How Nail Plate Biopsy Can Differentiate Onychomycosis From Trauma-Induced Nail Dystrophy  

Nail unit dystrophy is defined by thickening, discoloration, and deformation of nail structures with a wide array of clinical presentations.^1,2 This dystrophy can be associated with infective agents invading the nail structures such as fungi and mold, or can be caused by non-infective conditions such as metabolic conditions, psoriasis, lichen planus, micro nail trauma, or neoplasms. Nail changes have been associated with a number of diseases such as clubbing with cardiopulmonary disease and splinter hemorrhaging with subacute bacterial endocarditis.³
 
While some types of nail dystrophy are nearly unnoticeable to the untrained eye, other types can cause pain with shoe gear and difficulty with maintaining appropriate nail hygiene. With a number of products available on the market to treat nail dystrophy, understanding the etiology of the nail dystrophy presented is vital to being able to address the underlying condition for an attempt at a clinical cure.
 
As reported by Shavelson and Bakotic, the clinical appearance of a thickened toenail is usually not thickening of the nail plate itself, but rather a “pathologic hyperkeratinization of the nail bed.”¹ Bakotic and Shavelson liken this hyperkeratinization to a “subungual callus” that is unable to be shed naturally with the overlying nail plate intact. The hyperkeratinized nail bed thereby creates a positive feedback for nail bed thickening secondary to microtrauma to the nail unit that induces reactive hyperkeratinization of the nail bed. The resultant hyperkeratinization of the nail bed then causes the nail plate to elevate and to eventually become onycholytic.¹ In the majority of cases involving onychomycosis, the nail bed is believed to have hyperkeratinized before the nail bed became infected with fungi.^1,3 Mycotic infections are postulated to occur with nail bed hyperkeratinization secondary to nail bed keratin being more loosely woven than that of the nail plate since it resembles the surrounding stratum corneum of the peripheral nail folds. Onycholysis of the elevated nail plate is also believed to create an environment for invasive fungi such as Trichophyton rubrum to collect.¹
 
Nail unit dystrophy is often evaluated with regards to possible fungal involvement, with or without hyperkeratinization of the nail bed. Roughly 50 percent of nail dystrophy is associated with onychomycosis, or fungal infection of the nail.² Anyone can become infected with toenail fungus, but the condition is mostly associated with increased age, diabetes, peripheral arterial disease, and immune deficiency. Most toenail fungus in the United States has been associated with the dermatophyte, Trichophyton rubrum.⁴ However, multiple mycoses can be associated with onychomycosis.⁵
 
The classic gold standard for diagnosing toenail fungus is through laboratory evaluation with KOH and periodic acid Schiff (PAS) microscopy and obtaining a fungal culture. A number of topical products and oral medications are marketed for treating nail fungus by either inhibiting the metabolism of the fungi or structurally damaging the fungi. The oral medications have been associated with elevating liver enzyme levels and causing gastrointestinal disturbances and headaches; whereas the topical therapies require a long process of up to 48 months needed to obtain a nail with 10 percent or less residual nail involvement.² Clinical studies of these products show that less than 12 percent of patients will get the result of a completely clear toenail. Up to 22 percent of patients will experience a relapsed toenail fungal infection within 3 years of treatment.⁴

A Closer Look at the Study and Results

It was the aim of this case series to evaluate 27 individuals (16 male and 11 female) with nail unit dystrophy through nail plate biopsy to differentiate onychomycosis from non-infective nail unit dystrophy via histopathologic findings and fungal culturing via PAS and Grocott’s methenamine silver (GMS) staining with Bako Pathology Services. These individuals all expressed concern for possible nail fungus, and were interested in starting oral medication therapy. Biopsies were taken with consent prior to a treatment course determined by the results.
 
It is the authors’ practice that patients who were found to have a positive fungal culture and nail dystrophy seen with histopathologic examination of the nail plate biopsy to be treated either with 12 weeks of terbinafine (Lamisil, Novartis) oral anti-fungal medication and Kerasal nail topical ointment (Kerasal) once daily, or with Clear Nails Urea (CN-U) (Steriweb Medical, LLC) topical ointment to the affected nails twice daily for the treatment period. Patients with negative fungal cultures reported but nail dystrophy noted on the pathology report were started on once daily Kerasal topical ointment to the affected nails. Patients were instructed to follow up every 2 months to assess nail changes and to have routine nail debridement.
 
The results of the 27 nail plate biopsies displayed on Table 1.0 show onychomycotic nail changes with 56 percent of males (9 out of 16) and 73 percent of females evaluated (8 out of 11) based on histopathological changes and positive PAS and GMS staining performed. Nail dystrophy described as total nail dystrophy, onycholysis, orthokeratotic keratinization, or onychoschizia was reported with 100 percent of males (16 out of 16) and 82 percent of females tested (9 out of 11). Alternatively, the data obtained from nail plate biopsies shows that nail dystrophy in the absence of toenail onychomycosis was prevalent among 37 percent (10 out of 27) of all individuals tested, whereas 7 percent (2 out of 27) individuals exhibited onychomycosis in the absence of nail dystrophy. Thereby, 60 percent of individuals tested had concurrent onychomycosis in the presence of nail dystrophy.

What You Should Know About Trauma-Induced Nail Dystrophy

While onychomycosis is more common in people with peripheral vascular disease, diabetes mellitus, or immunocompromised states, this infective process can occur in anyone at any age.³ The current case study revealed an average male age of 44 and female age of 47 with the study including one 4-year-old female with nail plate biopsy positive for onychomycosis. This is a common diagnosis that is reported to affect up to 10 percent of the normal population, and up to 60 percent of the geriatric population.⁴
 
Asymmetric gait toenail unit syndrome (AGNUS) is the result of trauma-induced nail dystrophy reported with up to 70 percent of nail dystrophies among shoe-wearing societies with a prevalence of 14.2 percent in the normal population. This type of dystrophy yields nail bed keratosis, abnormalities in nail curvature, and onycholysis secondary to excessive pressures placed on the digits from shoe gear. As discussed earlier, these nail deformities are predisposing for onychomycosis and are believed to occur concomitantly.⁶ Because hyperkeratinization and onycholysis of the nail unit complex are associated with onychomycosis, treating the nail fungus without addressing the nail unit dystrophy often yields recurrence.¹
 
Kerasal is a topical solution composed of propylene glycol, urea, and lactic acid applied daily to the nail plate to decrease nail thickness and nail bed hyperkeratosis. This product is marketed to improve nail appearance with associated onychomycosis or psoriasis related nail dystrophy. Clinical trials suggested noticeable improvements to the nail plate in 1 week among 65 percent of patients tested and 82 percent of patients after week 2.⁷ Due to the increased risk of fungal infection in the presence of nail dystrophy, the authors support continuing daily application of Kerasal to affected nails until total new nail growth occurs.
 
Terbinafine is an oral antifungal administered for 12 weeks daily. This drug is metabolized by the liver and is excreted by the kidney. This drug, and other oral antifungal medications, are known to have association with elevated liver enzymes with prolonged use. Therefore, it is often recommended that patients receive routine bloodwork to ensure liver enzymes are normal before use and every 1 month during the treatment course. Oral antifungals prevent the further growth or replication of fungi; however, they will not resolve any fungi present before treatment.
 
Clear Nails-Urea (CN-U) is a urea-based topical gel applied to dystrophic nail plates daily to decrease hyperkeratosis to nail bed and improve dystrophic nail changes via penetration of a polyhexamethylene biguanide (PHMB) through the nail plate to the nail bed. PHMB has been long studied as an antifungal as well as antibacterial agent. Urea based topical solutions are trademarked with numerous product names, with the goal to soften nail plates to allow debridement of the nail plate without need for nail removal. The authors utilize this topical solution alongside terbinafine 250mg daily for 12 weeks for patients with normal blood liver enzyme levels and nail plate biopsies positive for onychomycosis in the presence of nail dystrophy.
 
Other options utilized for treating onychomycosis include oral medications such as itraconazole, ketoconazole, and griseofulvin in similar pulse-dosed or once weekly administration. There are also a multitude of topical solutions such as ciclopirox 8% and amorolfine 5% sold over-the-counter, or efinaconazole 10% and other prescription based products.² The costs of such topical products can vary monthly from $30-1000+ with mixed long term results. The need for daily application for a series of months to a year is difficult for patient compliance and optimal results can be difficult to obtain.
 
With any topical or oral medications to treat nail dystrophy in the presence or absence of onychomycosis, routine nail debridement is key to prevent onycholysis and trauma-induced nail dystrophy from relapsing. Such recurrence yields a new niche for fungi to infect and repopulate within. Reassessment of the proximal nail bed ensures that treatment is adequate as the new toenail grows in over the 8–10 month growth period.

In Conclusion

Trauma-induced nail dystrophy and onychomycosis have fairly similar clinical characteristics and can be difficult to differentiate based solely on clinical judgment. The results of this case series are consistent with prior studies showing that onychomycosis is closely associated with nail dystrophy obtaining 60% prevalence in the current study. To assume that all dystrophic nails are onychomycotic that should therefore be treated with antifungal medications would have yielded a mismanagement of 37% of the patients studied that had no findings of onychomycosis with nail plate biopsy and specimen staining. While no neoplasms were identified in this study, nail dystrophy isolated to a single nail not responding to standard of care should be biopsied regardless for isolating onychomycosis as subungual amelanotic melanoma or another non-melanocytic lesion may be present.⁸
 
Alex Pilkinton, DPM, practices at Wiemer Family Podiatry in Havertown, PA.
 
Robby Wiemer, DPM, practices at Wiemer Family Podiatry in Havertown, PA.
 
Disclosures and Conflicts of Interest: The listed authors have no financial disclosures or conflicts of interest to report pertaining to the following case study.