Laser Therapy for Onychomycosis: Fact or Fiction?

Keywords:laser, treatment, medical, fibers,  Time:10-11-2015

1. Introduction

Systemic antifungal drugs are the mainstay of therapy for this chronic disease. When taken for a  12-week course, oral terbinafine has a mycologic cure rate of 71%–82% and a maximal clinical response rate of 60%–70% [7,8]. However, patients are often poorly compliant with the lengthy duration of treatment, resulting in sub-therapeutic concentrations reaching the nail plate [9]. Additionally, terbinafine can elevate liver enzymes and has rarely progressed to fulminant liver failure. Accordingly, it requires routine blood testing and is contraindicated in patients with chronic or active liver disease [10]. Additional adverse events include headache, loss of taste, and abdominal discomfort and induction of  a lupus-like syndrome. Itraconazole, another FDA-approved systemic antifungal drug utilized to manage onychomycosis, has much lower mycologic and clinical clearing rates, and may induce cardiac toxicity; it is also associated with a plethora of drug-drug interactions, making it an equally unattractive  treatment modality. In light of these limitations, laser therapy has been proposed as an alternative option for onychomycosis therapy. Currently utilized for a wide variety of medical and cosmetic skin disorders, dermatological lasers, supporters argue, offer a convenient solution with minimal side effects [11]. Treatment is administered in the medical setting (office/hospital), thus eliminating the requirement for patient adherence. Laser therapy also has the potential to treat those patients where systemic antifungals are either contraindicated or associated with possible drug-drug interactions [4]. Although the mechanism of action remains unknown, several theories exist. By the principle of selective photothermolysis, based on differences in thermal conductivity, laser energy may be preferentially absorbed by fungal pathogens resulting in photothermal and photomechanical damage  that spares surrounding human tissues [4,12]. An alternate theory suggests the formation of free radicals by incident laser energy and light absorption by fungal pigment xanthomegnin, present in high concentration in Trichophyton rubrum [13]. Since 2010, eight lasers have received regulatory approval for the “temporary cosmetic improvement” of onychomycosis, the clearance of these devices established upon “substantial equivalence” in technological specifications and safety to predicate devices [3,14].
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2. Methods

We conducted an extensive PubMed literature search, with the following criteria: “(laser) AND (onychomycosis)” and “(onychomycosis) AND (laser)”. Articles written in a language other than English or prior to ten years ago were excluded. Of the 70 eligible results, 17 were original studies, examined presently, 21 were reviews, and 32 were other commentaries or correspondence (Table S1).

3. Results and Discussion

Following Hochman’s pilot study, Kimura and colleagues enrolled 13 patients (37 toenails) to be treated with a 0.3-ms Nd:YAG laser [16]. Subjects received one to three treatments at four or eight week intervals, for an average of 2.4 treatments per patient. To measure clinical improvement, the authors calculated the ratio of clear nail growth to total length of toenail at baseline and at 8, 16, or 24 weeks post-treatment. They found 30 toenails (81%) with “complete” or “moderate” to “significant” clearance. Nineteen of those toenails (51%) showed “complete” clearance of which 100% tested negative for fungi on direct microscopy. This study was limited by small sample size and the authors did not stratify improvement by patient. In addition, it was unclear what degree of change in the nail merited designation of “moderate” or “significant” clearance. Noted in the authors’ disclosure, an equipment loan was received from laser production company, Cutera, Inc. (Bayshore Blvd., Brisbane, CA, USA). Waibel assigned 21 patients with onychomycosis verified by culture and PAS stain into three treatment arms, corresponding to a 1064-nm laser, 1319-nm laser, or BroadBand Light from a filtered flash lamp [17]. Patients received four treatments one week apart. At six months, 20 of 21 patients had negative cultures. Though clinical improvement was not quantified, in general, toenails had decreased subungual debris, discoloration, and onycholysis. One of the authors of the study disclosed a financial interest in the commercialization of this laser technology. S. Tyler Hollmig and colleagues conducted the first randomized clinical trial evaluating  FDA-approved JOULE ClearSense Nd:YAG laser [18]. The authors randomized 27 patients with culture-confirmed toenail onychomycosis in a 2:1 ratio of treatment group to control group. Using the protocol recommended by Sciton, patients received two sessions separated by a two-week interval.  At three months, the authors found no statistically significant difference between treatment and control groups when evaluating negative culture in all ten toenails (p = 0.49) and proximal nail plate clearance (p = 0.18). At 12 months, the modest improvement of proximal nail plate clearance seen in the laser group was not sustained when compared to the control (0.24 mm vs. 0.15 mm, p = 0.59).

In a controlled pilot study, Choi investigated a 1444-nm Nd:YAG laser with toenail scrapings from 20 patients with onychomycosis [19]. The trial consisted of three arms: a control group and two treatment groups at 300 and 450 J. Compared to the control, the authors found an average reduction rate in the number of colony-forming units (CFUs) of 75.9% for the group treated with 300 J and 85.5% for those receiving 450 J, with no significant difference between the two energy settings. At 450 J, scanning electron microscopy revealed disintegration of fungal and toenail structures in the nail plate, and the dishes displayed “marked disfigurements”. The authors admitted that “among the controls, the number of CFUs was highly variable”. Carney and colleagues conducted a multi-part study to determine the fungicidal temperature of Trichophyton rubrum in vitro and whether it is reproducible by a Nd:YAG 1064-nm laser in vivo [20]. They found a fungicidal effect for T. rubrum at 50 °C after 15 min. Fungicidal effect was determined by counting the number of colony-forming units on potato dextrose agar after exposure to seven different heat and time regimens: 5 min at 45 °C; 2, 5, 10, and 15 min at 50 °C; and 2 and 5 min at  55 °C. Confluent growth was defined as 400 CFU for T. rubrum. However, no growth inhibition was producible in vitro with direct laser irradiation to fungal colonies. The in vitro arms of the study were controlled and the examiners measuring colony growth were blinded. The in vivo portion of the study enrolled 10 patients with 14 onychomycotic great toenails for a 24-week pilot study, and treated them at a fluence of 16 J/cm2 and pulse duration 0.3 ms at weeks 0, 1, 2, 3, and 7. No control arm was used. To quantify clinical improvement, the authors calculated an Onychomycosis Severity Index (OSI) accounting for area of nail plate involvement, proximity of disease to the matrix, and degree of subungual hyperkeratosis [21]. Eight of the 14 nails showed improvement in the percent of disease involvement of the target nail, with two approaching more severe infection post-treatment. However, this improvement did not correlate with mycological cure assessed by culture and KOH. Moreover, the authors determined that the settings of the laser permitted a maximum temperature of 40 °C. Given patients’ complaints of mild pain at a fluence of 16 J/cm2, they concluded that aggressive settings to achieve the temperature necessary to effect cell death (50 °C) would not be practical clinically.

3.1.2. Long Pulse Nd:YAG Lasers

In 2012, Zhang conducted a prospective clinical trial evaluating the 1064-nm PinPointe FootLaser with a 30-ms pulse duration [22]. Thirty-three patients (154 nails) were randomly distributed into  two groups to receive four or eight sessions of laser treatment (groups 1 and 2, respectively), at  one-week intervals. The patients were selected based on microscopic examination demonstrating fungal infection and followed at 8, 16, and 24 weeks post-treatment. To quantify clinical improvement, the authors calculated an “effective rate” representative of the percentage of newly grown nail with respect to baseline. In group 1, the effective rate at weeks 8, 16, and 24 was 63%, 62%, and 51%, respectively; in group 2, 68%, 67%, and 53%. The treatment effect was not significantly different between groups  1 and 2 (p > 0.05).The positive rates for microscopic examination and fungal culture were higher at  24 weeks than those at 8 weeks, suggesting relatively rapid recurrence of infection. Moon and colleagues investigated the 1064-nm long-pulsed Sciton ClearSense laser of 0.3-ms pulse duration [23]. Thirteen patients (43 nails) with onychomycosis confirmed by KOH preparation and culture received five treatment sessions at 4-week intervals with a single follow-up at one month after the final treatment. They concluded that all patients achieved a “good response”, defined by least 50% clearance of turbid nail, however did not clarify as to whether this occurred in at least one nail or all affected nails. “Complete cure”, with negative culture and grossly normal appearing nail, was determined in four of the 43 nails (9.4%). The authors did not include patients who had total dystrophic onychomycosis. This study was limited by small sample size and lack of long-term data. In a small study enrolling 12 patients with distal lateral subungual onychomycosis, Noguchi et al. [24] evaluated a 0.5-ms Nd:YAG laser. The patients received three treatments directed at a single great toenail and were evaluated at six months based on the reduction of turbidity observed in the nail plate.