Role of Q-switched neodymium-doped yttrium aluminum garnet laser in combination with fractional carbon dioxide laser for the treatment of onychomycosis

INTRODUCTION

Onychomycosis, a chronic and recurrent fungal infection of the nail plate, presents challenges in treatment for both patients and clinicians. Onychomycosis comprises about 50% of nail disorders, predominantly affecting older adults with diabetes mellitus, peripheral arterial disease, or immunosuppression.^[1,2] Toenails are more susceptible due to limited ventilation and care.^[3] Clinically, affected nails exhibit yellowish-white or brown discoloration, detachment (onycholysis), subungual hyperkeratosis, thickening (onychauxis), and increased fragility.^[4,5] Occasionally, black pigmentation may occur, attributed to the Melanoides variant of Trichophyton rubrum or other fungi, termed fungal melanonychia [Figure 1].^[6] Total dystrophic onychomycosis represents the most severe form, characterized by thickened, friable, and yellowish nails, often accompanied by concurrent tinea pedis [Figure 2].^[4,7] Oral antifungals, such as itraconazole and terbinafine, are the gold standard treatments, although with variable degrees of improvement.^[8] Effective management requires months of oral antifungal administration. Recurrence rates can be as high as 50%, and exceed 50% in clinical settings.^[9] The slow growth rate of the nail plate prolongs treatment duration, decreasing patient adherence due to delayed improvement. Increased awareness prompts many patients to seek alternatives to long-term oral medication, fearing potential liver complications. In addition, the extended treatment regimen poses difficulties for geriatric patients, those on polypharmacy, and individuals with preexisting organ dysfunction. While measures such as footwear disinfection and maintaining foot hygiene and ventilation are feasible, patients with predisposing factors or immunosuppressive conditions necessitate safer and more effective treatment options.

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Figure 1:

Fungal melanonychia.

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Figure 2:

Total dystrophic onychomycosis accompanied with tinea pedis.

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Lasers have enhanced treatment outcomes across diverse medical conditions, necessitating assessment of their efficacy in nail abnormalities. Several studies have explored the ablative potential of high-powered carbon dioxide (CO₂) lasers in nail disorders since the 1980s.^[10-12] However, concerns persist due to unestablished efficacy, the absence of standardized protocols, and the associated procurement costs leading to elevated treatment expenses. Furthermore, the lack of comparative studies between different laser modalities compounds these apprehensions regarding their utilization in onychomycosis.

A 2022 review by the authors of this study assessed 57 studies on laser therapy for onychomycosis.^[13] Perforated CO₂ lasers yielded the best outcomes followed by long-pulsed neodymium-doped yttrium aluminium garnet (Nd: YAG) lasers.

Fractional CO₂ laser combined with topical antifungals and quasi long-pulse (300 ms) Nd: YAG lasers showed promise in shortening treatment duration and enhancing results. Q-switched Nd: YAG and fractional CO₂ lasers are commonly available in dermatology clinics.^[13-15]

Lasers operate through selective thermolysis, targeting specific tissues without affecting surrounding areas. The parameters must be finely adjusted to achieve optimal fungal destruction while preventing pain and tissue necrosis.^[16] To penetrate the nail plate and surrounding skin, wavelengths between 750 nm and 1300 nm are necessary.^[17] Pulse duration should be shorter than the thermal relaxation time (TRT) of the target tissue to avoid pain and necrosis. As TRT varies with the structure, thermal diffusivity, and cell wall composition, it is variable for fungal conidia, hyphae, and mycelia (3/4^th and 2/3^rd of the conidia, respectively). TRT is 0.7 ms; therefore, spacing between two pulses should be long enough to allow heat to dissipate to prevent pain and necrolysis of the tissue but short enough to provide enough heat accumulation for fungal tissue destruction.^[8] Microsecond pulses use differences in TRTs between fungi and dermal tissue, elevating fungal temperature while maintaining dermal temperature.^[16] Spot size determines tissue penetration depth, with larger spots delivering optimal energy fluence while minimizing side effects.

MATERIALS AND METHODS

Treatment protocol

A total of six monthly sessions, combining 1,064 nm nanosecond Q-switched Nd: YAG laser, microsecond quasi mode, and fractional CO₂ laser, were done.

Topical lignocaine was applied on the proximal nail fold for 45 min before each session.

• The first round of laser was done with quasi (300 ms) mode of 1064 Nd: YAG laser at the highest fluences produced by this laser. The patients were informed before the session that the nails were being heated, and he/she should inform the clinician in case of discomfort. Patients with moderate-to-severe hyperkeratosis could not feel the heat; hence, the number of shots was limited to 80–100 for great toes and 50 for small toes.

• The second round of laser was done with 1,064 nm Q-switched mode. Energies were adjusted according to the comfort of the patient, and patients were pre- informed about mild pricking sensation at the time of the laser.

• The third round of laser was done with a 10,600 nm fractional CO₂ laser to form a net of fenestrations [Figure 3 and Table 1].

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Figure 3:

Net of fenestrations formed by carbon dioxide laser.

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Table 1: Laser parameters of Q-switched Nd: YAG laser and fractional CO₂ laser used for monthly sessions. Both the lasers were used together in the same sitting.

S. No.	Laser/mode used	No. of passes	Laser Parameters
1.	1,064 nm Nd: YAG quasi mode laser	Multiple passes till heating	6 mm spot size, 5 J/cm2 energy, frequency 5 Hz 8 mm spot size, 2.8 J/cm2 energy, frequency 5 Hz
2.	Long-pulse 1,064 nm Nd: YAG laser	a. 2–3 passes b. 5–6 passes	6 mm spot size at 3–4 J/cm2 energy, frequency 5 Hz 8 mm spot size at 1.8–2.2 J/cm2 energy, frequency 5 Hz
3.	Fractional CO2 laser	4 passes	30 mJ energy at 5% density

CO₂: Carbon dioxide, Nd: YAG: Neodymium-doped yttrium aluminum garnet

Photographs were taken before each session and at follow-ups after the completion of laser sessions.

The patients were advised to take the tablet paracetamol in case of pain or discomfort and were prescribed a combination of steroid and antibiotic cream twice daily for three days on the proximal nail fold to prevent post-treatment inflammation. Daily topical 2% sertaconazole nitrate lotion was continued along with laser sessions.

Measurement of response

1. The cosmetic response was assessed as per patient observation by the visual analog score (VAS) system after three and six sessions and three and six months after the sixth session. Results of the treatment were measured on the basis of improvement in color, decrease in the area of involvement, and decrease in the thickness of the nail plate. The VAS grading and outcomes measured are shown in Table 2.

2. Treatment outcome and clinical response were measured by the clinician by comparing the pre-treatment onychomycosis severity index (OSI) score with the score obtained 6 months after the completion of the laser sessions on the basis of area of involvement, proximity to the matrix, and presence of a dermatophytoma and/or >2 mm subungual hyperkeratosis [Table 3]. The OSI scores were compared using student’s t-test, and P < 0.05 was considered to be statistically significant.

3. Mycological cure was measured by fungal cultures performed at the six-month follow-up.

Table 2: Grading of improvement according to VAS system.

S. No.	Improvement (%)	Grade	Improvement
1.	0	0	No improvement
2.	0–25	1	Poor improvement
3.	26–75	2	Moderate improvement
4.	>76	3	Good improvement
5.	100	4	Complete clinical clearance

VAS: Visual analog score

Table 3: Parameters for measurement of onychomycosis severity index (OSI).

Area of involvement of nail plate (%)	Points	Proximity to matrix	Points	Patch/streak/SH*	Points
1–10	1	Distal groove	1	Yes	10
11–25	2		2	No	0
26–50	3		3
51–75	4		4
>76	5	Matrix involvement	5

OSI: (Points for area of involvement×Points for proximity to matrix)+dermatophytoma or SH. *Dermatophytoma can be present as a patch or streak. SH: Subungual Hyperkeratosis

RESULTS

Patient satisfaction and cosmetic response

The VAS was recorded after the third and sixth sessions and three and six months after the sixth session [Table 5]. The initial improvement was first noticed near the proximal nail fold. Of the 20 patients treated, 5 (25%) showed complete cosmetic clearance after six sessions. After three months of completion of sessions, 15 (75%) patients had complete clearance with no relapses, which was maintained at six months [Table 6 and Figure 4]. Two patients had onycholytic pockets, which gradually resolved ([Figure 5], patient 1).

Table 5: VAS after three and six sessions, 3 months after the sixth session, and 6 months after the sixth session, OSI score pre- and post-completion of treatment duration, along with results of fungal cultures 6 months after sixth session.

S. No.	Average OSI pre treatment	OSI grading pre treatment	VAS after 3 sessions	VAS after 6th session	VAS at 3 months follow-up	VAS at 6 months follow-up	Average OSI at 6 months follow-up	OSI grading at 6 months follow-up	Fungal culture at 6 months follow-up	Response
1.	6.3	Moderate	1	3	4	4	0	clearance	Negative	cured
2.	4	Mild	2	3	4	4	0	clearance	Negative	cured
3.	5	Mild	2	2	4	4	0	clearance	Negative	cured
4.	8	Moderate	0	2	3	3	1.67	mild	Negative	cured
5.	6.2	Moderate	2	4	4	4	1	mild	Negative	cured
6.	2	Mild	2	3	4	4	0	clearance	Negative	cured
7.	4.75	Mild	3	4	4	4	0	clearance	Negative	cured
8.	12	Moderate	2	3	4	4	0	clearance	Negative	cured
9.	6.3	Moderate	2	3	4	4	2	mild	Negative	cured
10.	28.2	Severe	1	2	2	2	22.4	severe	Positive	negligible
11.	4	Mild	2	3	3	2	3	mild	Positive	mild
12.	13.3	Moderate	2	3	4	4	0.67	clearance	Negative	cured
13.	6	Moderate	3	4	4	4	0	clearance	Negative	cured
14.	12	Moderate	1	3	4	4	1	mild	Negative	cured
15.	10.75	Moderate	2	2	3	2	9.25	moderate	Positive	mild
16.	6	Moderate	2	3	4	4	0	clearance	Negative	cured
17.	2	Mild	3	4	4	4	0	clearance	Negative	cured
18.	7.6	Moderate	1	2	3	3	2	mild	Negative	cured
19.	5.9	Moderate	2	4	4	4	1	mild	Negative	cured
20.	12	moderate	2	3	4	4	2	mild	Negative	cured

VAS: Visual analog score, OSI: Onychomycosis severity index

Table 6: Number and percentage of patients showing clinical improvement at each follow-up: after three sessions, six sessions, 3 months after the sixth session, and 6 months after the sixth session.

	Number of patients (percentage) n=(%)
	No improvement	Poor improvement	Moderate improvement	Good improvement	Complete clearance
VAS after 3 sessions	1 (5)	4 (20)	12 (60)	3 (15)	0
VAS after 6 sessions	0	0	5 (25)	10 (50)	5 (25)
Follow-up at 3 months	0	0	1 (5)	7 (35)	15 (75)
Follow-up at 6 months	0	0	3 (15)	2 (10)	15 (75)

VAS: Visual analog score

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Figure 4:

Bar chart showing response to laser treatment in the form of clinical clearance as improvement in visual analog score at 3 sessions, 6 sessions, 3 months follow-up and 6 months follow-up, and negative fungal cultures at 6 months follow-up. VAS: Visual analog score.

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Figure 5:

Clinical appearance of nails with onychomycosis before the laser sessions (images a), at the end of 6 sessions (images b) and at 6 months follow-up (images c).

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Two patients had shown a decrease in VAS during the sessions, but indicated a relapse after stopping the laser sessions. The patient on methotrexate had presented with highly hyperkeratotic nails. At the end of six sessions, he showed mild improvement in the form, a decrease in hyperkeratosis, and a decrease in the area of involvement in a few nails [Figure 6].

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Figure 6:

A patient on methotrexate with highly hyperkeratotic nails in right foot (a) and left foot (c). At the end of six sessions, he showed mild improvement in right foot (b) and left foot (d) in the form of decrease in hyperkeratosis and decrease in the area of involvement in few nails.

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Clinical efficacy

The OSI evaluated before the start of the laser sessions was compared with OSI measured six months after completion of the laser sessions [Figure 7]. A highly significant response (P < 0.001) to this treatment protocol was observed.

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Figure 7:

Comparison of pre-treatment and post laser treatment (at 6 months follow-up) onychomycosis severity index score, depicting combined clinical efficacy of both the laser modalities.

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DISCUSSION

Onychomycosis is the most common infective nail disorder, constituting 50% of all nail disorders.^[2] T. rubrum and T. interdigitale are the most common causative dermatophytes, followed by molds, such as Fusarium, Aspergillus, and Acremonium. Yeasts, like Candida, are commonly found in individuals with predisposing factors, such as diabetes and immunosuppression.^[4]

Onychomycosis is a difficult condition to treat due to the slow growth rate of the nail plate. The treatment is prolonged and can exceed more than a year. Oral antifungals are contraindicated in patients with active or chronic liver and kidney diseases. Some patients may refuse oral medications due to the prolonged duration and the possible side effects of such extended regimens. Relapses are also fairly common due to residual spores.^[18] In addition, the fungal elements are believed to form a biofilm, making them refractory to therapy.^[19] All these factors have made the formulation of alternative treatment methods essential.

Early reviews on the use of lasers in onychomycosis have given no consensus on the effectiveness of lasers.^[16,20-22] Although the results have been mixed, these studies have definitely proven that lasers hold a future in the treatment of onychomycosis. A review article written by the authors of this study concluded that perforated CO₂ laser had the best results followed by long-pulsed Nd: YAG laser.^[13] We inferred that fractional CO₂ laser in conjunction with a topical antifungal and with the use of quasi long-pulse (300 ms) mode of 1,064 nm Nd: YAG laser, shortened the treatment length and improved outcomes.^[13] These are more readily available technologies in dermatology clinics, which prompted the authors to evaluate the efficacy of these lasers in their own practice.

It has been proven that complete fungal growth impairment can be achieved at temperatures above 50°C.^[23] Nd: YAG lasers emit near-infrared light at a wavelength of 1,064 nm, which raises the tissue temperature to 60°C.^[24] This temperature can cause fungal protein denaturation and collagen coagulation.

Long-pulsed Nd: YAG lasers have pulse duration in milliseconds. Due to the longer wavelength, the depth of penetration is deeper, but the degree of non-specific heating is high. Hence, a cooling system is required.^[22] Moreover, the 1,064 nm lasers have melanin as their target chromophore. Melanoides variant of T. rubrum or other fungi (Neoscytalidium dimidiatum or Aspergillus niger) have melanin as an essential element of the fungal cell wall.^[6]

Studies have shown successful treatment of onychomycosis with fractional CO₂ lasers combined with topical antifungals.^[25,26] Fractional CO₂ laser works by vaporization of the target tissue. This has a photothermal effect on the fungi, causes exfoliation of the nail plate, forms fenestrations, and enhances the absorption and effect of topical antifungals.^[27]

In this study, we evaluated the role of 1,064 nm Q-switched Nd: YAG laser and fractional CO₂ laser in onychomycosis non-responsive to oral antifungals. The resistance to treatment can be attributed to the formation of a biofilm by the arthrospores, making the fungus refractive to the therapy. Laser therapy is not affected by biofilm formation.^[19] Of the 20 patients included in the study, 60% were men. In addition, the number of involved nails of the feet was more (n = 57) than that of the hands (n = 20). This can be attributed to lesser hygiene of feet, which increases with age due to physical disability. Patients also tend to be less concerned with the cosmetic appearance of nails of feet unless multiple nails or massive hyperkeratosis is involved.

In this study, we combined two spot sizes (6 mm and 8 mm) at different energy levels of 1,064 Q-switched Nd: YAG laser using both nanosecond 1,064 nm and long-pulse quasi mode. This was done to give a combination of energies focused at different depths and destroy the fungal hyphae using thermal (photo-thermolytic) and mechanical (photo-chemical) action of the laser causing denaturation of the fungal cells.^[19] A fractional CO₂ laser was used to enhance the absorption of topical antifungal medication by the formation of a grid of fenestrations on the nail plate.^[27]

In our study, 17 (85%) patients had negative fungal cultures at the last follow-up (six months after the laser sessions), indicating no relapse at six months. The clinical response was measured by comparing the OSI score before starting the laser treatment and the score at the last follow-up (six months after the sixth session). A significant difference in the two sets of values (P < 0.001) showed a good response to treatment. This clinical clearance was also maintained at six months.

VAS was used as a tool to measure the cosmetic response as observed by the patients. Progressive improvement of the VAS is an indicator of a positive response to the treatment. Fifteen (75%) out of the 20 patients showed complete clinical clearance at three months after completion of the six monthly sessions.

The results of our study show that the dose of energies administered by our treatment protocol produced temperatures high enough to serve as a deactivating dose for the fungus. It was observed that the study showed promising results with mild-to-moderate disease. The three patients, who did not respond to the treatment, had significant subungual hyperkeratosis, which takes more time to respond to any form of treatment. Lack of optimal response to treatment can also be attributed to old age and the presence of a concurrent underlying disease.

In contrast to the results of our study, in a study by Carney et al., no inhibition of the fungal colonies and no clinical improvement were observed after treatment with Nd: YAG laser.^[28] Similarly, Hees et al. were unable to show satisfactory results both in a pilot study in 2012 and a study in 2014.^[29] The results of our study are in compliance with the satisfactory results of other studies evaluating the effects of Q-switched Nd: YAG laser in onychomycosis.^[30-33] Similar to this study, studies by Lim et al., Zhou et al., Arora et al., and Bhatta et al. evaluating the role of fractional CO₂ laser also show positive results.^[25-27,34] Our study is compared with other similar studies in Table 7.

CONCLUSION

We can infer from our study that at the six months follow-up after the laser sessions, 75% of our patients had complete cosmetic clearance, with 85% of patients having negative fungal cultures indicating no relapse at 6 months, and a highly significant clinical response in OSI (P < 0.001) to this treatment protocol combining Q-switched Nd: YAG laser and fractional CO₂ laser. Thus, we can definitely conclude that our study shows a promising use of lasers in the treatment of onychomycosis without the administration of oral anti-fungal drugs.

This study includes non-responder patients who opted out of further oral antifungal medication; hence, it was pertinent to formulate an effective alternate treatment option. These modalities are easily available in a dermatological setup; thus, they can either be combined with oral and topical antifungal treatments or used as stand-alone options.