Cutaneous and Ocular Toxicology

ISSN: 1556-9527 (Print) 1556-9535 (Online) Journal homepage: http://www.tandfonline.com/loi/icot20

Effect of oral photochemotherapy (8methoxypsoralen + UVA) on the electrophysiologic function of retina Nasser Shoeibi, Ahmadreza Taheri, Maliheh Nikandish, Arash Omidtabrizi, Nasim Khosravi, Maryam Kadkhoda & Somayeh Ghassemi Moghaddam To cite this article: Nasser Shoeibi, Ahmadreza Taheri, Maliheh Nikandish, Arash Omidtabrizi, Nasim Khosravi, Maryam Kadkhoda & Somayeh Ghassemi Moghaddam (2015): Effect of oral photochemotherapy (8-methoxypsoralen + UVA) on the electrophysiologic function of retina, Cutaneous and Ocular Toxicology To link to this article: http://dx.doi.org/10.3109/15569527.2015.1041032

Published online: 05 May 2015.

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Date: 02 October 2015, At: 06:01

http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2015.1041032

RESEARCH ARTICLE

Effect of oral photochemotherapy (8-methoxypsoralen + UVA) on the electrophysiologic function of retina Nasser Shoeibi1, Ahmadreza Taheri2, Maliheh Nikandish3, Arash Omidtabrizi4, Nasim Khosravi1, Maryam Kadkhoda5, and Somayeh Ghassemi Moghaddam5

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Faculty of Medicine, Retina Research Center, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran, 2Faculty of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Cutaneous Leishmaniasis Research Center, Mashhad, Islamic Republic of Iran, 3 Khatam Al Anbia Eye Hospital, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran, 4Department of Ophthalmology, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran, and 5School of Paramedicine, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran Abstract

Keywords

Context: Since we had observed electroretinographic (ERG) abnormalities in some patients undergoing photochemotherapy with normal eye examination, we decided to investigate the effects of this therapy on retinal function. Objective: To investigate the effects of oral photochemotherapy (8-methoxypsoralen + Ultraviolet-A) on electrophysiologic function of retina. Materials and methods: Patients with vitiligo, psoriasis or eczema were enrolled. Patients with any abnormal eye exam or a positive drug or family history for retinal disease were excluded. Baseline standard ERG was provided with the RETIport32 device. The second ERG was performed 6 months after the first and at least 1 week after the last photochemotherapy session (mean number of sessions: 45 ± 11). The outcome measures were changes in rod response, standard combined response, single-flash cone response, 30-Hz flicker (N1-P1) and oscillatory potentials amplitudes. Results: Forty patients were enrolled; 20 of them (mean age: 31.1 ± 12 years) completed the study. The mean rod response b-wave amplitude decreased from 88.9 ± 47.5 to 86.4 ± 36.6 and standard combined response b-wave amplitude decreased from 266.52 to 261.85 mV (p ¼ 0.422 and p ¼ 0.968, respectively) and the standard combined response a-wave amplitude increased from 155.4 ± 40.0 at baseline to 165.1 ± 48.4 in the follow-up ERG (p ¼ 0.092). The mean singleflash cone response a-wave amplitude decreased insignificantly in the follow-up ERG trace (34.5 ± 13.7 and 29 ± 15.4, respectively, p ¼ 0.242). The mean single-flash cone response b-wave amplitude showed an insignificant increase (p ¼ 0.087). The amplitudes of 30-Hz flicker wave and oscillatory potentials did not change significantly in the follow-up ERG (p ¼ 0.551 and p ¼ 0.739, respectively). Conclusion: Since no significant change in ERG traces was observed, oral photochemotherapy seems safe for retinal electrophysiologic function.

Electroretinography, photochemotherapy, psoriasis, retina, vitiligo

Introduction The therapeutic effects of the ultraviolet (UV) light on cutaneous diseases have been described decades ago1. Among the diseases that may respond to UV therapy, vitiligo and psoriasis are more common. Application of photosensitizing agents such as psoralen to augment the effects of long-wave UV radiation (PUVA therapy) has begun since 50 years ago1. In oral PUVA therapy, the patient is exposed to UV radiation after consumption of psoralen compounds.

Address for correspondence: Arash Omidtabrizi, Department of Ophthalmology, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran. E-mail: [email protected]

History Received 7 January 2015 Revised 22 March 2015 Accepted 11 April 2015 Published online 5 May 2015

Psoralens react with DNA and are excited by UV-A which induces therapeutic and potential side effects2. UV-A penetrates into the crystalline lens and can potentially induce premature cataract formation3. Careful eye protection mainly by wearing UV filtering glasses is highly recommended during PUVA therapy. In 1987, the electrophysiologic function of the retina was evaluated before and 2 h after psoralen consumption4. That study showed excessive sensitivity of the photoreceptors in the light-adapted and early dark-adapted phases. It should be noted that psoralen remains in blood circulation for 18 h, so its photosensitizing effect can be imposed during this time, when the patient may have no protective glasses5. Therefore, if they are exposed to sunlight or other UV sources, it would be equally dangerous.

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About 2 years ago, one patient with psoriasis and one patient with vitiligo, being under PUVA therapy and having normal visual acuity and fundus examination, underwent electroretinography (ERG) test for an investigational purpose. Interestingly, abnormal electroretinograms were recorded for both of them. There was no related history of ocular or systemic disorders in patients or their close relatives and no particular drug history having a relation with retinal dysfunction. Therefore, we decided to make it clear whether this ERG abnormality was an incidental finding or associated with the cutaneous disease or PUVA therapy. If the third hypothesis proved to be true, then PUVA therapy could no longer be considered as a safe treatment, having in mind the fact that many patients need dozens of sessions for improvement of their cutaneous disease. Our study was conducted in two steps. Step 1 that has been published6, evaluated the baseline electrophysiologic dysfunction of the retina in psoriasis and vitiligo. Step 2 which is the present article, evaluates the effect of PUVA therapy on retinal electrophysiologic function.

Methods This prospective case series study was carried out from July 2011 to October 2012 with the approval of the Institutional Review Board and Ethics Committee of Mashhad University of Medical Sciences. The study was explained to the patients and a written informed consent was obtained. Patients with vitiligo, psoriasis or eczema who were eligible candidates for oral PUVA therapy were enrolled in this study. Subjects with any abnormal eye exam which might possibly affect the retinal function, such as retinal pigmentary changes, active or previous retinochoroiditis, intermediate uveitis, retinal detachment or any media opacity that could

Figure 1. Post-treatment rod response ERG trace of a patient with vitiligo, superimposed on his pre-treatment trace.

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affect ERG responses or prevent complete funduscopy were excluded. Patients with a history of (hydroxy) chloroquine, phenothiazines, tamoxifen and oral isotretinoin consumption and any family history of genetic retinal diseases were also excluded. In addition, a patient was also cut off from the study if he or she developed any ophthalmic disease such as retinitis, vitritis or retinal detachment during the study course which could affect retinal function or ERG response. A 6-month follow-up period was necessary to inscribe the patient’s data into the analysis system. A detailed history including past medical, ocular, drug and family history was obtained and recorded in a questionnaire. Complete eye examination including uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), slit lamp examination and ophthalmoscopy was performed. Visual acuity was measured with the Snellen chart. Subsequently, a baseline standard ERG was provided by a single-experienced technician. Standardized full-field ERGs were elicited with Ganzfeld stimuli using the commercial ERG system (Retiport32; Roland Consult) and Silver/nylon fiber electrodes (DTL, Laird Technologies, Sauquoit Inc., Scranton, PA), according to International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines7. The active electrode was inserted into the inferior fornix of each eye. The reference and ground electrodes were placed near the temporal orbital rim and on the forehead, respectively. ERG traces were obtained from both eyes. The ISCEV-ERG GF program which is an integrated part of the system (Roland Consult, Electrophysiologic Diagnostic Systems, Wiesbaden, Germany) was used to record standard ERG traces. Darkadapted ERGs were performed after 20-min dark adaptation, and 10-min light adaptation was needed before recording light-adapted ERG traces. The band pass of the amplifiers was 1–300 Hz. Figures 1–4 show the post-PUVA therapy

DOI: 10.3109/15569527.2015.1041032

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Figure 2. Post-treatment standard combined response ERG trace of a patient with vitiligo, superimposed on his pre-treatment trace.

Figure 3. Post-treatment single-flash cone response ERG trace of a patient with vitiligo, superimposed on his pre-treatment trace.

dark- and light-adapted ERG traces of one of the studied patients superimposed on the pre-treatment traces with all the scales preserved. Treatment protocol 8-Methoxypsoralen with the dosage of 0.3–0.6 mg/kg was administered orally 1–3 h before exposure. The initial UVA dose was 0.5 J/cm2. Irradiation was given 2–3 times weekly. Dose increments were implied once a week and a minimally perceptible erythema was considered as a clinical indicator of

adequate dosage. After observing a clinical response, the treatment sessions were decreased. Patients were instructed to wear sunglasses outdoors for at least 18 h after every therapeutic session. After 6 months of the first PUVA therapy session (mean sessions & 45), a complete ophthalmic examination was performed. If any change from the previous examination was observed, it was recorded in the questionnaire. Then the second ERG was performed with the same device and by the same operator. There was at least 1-week interval between the final session of PUVA therapy and the second ERG testing.

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Figure 4. Post-treatment 30-Hz flicker (N1-P1) ERG trace of a patient with vitiligo, superimposed on his pre-treatment trace.

Table 1. Comparison between baseline and post-PUVA therapy ERG wave amplitudes (paired t test).

Rod response b-wave Standard combined response a-wave Standard combined response b-wave Single-flash cone response a-wave Single-flash cone response b-wave 30-Hz flicker (N1-P1) Oscillatory potentials

Mean baseline amplitude (mV) ± SD

Mean post-PUVA therapy amplitude (mV) ± SD

p Value

88.9 ± 47.5 155.4 ± 40.0 266.5 ± 87.0 34.5 ± 13.7 71.5 ± 25.2 66.3 ± 3.3 40.3 ± 12.9

86.4 ± 36.6 165.1 ± 48.4 261.8 ± 98.5 29 ± 15.4 73.4 ± 32.0 65.8 ± 3.9 41.1 ± 12.4

0.42 0.09 0.97 0.24 0.09 0.55 0.74

The outcome measures were changes in rod response, standard combined response, single-flash cone response, 30Hz flicker (N1-P1) and oscillatory potentials wave amplitudes. Statistical analysis was performed using the SPSS software, (Statistical Package for Social Sciences version 13.0 SPSS, Inc., Chicago, IL). Qualitative variables were expressed as percentages, and quantitative data were expressed as mean values with standard deviations (SDs). The paired t-test was used for inferential statistics. Analysis was done both by intention to treat and per protocol. Normal distribution of quantitative data was assessed using the Kolmogorov–Smirnov test. A p value 50.05 was regarded as statistically significant. There was no statistically significant difference between the two eyes of the patients in any of the wave amplitudes and latencies; therefore, only right eyes of the patients were selected and analyzed. The p values were adjusted by Bonferroni’s correction in order to avoid the possible inflation of p values owing to multiple comparisons.

Results In total, 40 patients were enrolled in the study. Baseline ERG was performed for all the patients. Eventually, 20 patients (10 vitiligo, 8 psoriasis and 2 eczema) completed the study and underwent the post-PUVA therapy ERG. Statistical analysis

was both by intention to treat (including all 40 patients) and per protocol (including 20 patients who completed the study). The patients’ mean age was 31.1 ± 12 years (range: 13–57 years). About 8 (40%) patients were male and 12 (60%) were female. The mean number of PUVA therapy sessions was 45 ± 11 times. The mean rod response b-wave amplitude was 88.91 mV at baseline versus 86.41 mV after PUVA therapy which showed a decrease, but not statistically significant (p ¼ 0.422, Table 1). Similarly, the amplitude of standard combined response b-wave did not significantly decrease. It was 266.52 mV at baseline and 261.85 mV post-PUVA therapy (p ¼ 0.968). The baseline mean single-flash cone response a-wave amplitude was 34.50 mV which became 29.00 mV after PUVA therapy; the decrease was not statistically significant (p ¼ 0.242). However, the latency of single-flash cone response a-wave did not show any significant change (p ¼ 0.185). The mean standard combined response a-wave amplitude showed an increase after PUVA therapy, but the difference was not significant (155.41 mV at baseline versus 165.08 mV after PUVA therapy, p ¼ 0.92). The mean single-flash cone response b-wave amplitude increased from 71.55 mV before PUVA therapy to 73.37 mV after the treatment. This increase was not statistically significant (p ¼ 0.087). The mean 30-Hz flicker (N1-P1) wave amplitude decreased from 66.35 to 65.83 mV which was also insignificant (p ¼ 0.551). The mean

Effect of PUVA therapy on ERG

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Table 2. Comparison between baseline and post-PUVA therapy ERG wave implicit times (paired t test).

Rod response b-wave Standard combined response a-wave Standard combined response b-wave Single-flash cone response a-wave Single-flash cone response b-wave 30-Hz flicker (N1) Oscillatory potentials

Mean baseline implicit time (ms) ± SD

Mean post-PUVA therapy implicit time (ms) ± SD

p Value

82.3 ± 8.5 18.9 ± 1.5 41.2 ± 1.8 13.6 ± 0.9 29.8 ± 1.6 45.1 ± 7.0 61.7 ± 7.0

78.1 ± 4.6 18.7 ± 1.40 40.6 ± 1.6 13.9 ± 0.7 30.5 ± 1.5 46.7 ± 1.9 63.2 ± 1.9

0.062 0.163 0.364 0.185 0.235 0.323 0.363

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Figure 5. Post-treatment oscillatory potentials ERG trace of a patient with vitiligo, superimposed on his pre-treatment trace.

baseline oscillatory potentials amplitude was 40.3 mV which showed an insignificant increment to 41.1 mV after PUVA therapy (p ¼ 0.739). There was no significant change in any of the ERG waves of the patients after PUVA therapy (p40.05). Implicit time did not change significantly after PUVA therapy in any of the ERG traces (Table 2).

Discussion In this study, the effect of PUVA therapy on retinal electrophysiologic function was investigated using ERG. We found insignificant decrease in the mean amplitude of rod response b-wave and standard combined response b-wave responses. Also, the mean single-flash cone response a-wave amplitude decreased insignificantly after 6 months of PUVA therapy. This result was confirmed by 30-Hz flicker amplitude that screens out the rod response and measures only the cone response. The decrease in 30-Hz flicker amplitude was minimal and not statistically significant. Therefore, we can acclaim that any of the cone, rod and combined responses are not affected by PUVA therapy. In addition, the mean standard combined response a-wave and single-flash cone response b-wave response amplitudes showed an increase after PUVA

therapy. Although this increase was not significant, it demonstrates that neither the increase nor the decrease in ERG response amplitudes have a strong relationship with PUVA therapy. However, in PUVA therapy, the eyes are protected by UV filtering glasses during and several hours after each session. Light damage to the eye has been recognized for a long time. In general, retinal light damage is most often attributed to visible (VIS) light exposure, rather than to UV light. Anterior portions of the eye, that are, the cornea and the lens, are highly susceptible to UV exposure, but the retina in the phakic eye is generally protected from excessive UV-B and UV-C exposure because of the absorption of wavelengths 5360 nm in the crystalline lens8. Nevertheless, the spectral band from 360 to 550 nm does penetrate into the anterior segment to reach the retina and contains photons sufficiently energetic to produce photochemical damage in the retina9. Psoralen intercalates between DNA base-pairs and forms psoralen DNA cross-links upon UV-A exposure10. As a result, DNA, RNA and protein synthesis are reduced and lead to decreased mitosis in these cells11. Two hours after oral administration of Oxsoralen, Methoxypsoralen has been detected in aqueous humor, vitreous gel, lens and retina of

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the guinea pig. These results point to the fact that the eyes of the patient must be protected from exposure to UV irradiation during and after psoralen UV treatment12. Studies which have investigated the effect of UV or psoralen on retina are scarce in the literature; maybe due to the concept that UV cannot reach the retina in toxic doses. In 1987, the effect of psoralen was investigated in 11 patients by ERG. Soueˆtre et al.4 showed that retinal sensitivity to light increased 2 h after consumption of posoralen and ERG responses were abnormal in single-flash cone response and early dark-adapted (rod response) phases. As we see in the latter study, although ERG was recorded only 2 h after methoxalen consumption, there were significant changes in the response of retina to light. Our study results showed no overall significant abnormality in ERG recordings after 6 months of PUVA therapy with psoralen. This can be described by the eye protection used, as UV filtering glasses, during and after every session resulting in limited penetration of UV light into the eyes. Bhupathy et al.13 also showed that an eye-pad can effectively protect the neonate’s eyes against UV during phototherapy. The ERG traces of the eyes of the patients with eye-pad protection were in normal limits at both dark- and light-adapted phases. A relatively small sample size and the lack of a control group were the main limitations of the present study. Unfortunately, as it was pointed out in the methods, the band pass of the amplifiers of our device was set at 1–300 Hz which is a little narrower than ISCEV recommendations (0.3–300 Hz). To alleviate this shortcoming, we analyzed the oscillatory potentials of the pre- and post-treatment ERG traces and presented the oscillatory potentials trace of the same patient whose other traces are presented in the ‘‘Results’’ part (Figure 5).

Conclusion The present study showed that PUVA therapy, if done with eye protection against UV during and after each session, is safe for retinal electrophysiology. Holding eye protection for

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18 h the day after each PUVA therapy session should be emphasized by dermatologists to make sure about its safety.

Declaration of interest The authors report no conflict declaration of interest.

References 1. Honigsmann H. History of phototherapy in dermatology. Photochem Photobiol Sci 2013;12:16–21. 2. Weichenthal M, Schwarz T. Phototherapy: how does UV work? Photodermatol Photoimmunol Photomed 2005;21:260–266. 3. Cox NH, Jones SK, Downey DJ, et al. Cutaneous and ocular sideeffects of oral photochemotherapy: results of an 8-year follow-up study. Br J Dermatol 1987;116:145–152. 4. Souetre E, De Galeani B, Gastaud P, et al. 5-Methoxypsoralen increases the sensitivity of the retina to light in humans. Eur J Clin Pharmacol 1989;36:59–61. 5. Honigsmann H. Phototherapy for psoriasis. Clin Exp Dermatol 2001;26:343–350. 6. Shoeibi N, Taheri AR, Nikandish M, et al. Electrophysiologic evaluation of retinal function in patients with psoriasis and vitiligo. Doc Ophthalmol 2014;128:131–136. 7. Marmor MF, Fulton AB, Holder GE, et al. ISCEV Standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol 2009;118:69–77. 8. Dillon J, Zheng L, Merriam JC, Gaillard ER. Transmission spectra of light to the mammalian retina. Photochem Photobiol 2000;71: 225–229. 9. Glickman RD. Ultraviolet phototoxicity to the retina. Eye Cont Lens 2011;37:196–205. 10. Baden HP, Parrington JM, Delhanty JD, Pathak MA. DNA synthesis in normal and xeroderma pigmentosum fibroblasts following treatment with 8-methoxypsoralen and long wave ultraviolet light. Biochim Biophys Acta 1972;262:247–255. 11. Rajpara AN, O’Neill JL, Nolan BV, et al. Review of home phototherapy. Dermatol Online J 2010;16:2. 12. Chakrabarti SG, Halder RM, Johnson BA, et al. 8-Methoxypsoralen levels in blood of vitiligo patients and in skin, ophthalmic fluids, and ocular tissues of the guinea pig. J Invest Dermatol 1986;87:276–279. 13. Bhupathy K, Sethupathy R, Pildes RS, et al. Electroretinography in neonates treated with phototherapy. Pediatrics 1978;61: 189–192.

Effect of oral photochemotherapy (8-methoxypsoralen + UVA) on the electrophysiologic function of retina.

Since we had observed electroretinographic (ERG) abnormalities in some patients undergoing photochemotherapy with normal eye examination, we decided t...
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