases and underlying pathologic conditions.

The nail unit includes the nail matrix, the lunula, the nail fold, the nail plate, and the nail bed. The nail matrix extends from under the proximal nail fold to the half-moon-shaped area (ie, the lunula) and is responsible for nail plate production. The nail bed lies under the nail plate and on top of the distal phalanx and extends from the lunula to just proximal to the free edge of the nail; its rich blood supply gives it its reddish color.

Nails grow slowly, and this should be kept in mind during the examination. Regrowth of a fingernail takes at least 6 months, and regrowth of a toenail may take 12 to 18 months. Therefore, a defect in the nail plate may reveal an injury that occurred—or a condition that began—several months before.¹

NAIL EXAMINATION ESSENTIALS

A complete examination includes all 20 nail units and the periungual skin. Patients should be instructed to remove nail polish from all nails, as it may camouflage dystrophy or disease of the nail. Photography and careful measurement help document changes over time.

LEUKONYCHIA STRIATA: WHITE NAIL LINES

White nail lines or leukonychia is classified as true or apparent, depending on whether the origin is in the nail matrix or the nail bed.

In true leukonychia, there is abnormal keratinization of the underlying nail matrix, resulting in parakeratosis within the nail plate and an opaque appearance on examination.² The white discoloration is unaffected by pressure, and the opacity moves distally as the nail grows out, which can be documented by serial photography on subsequent visits.

Apparent leukonychia involves abnormal nail bed vasculature, which changes the translucency of the nail plate. The whiteness disappears with pressure, is unaffected by nail growth, and will likely show no change on later visits with serial photography.³

True leukonychia

Leukonychia striata, a subtype of true leuko­nychia, is characterized by transverse or longitudinal bands. It is most often associated with microtrauma, such as from a manicure.⁴ Lines due to trauma are typically more apparent in the central part of the nail plate; they spare the lateral portion and lie parallel to the edge of the proximal nail fold.⁵

Onychomycosis. White longitudinal bands may also be seen in onychomycosis, a fungal infection of the nail accounting for up to 50% of all cases of nail disease. The infection may present as irregular dense longitudinal white or yellowish bands or “spikes” on the nail plate with associated hyperkeratosis, known as a dermatophytoma (Figure 1).

If a fungal infection is suspected, a potassium hydroxide stain can be performed on the subungual debris, which is then examined with direct microscopy.⁶ Alternatively, the physician can send a nail plate clipping in a 10% buffered formalin container with a request for a fungal stain such as periodic acid-Schiff.⁷ Microscopic examination of a dermatophytoma shows a dense mass of dermatophyte hyphae, otherwise known as a fungal abscess.⁸

The physician can play an important role in diagnosis because clinical findings suggestive of a dermatophytoma are associated with a poor response to antifungal therapy.⁹

Inherited diseases. White longitudinal bands are also an important clue to the rare autosomal dominant genodermatoses Hailey-Hailey disease (from mutations of the ATP2A2 gene) and Darier disease (from mutations of the ATP2C1 gene). Patients with Hailey-Hailey disease may have nails with multiple parallel longitudinal white stripes of variable width originating in the lunula and most prominent on the thumbs.^10–12 These patients also have recurrent vesicular eruptions in flexural skin areas, such as the groin, axilla, neck, and periumbilical area causing significant morbidity.

Patients with Darier disease may have nails with alternating red and white longitudinal streaks, described as “candy-cane,”¹³ as well as wedge-shaped distal subungual keratosis accompanied by flat keratotic papules on the proximal nail fold.¹⁴ These nail changes are reported in 92% to 95% of patients with Darier disease.^15,16 Patients typically have skin findings characterized by keratotic papules and plaques predominantly in seborrheic areas and palmoplantar pits, as well as secondary infections and malodor causing significant morbidity.¹⁵ Therefore, knowing the characteristic nail findings in these diseases may lead to more rapid diagnosis and treatment.

Mees lines. Leukonychia striata can present as transverse white lines, commonly known as Mees lines. They are 1- to 2-mm wide horizontal parallel white bands that span the width of the nail plate, usually affecting all fingernails.¹⁷ They are not a common finding and are most often associated with arsenic poisoning. They can also be used to identify the time of poisoning, since they tend to appear 2 months after the initial insult.

Mees lines are also associated with acute systemic stresses, such as acute renal failure, heart failure, ulcerative colitis, breast cancer, infections such as measles and tuberculosis, and systemic lupus erythematosus, and with exposure to toxic metals such as thallium.³

Apparent leukonychia

Apparent leukonychia can alert the physician to systemic diseases, infections, drug side effects, and nutrient deficiencies. Specific nail findings include Muehrcke lines, “half-and-half” nails, and Terry nails.

Muehrcke lines are paired white transverse bands that span the width of the nail bed and run parallel to the distal lunula. They were first described in the fingernails of patients with severe hypoalbuminemia, some of whom also had nephrotic syndrome, which resolved with normalization of the serum albumin level. Muehrcke lines have since been reported in patients with liver disease, malnutrition, chemotherapy, organ transplant, human immunodeficiency virus (HIV) infection, and acquired immunodeficiency syndrome.^3,18 They are associated with periods of metabolic stress, ie, when the body’s capacity to synthesize proteins is diminished.¹⁹

Half-and-half nails, or Lindsay nails, are characterized by a white band proximally, a pink or red-brown band distally, and a sharp demarcation between the two (Figure 2). They were originally described in association with chronic renal disease,²⁰ and surprisingly, they resolve with kidney transplant but not with hemodialysis treatment or improvement in hemoglobin or albumin levels.^21–23 Half-and-half nails have been reported with Kawasaki disease, hepatic cirrhosis, Crohn disease, zinc deficiency, chemotherapy, Behçet disease, and pellagra.^3,24,25 They should be distinguished from Terry nails, which are characterized by leukonychia involving more than 80% of the total nail length.²⁶

Terry nails were originally reported in association with hepatic cirrhosis, usually secondary to alcoholism²⁷ but have since been found with heart failure, type 2 diabetes mellitus, pulmonary tuberculosis, reactive arthritis, older age, Hansen disease, and peripheral vascular disease.^3,26,28,29

LONGITUDINAL MELANONYCHIA: VERTICAL BROWN-BLACK NAIL LINES

Longitudinal melanonychia is the presence of black-brown vertical lines in the nail plate. They have a variety of causes, including blood from trauma; bacterial, fungal, or HIV infection; drug therapy (eg, from minocycline); endocrine disorders (Addison disease); exogenous pigmentation; or excess melanin production within the nail matrix.^30–32 They may also be a sign of a benign condition such as benign melanocytic activation, lentigines, or nevi, or a malignant condition such as melanoma (Figure 3).^33,34

When to suspect melanoma and refer

Although melanoma is less commonly associated with brown-black vertical nail lines, awareness of melanoma-associated longitudinal melanonychia reduces the likelihood of delayed diagnosis and improves patient outcomes.³⁵ Also, it is important to remember that although nail melanoma is more common in the 5th and 6th decades of life, it can occur at any age, even in children.³⁶

Findings that raise suspicion of nail melanoma (Table 1)^33,37 and that should prompt referral to a dermatologist who specializes in nails include the following:

• A personal or family history of melanoma
• Involvement of a “high-risk” digit (thumb, index finger, great toe),^30,31,38 although nail melanoma can occur in any digit
• Any new vertical brown-black nail pigmentation in a fair-skinned patient
• Only one nail affected: involvement of more than one nail is common in people with darker skin, and nearly all patients with darker skin exhibit longitudinal melanonychia by age 50³¹
• Changes in the band such as darkening, widening, and bleeding
• A bandwidth greater than 6 mm³³
• A band that is wider proximally than distally³⁴
• Nonuniform color of the line
• Indistinct lateral borders
• Associated with pigmentation of the nail fold (the Hutchinson sign, representing subungual melanoma),^31,39 nail plate dystrophy, bleeding, or ulceration.³³

While these features may help distinguish benign from malignant causes of longitudinal melanonychia, the clinical examination alone may not provide a definitive diagnosis. Delayed diagnosis of nail melanoma carries a high mortality rate; the internist can promote early diagnosis by recognizing the risk factors and clinical signs and referring the patient to a dermatologist for further evaluation with nail biopsy.

LONGITUDINAL ERYTHRONYCHIA: VERTICAL RED NAIL LINES

Longitudinal erythronychia—the presence of one or more linear red bands in the nail unit—can be localized (involving only one nail) or polydactylous (involving more than one nail). The localized form is usually due to a neoplastic process, whereas involvement of more than one nail may indicate an underlying regional or systemic disease.¹³Table 2 lists indications for referral to a nail specialist.

General features on examination

Clinical examination reveals one or more linear, pink-red streaks extending from the proximal nail fold to the distal free edge of the nail plate (Figure 4). The width of the band typically ranges from less than 1 mm to 3 mm.⁴⁰ Other features may include splinter hemorrhages within a red band, a semitransparent distal matrix, distal V-shaped chipping, splitting, onycholysis of the nail plate, and reactive distal nail bed and hyponychial hyperkeratosis. These features can be visible to the naked eye but may be better viewed with a magnifying glass, a 7× loupe, or a dermatoscope.¹³

Localized longitudinal erythronychia is usually seen in middle-aged individuals and is most commonly found on the thumbnail, followed by the index finger.^41,42 The condition may be asymptomatic, but the patient may present with pain or with concern that the split end of the nail catches on fabrics or small objects.⁴²

Glomus tumor

Intense, pulsatile pain with sensitivity to cold and tenderness to palpation is highly suggestive of glomus tumor,⁴³ a benign neoplasm that originates from a neuromyoarterial glomus body. Glomus bodies are located throughout the body but are more highly concentrated in the fingertips, especially beneath the nails, and they regulate skin circulation. Therefore, the nail unit is the most common site for glomus tumor.^44,45 A characteristic feature of subungual glomus tumor is demonstration of tenderness after pin-point palpation of the suspected tumor (positive Love sign).⁴⁵ While it is typical for glomus tumor to affect only one nail, multiple tumors are associated with neurofibromatosis type 1.⁴⁶ Confirmation of this diagnosis requires referral to a dermatologist.

Other causes of localized red nail lines

Onychopapilloma, a benign idiopathic tumor, is the most common cause of localized longitudinal erythronychia. Unlike glomus tumor, it is usually asymptomatic.^42,47 Less common benign conditions are warts, warty dyskeratoma, benign vascular proliferation, a solitary lesion of lichen planus, hemiplegia, and postsurgical scarring of the nail matrix. In some cases, the lines are idiopathic.^42,43

Malignant diseases that can present as localized longitudinal erythronychia include invasive squamous cell carcinoma, squamous cell carcinoma in situ (Bowen disease), and, less frequently, amelanotic melanoma in situ, malignant melanoma, and basal cell carcinoma.⁴² Squamous cell carcinoma in situ most commonly presents in the 5th decade of life and is the malignancy most commonly associated with localized longitudinal erythronychia. Clinically, there is also often nail dystrophy, such as distal subungual keratosis or onycholysis.⁴³

Patients with asymptomatic, stable localized longitudinal erythronychia may be followed closely with photography and measurements. However, any new lesion or a change in an existing lesion should prompt referral to a dermatologist for biopsy.¹³

Red streaks on more than one nail

Polydactylous longitudinal erythronychia usually presents in adults as red streaks on multiple nails and, depending on the presence or absence of symptoms (eg, pain, splitting), may be the patient’s chief complaint or an incidental finding noted by the astute clinician. Often, it is associated with systemic disease, most commonly lichen planus or Darier disease.

Lichen planus is a papulosquamous skin disease with nail involvement in 10% of patients and permanent nail dystrophy in 4%. Common nail findings include thinning, longitudinal ridging, and fissuring, as well as scarring of the nail matrix resulting in pterygium. Linear red streaks may accompany these more typical nail findings.¹³ Patients with Darier disease present with alternating red and white linear bands on multiple nails as in leukonychia striata.

Less frequently, polydactylous longitudinal erythronychia is associated with primary and systemic amyloidosis, hemiplegia, graft-vs-host disease, acantholytic epidermolysis bullosa, acantholytic dyskeratotic epidermal nevus, acrokeratosis verruciformis of Hopf, or pseudobulbar syndrome, or is idiopathic.^13,42,48 Therefore, the physician evaluating a patient with these nail findings should focus on a workup for regional or systemic disease or refer the patient to a dermatologist who specializes in nails.

BEAU LINES

Beau lines are a common finding in clinical practice. They are not true lines, but transverse grooves in the nail plate that arise from the temporary suppression of nail growth within the nail matrix that can occur during periods of acute or chronic stress or systemic illness (Figure 5).⁴⁹

The precipitating event may be local trauma or paronychia, chemotherapeutic agents cytotoxic to the nail matrix, or the abrupt onset of systemic disease.^18,50 The grooves have also been associated with rheumatic fever, malaria, pemphigus, Raynaud disease, and myocardial infarction, as well as following deep-sea dives.^51–53 The distance of a Beau line from the proximal nail fold can provide an estimate of the time of the acute stress, based on an average growth rate of 3 mm per month for fingernails and 1 mm per month for toenails.⁴⁹