Photodermatology, Photoimmunology & Photomedicine
LETTER TO THE EDITOR
Is photodynamic diagnostic flexible ureterorenoscopy suitable for a patient presenting with chronic actinic dermatitis? Ronan Valentine1, Slawomir Kata2, Sally Ibbotson1, Ghulam Nabi2 & Harry Moseley1
1
Photobiology Unit, Ninewells Hospital and Medical School, Dundee, UK. 2 Department of Urology, Ninewells Hospital and Medical School, Dundee, UK.
Correspondence: Dr Ronan Valentine, Ph.D., Photobiology Unit, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. Tel: +441382 383382 e-mail: [email protected]
Accepted for publication: 14 May 2015 Conflicts of interest: None declared.
To the Editor, Photodynamic diagnosis (PDD) when combined with flexible ureterorenoscopy (PDD-FURS) is an important technique, which aids the visualization of tumours in the upper urinary tract. PDD-FURS relies on the oral administration of 5-aminolevulinic acid (5-ALA) to the referred patient three hours prior to the procedure rendering the patient photosensitive. Recording skin protoporphyrin IX (PpIX) fluorescence levels can be indicative of skin photosensitivity. Our study aimed to quantify a patient’s skin photosensitivity at various times before, during and after their PDD-FURS procedure. While PDD-FURS has a proven record in patient safety and efficacy (1, 2), caution must be exercised among some patients who are potentially at high risk from unwanted side effects, such as skin photosensitivity. Strategies linked to avoiding PDD-FURS induced skin photosensitization include ensuring low light exposure levels in occupied rooms and opaque curtains across any room windows. Also, consideration may be given to actively exposing the skin to low-dose light levels starting immediately following 5-ALA oral administration. An optical biopsy system (OBS), which works on the principle of fluorescence spectroscopy, has been widely used to measure PpIX fluorescence spectra from the surface of the skin (3–5). In this report, the OBS was used to monitor PpIX fluorescence ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12183
from a 49-year-old female patient undergoing PDD-FURS who had a documented history of the photosensitivity disorder, chronic actinic dermatitis (CAD). Monochromator phototesting of the patient to ultraviolet B (UVB), ultraviolet A (UVA) and visible wavebands produced normal immediate responses, however, showed delayed sensitivity in the UVB waveband, 305 5 nm and UVA waveband, 335 27 nm. The patient’s thresholds to erythema production following UVB (305 5 nm) and UVA (335 27 nm) radiation exposure were 0.027 J/cm2 (normal range >0.033 J/cm2) and 1 J/cm2 (normal range >3.9 J/cm2), respectively. Current medications prescribed to this patient included flavoxate hydrochloride, hydroxocobalamin, levothyroxine sodium, epipen and paracetamol. 5-aminolevulinic acid, a photosensitizer prodrug and precursor to PpIX, was orally administered to the patient three hours prior to the PDD-FURS procedure. While photosensitivity of approximately 24 h is a side effect of PDD-FURS resulting from the oral administration of 5ALA (6), consideration must be given to those patients who typically present with abnormal skin photosensitivity even without exogenous 5-ALA. The risk of provoking unprecedented sensitivity to visible light following 5-ALA administration in this patient could not be ruled out as visible and UV radiation sensitivity can be coincident among patients with CAD. The aim of this report was to measure the patient’s skin PpIX fluorescence levels at the time of 5-ALA administration and the following 24 h. The goal of the OBS measurements was to enable the urological surgeon to make an informed decision with regard to discharging the patient after 24 h. Also, during this time, luxmeter readings were recorded in an effort to measure the light intensity within hospital rooms and the potential light exposure risk to photosensitive patients.
METHODS OBS measurements Optical biopsy system fluorescence measurements were recorded from the left cheek of the photosensitive 279
Letter to the Editor
patient over a period of 24 h, starting from the time of drug administration. This period of assessment served to determine the patient’s skin photosensitivity as a result of 5-ALA administration prior to PDD-FURS. A black dot was marked next to the chosen measurement site on the patient’s cheek, and an initial baseline skin PpIX fluorescence measurement was taken, immediately before 5-ALA administration. The patient then received 5-ALA orally, which was reconstituted by adding 50 ml of fresh water to one vial of 5-ALA (1.5 mg). Immediately following 5-ALA administration, skin PpIX fluorescence measurements were taken and documented as the time = 0 time point. Additional measurements were taken frequently over the first seven hours and then once further at 24 h. A total of 14 different time points were used to ascertain the rise and fall of skin PpIX fluorescence associated with the PDD-FURS procedure. An average of three measurements was taken at each time point. The initial baseline PpIX fluorescence measurement was subtracted from each time point measurement. The patient’s test area was not protected from light exposure during the 24-hour observational period.
Luxmeter readings A luxmeter (ISO-TECH, ILM350) was used to determine the light intensity of the various hospital rooms and corridors, which the patient occupied after being administered 5-ALA. The patient pathway was, therefore, traced from their overnight room, through the corridors to the theatre area, the theatre area, operating room, recovery and back inside their overnight room. All readings were recorded at bed height. The luxmeter readings and OBS measurements were recorded concurrently.
Fig. 1. PpIX fluorescence intensity as a function of wavelength at various time points after the administration of exogenous 5-ALA for PDD-FURS.
5-ALA administration, the skin PpIX fluorescence buildup was initially rapid. A slight plateau was then observed between two and three hours followed by an overall PpIX fluorescence decrease between three hours and 24 h. Interestingly, the PpIX fluorescence intensity gradually increased between 4.5 h and 7 h when the patient was either in the operating room or recovery with the lights switched off in both cases.
Luxmeter readings Luxmeter readings were recorded from each hospital area occupied by the patient during their pathway to theatre. The specific hospital area, lux and whether the overhead lights were on, off or dimmed were documented. Table 1 lists the luxmeter readings recorded from each area and a description of the lighting.
RESULTS DISCUSSION OBS measurements Figure 1 illustrates skin PpIX fluorescence intensity spectra during the three-hour 5-ALA incubation time along with the seven-hour and 24-h time points. Maximum skin PpIX fluorescence was observed two hours following oral administration of 5-ALA. A total of 24 h after the administration of 5-ALA, skin PpIX fluorescence levels were comparable to the initial baseline PpIX fluorescence. Peak PpIX fluorescence intensity is typically observed at 635 nm. Consequently, the PpIX fluorescence recorded at this wavelength was plotted as a function of time point measurement (Fig. 2). As expected, following 280
It should be highlighted that the patient’s photosensitivity disorder was not monitored over the 24-h observational period but rather their skin PpIX fluorescence levels measured. Upon observing PpIX fluorescence levels from the patient’s cheek using an OBS, we found that the PpIX fluorescence rapidly increased over a twohour period following oral 5-ALA administration (7). Subsequently, the PpIX fluorescence decreased from two hours to five hours and then started to increase once again up to seven hours. PpIX fluorescence peaks at approximately 3–8 h have been reported in the literature (6). Also, previously published results from our group on normal human skin indicated that peak skin fluoresPhotodermatol Photoimmunol Photomed 2015; 31: 279–281 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Letter to the Editor
Table 1. The hospital area, lux and lighting mode were recorded in relation to the patient’s journey to theatre Hospital area
Luxmeter (lux)
Lighting (On/Off/Dim)
Overnight Room Ward 9 Corridor Level 6 Corridor Theatre Area Operating Room Recovery
330/2 450 250 420/45 560/5 30
On/Off On On On/Dim On/Off Dim
330 lux and 2 lux corresponds to the lights switched on and off, respectively. Fig. 2. PpIX fluorescence intensity at 635 nm measured 14 times between t = 0 up to 24 h after 5-ALA administration
cence was observed at seven hours following topical application of 5-ALA under occlusion for 1–3 h (4). The peaks observed between 4.5 hours and seven hours (Fig. 2) could be attributed to the fact that the patient was either in the operating room or recovery with the lights off. Consequently, skin PpIX photobleaching from the operating room lights may have been negligible enabling a build-up of skin PpIX fluorescence over time. Furthermore, the decrease in skin PpIX fluorescence between three hours and five hours could be due to the higher light intensity (420 lux) in the theatre area where the patient was waiting prior to entering theatre. Finally, 24 h after 5-ALA administration, the skin PpIX fluorescence intensity was almost completely eliminated and therefore similar to those levels at baseline before 5-ALA administration (8).
While routine PDD-FURS for a patient involves a three-hour 5-ALA incubation period, followed by PDD and a discharge after 24 h post 5-ALA administration, it was important to ascertain the safety of discharge at this time point given the patient’s photosensitivity history. Excess levels of PpIX may increase a photosensitive patient’s likelihood of unnecessary skin erythema. There was no evidence of PDD-FURS induced skin erythema postoperation, and the OBS fluorescence measurements consolidated the clinical decision of safely discharging this patient after 24 h. This case suggests that no extra burden is carried by patients with CAD who receive 5-ALA as part of their PDD-FURS procedure. Notably, skin PpIX fluorescence was observed to peak two hours after oral 5-ALA administration. Further work is warranted to ascertain more exact operating time points considering patient variability, PpIX fluorescence measurement sites and room lighting intensities.
REFERENCES 1. Aboumarzouk OM, Ahmad S, Moseley H, Kata SG. Accuracy of photodynamic diagnosis in the detection and follow-up of patients with upper urinary tract lesions: initial 3-year experience. Arab J Urol 2012; 10: 138–142. 2. Aboumarzouk OM, Mains E, Moseley H, Kata SG. Diagnosis of upper urinary tract tumours: is photodynamic diagnosis assisted ureterorenoscopy required as an addition to modern imaging and ureterorenoscopy? Photodiagnosis Photodyn Ther 2013; 10: 127–133. 3. Valentine RM, Ibbotson SH, Brown CTA, Wood K, Moseley H. A quantitative comparison of 5-aminolaevulinic acidand methyl aminolevulinate-induced
fluorescence, photobleaching and pain during photodynamic therapy. Photochem Photobiol 2011; 87: 242–249. 4. Lesar A, Ferguson J, Moseley H. A time course investigation of the fluorescence induced by topical application of 5aminolevulinic acid and methyl aminolevulinate on normal human skin. Photodermatol Photoimmunol Photomed 2009; 25: 191–195. 5. Nadeau V, O’Dwyer M, Hamden K, Tait I, Padgett M. In vivo measurement of 5aminolaevulinic acid-induced protoporphyrin IX photobleaching: a comparison of red and blue light of various intensities. Photodermatol Photoimmunol Photomed 2004; 20: 170–174.
Photodermatol Photoimmunol Photomed 2015; 31: 279–281 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
6. Peng Q, Warloe T, Berg K et al. 5Aminolevulinic Acid – Based Photodynamic Therapy. Cancer 1997; 79: 2282–2308. 7. Messmann H, Endlicher E, Knuchel R. Fluorescence endoscopy for the detection of low and high grade dysplasia in ulcerative colitis using systemic or local 5aminolaevulinic acid sensitisation. Gut 2003; 52: 1003–1007. 8. Pottier RH, Chow YFA, LaPlante JP, Truscott TG, Kennedy JC, Beiner LA. Non-invasive technique for obtaining fluorescence excitation and emission spectra in vivo. Photochem Photobiol 1986;44:679–687.
281
LETTER TO THE EDITOR
Is photodynamic diagnostic flexible ureterorenoscopy suitable for a patient presenting with chronic actinic dermatitis? Ronan Valentine1, Slawomir Kata2, Sally Ibbotson1, Ghulam Nabi2 & Harry Moseley1
1
Photobiology Unit, Ninewells Hospital and Medical School, Dundee, UK. 2 Department of Urology, Ninewells Hospital and Medical School, Dundee, UK.
Correspondence: Dr Ronan Valentine, Ph.D., Photobiology Unit, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. Tel: +441382 383382 e-mail: [email protected]
Accepted for publication: 14 May 2015 Conflicts of interest: None declared.
To the Editor, Photodynamic diagnosis (PDD) when combined with flexible ureterorenoscopy (PDD-FURS) is an important technique, which aids the visualization of tumours in the upper urinary tract. PDD-FURS relies on the oral administration of 5-aminolevulinic acid (5-ALA) to the referred patient three hours prior to the procedure rendering the patient photosensitive. Recording skin protoporphyrin IX (PpIX) fluorescence levels can be indicative of skin photosensitivity. Our study aimed to quantify a patient’s skin photosensitivity at various times before, during and after their PDD-FURS procedure. While PDD-FURS has a proven record in patient safety and efficacy (1, 2), caution must be exercised among some patients who are potentially at high risk from unwanted side effects, such as skin photosensitivity. Strategies linked to avoiding PDD-FURS induced skin photosensitization include ensuring low light exposure levels in occupied rooms and opaque curtains across any room windows. Also, consideration may be given to actively exposing the skin to low-dose light levels starting immediately following 5-ALA oral administration. An optical biopsy system (OBS), which works on the principle of fluorescence spectroscopy, has been widely used to measure PpIX fluorescence spectra from the surface of the skin (3–5). In this report, the OBS was used to monitor PpIX fluorescence ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12183
from a 49-year-old female patient undergoing PDD-FURS who had a documented history of the photosensitivity disorder, chronic actinic dermatitis (CAD). Monochromator phototesting of the patient to ultraviolet B (UVB), ultraviolet A (UVA) and visible wavebands produced normal immediate responses, however, showed delayed sensitivity in the UVB waveband, 305 5 nm and UVA waveband, 335 27 nm. The patient’s thresholds to erythema production following UVB (305 5 nm) and UVA (335 27 nm) radiation exposure were 0.027 J/cm2 (normal range >0.033 J/cm2) and 1 J/cm2 (normal range >3.9 J/cm2), respectively. Current medications prescribed to this patient included flavoxate hydrochloride, hydroxocobalamin, levothyroxine sodium, epipen and paracetamol. 5-aminolevulinic acid, a photosensitizer prodrug and precursor to PpIX, was orally administered to the patient three hours prior to the PDD-FURS procedure. While photosensitivity of approximately 24 h is a side effect of PDD-FURS resulting from the oral administration of 5ALA (6), consideration must be given to those patients who typically present with abnormal skin photosensitivity even without exogenous 5-ALA. The risk of provoking unprecedented sensitivity to visible light following 5-ALA administration in this patient could not be ruled out as visible and UV radiation sensitivity can be coincident among patients with CAD. The aim of this report was to measure the patient’s skin PpIX fluorescence levels at the time of 5-ALA administration and the following 24 h. The goal of the OBS measurements was to enable the urological surgeon to make an informed decision with regard to discharging the patient after 24 h. Also, during this time, luxmeter readings were recorded in an effort to measure the light intensity within hospital rooms and the potential light exposure risk to photosensitive patients.
METHODS OBS measurements Optical biopsy system fluorescence measurements were recorded from the left cheek of the photosensitive 279
Letter to the Editor
patient over a period of 24 h, starting from the time of drug administration. This period of assessment served to determine the patient’s skin photosensitivity as a result of 5-ALA administration prior to PDD-FURS. A black dot was marked next to the chosen measurement site on the patient’s cheek, and an initial baseline skin PpIX fluorescence measurement was taken, immediately before 5-ALA administration. The patient then received 5-ALA orally, which was reconstituted by adding 50 ml of fresh water to one vial of 5-ALA (1.5 mg). Immediately following 5-ALA administration, skin PpIX fluorescence measurements were taken and documented as the time = 0 time point. Additional measurements were taken frequently over the first seven hours and then once further at 24 h. A total of 14 different time points were used to ascertain the rise and fall of skin PpIX fluorescence associated with the PDD-FURS procedure. An average of three measurements was taken at each time point. The initial baseline PpIX fluorescence measurement was subtracted from each time point measurement. The patient’s test area was not protected from light exposure during the 24-hour observational period.
Luxmeter readings A luxmeter (ISO-TECH, ILM350) was used to determine the light intensity of the various hospital rooms and corridors, which the patient occupied after being administered 5-ALA. The patient pathway was, therefore, traced from their overnight room, through the corridors to the theatre area, the theatre area, operating room, recovery and back inside their overnight room. All readings were recorded at bed height. The luxmeter readings and OBS measurements were recorded concurrently.
Fig. 1. PpIX fluorescence intensity as a function of wavelength at various time points after the administration of exogenous 5-ALA for PDD-FURS.
5-ALA administration, the skin PpIX fluorescence buildup was initially rapid. A slight plateau was then observed between two and three hours followed by an overall PpIX fluorescence decrease between three hours and 24 h. Interestingly, the PpIX fluorescence intensity gradually increased between 4.5 h and 7 h when the patient was either in the operating room or recovery with the lights switched off in both cases.
Luxmeter readings Luxmeter readings were recorded from each hospital area occupied by the patient during their pathway to theatre. The specific hospital area, lux and whether the overhead lights were on, off or dimmed were documented. Table 1 lists the luxmeter readings recorded from each area and a description of the lighting.
RESULTS DISCUSSION OBS measurements Figure 1 illustrates skin PpIX fluorescence intensity spectra during the three-hour 5-ALA incubation time along with the seven-hour and 24-h time points. Maximum skin PpIX fluorescence was observed two hours following oral administration of 5-ALA. A total of 24 h after the administration of 5-ALA, skin PpIX fluorescence levels were comparable to the initial baseline PpIX fluorescence. Peak PpIX fluorescence intensity is typically observed at 635 nm. Consequently, the PpIX fluorescence recorded at this wavelength was plotted as a function of time point measurement (Fig. 2). As expected, following 280
It should be highlighted that the patient’s photosensitivity disorder was not monitored over the 24-h observational period but rather their skin PpIX fluorescence levels measured. Upon observing PpIX fluorescence levels from the patient’s cheek using an OBS, we found that the PpIX fluorescence rapidly increased over a twohour period following oral 5-ALA administration (7). Subsequently, the PpIX fluorescence decreased from two hours to five hours and then started to increase once again up to seven hours. PpIX fluorescence peaks at approximately 3–8 h have been reported in the literature (6). Also, previously published results from our group on normal human skin indicated that peak skin fluoresPhotodermatol Photoimmunol Photomed 2015; 31: 279–281 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Letter to the Editor
Table 1. The hospital area, lux and lighting mode were recorded in relation to the patient’s journey to theatre Hospital area
Luxmeter (lux)
Lighting (On/Off/Dim)
Overnight Room Ward 9 Corridor Level 6 Corridor Theatre Area Operating Room Recovery
330/2 450 250 420/45 560/5 30
On/Off On On On/Dim On/Off Dim
330 lux and 2 lux corresponds to the lights switched on and off, respectively. Fig. 2. PpIX fluorescence intensity at 635 nm measured 14 times between t = 0 up to 24 h after 5-ALA administration
cence was observed at seven hours following topical application of 5-ALA under occlusion for 1–3 h (4). The peaks observed between 4.5 hours and seven hours (Fig. 2) could be attributed to the fact that the patient was either in the operating room or recovery with the lights off. Consequently, skin PpIX photobleaching from the operating room lights may have been negligible enabling a build-up of skin PpIX fluorescence over time. Furthermore, the decrease in skin PpIX fluorescence between three hours and five hours could be due to the higher light intensity (420 lux) in the theatre area where the patient was waiting prior to entering theatre. Finally, 24 h after 5-ALA administration, the skin PpIX fluorescence intensity was almost completely eliminated and therefore similar to those levels at baseline before 5-ALA administration (8).
While routine PDD-FURS for a patient involves a three-hour 5-ALA incubation period, followed by PDD and a discharge after 24 h post 5-ALA administration, it was important to ascertain the safety of discharge at this time point given the patient’s photosensitivity history. Excess levels of PpIX may increase a photosensitive patient’s likelihood of unnecessary skin erythema. There was no evidence of PDD-FURS induced skin erythema postoperation, and the OBS fluorescence measurements consolidated the clinical decision of safely discharging this patient after 24 h. This case suggests that no extra burden is carried by patients with CAD who receive 5-ALA as part of their PDD-FURS procedure. Notably, skin PpIX fluorescence was observed to peak two hours after oral 5-ALA administration. Further work is warranted to ascertain more exact operating time points considering patient variability, PpIX fluorescence measurement sites and room lighting intensities.
REFERENCES 1. Aboumarzouk OM, Ahmad S, Moseley H, Kata SG. Accuracy of photodynamic diagnosis in the detection and follow-up of patients with upper urinary tract lesions: initial 3-year experience. Arab J Urol 2012; 10: 138–142. 2. Aboumarzouk OM, Mains E, Moseley H, Kata SG. Diagnosis of upper urinary tract tumours: is photodynamic diagnosis assisted ureterorenoscopy required as an addition to modern imaging and ureterorenoscopy? Photodiagnosis Photodyn Ther 2013; 10: 127–133. 3. Valentine RM, Ibbotson SH, Brown CTA, Wood K, Moseley H. A quantitative comparison of 5-aminolaevulinic acidand methyl aminolevulinate-induced
fluorescence, photobleaching and pain during photodynamic therapy. Photochem Photobiol 2011; 87: 242–249. 4. Lesar A, Ferguson J, Moseley H. A time course investigation of the fluorescence induced by topical application of 5aminolevulinic acid and methyl aminolevulinate on normal human skin. Photodermatol Photoimmunol Photomed 2009; 25: 191–195. 5. Nadeau V, O’Dwyer M, Hamden K, Tait I, Padgett M. In vivo measurement of 5aminolaevulinic acid-induced protoporphyrin IX photobleaching: a comparison of red and blue light of various intensities. Photodermatol Photoimmunol Photomed 2004; 20: 170–174.
Photodermatol Photoimmunol Photomed 2015; 31: 279–281 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
6. Peng Q, Warloe T, Berg K et al. 5Aminolevulinic Acid – Based Photodynamic Therapy. Cancer 1997; 79: 2282–2308. 7. Messmann H, Endlicher E, Knuchel R. Fluorescence endoscopy for the detection of low and high grade dysplasia in ulcerative colitis using systemic or local 5aminolaevulinic acid sensitisation. Gut 2003; 52: 1003–1007. 8. Pottier RH, Chow YFA, LaPlante JP, Truscott TG, Kennedy JC, Beiner LA. Non-invasive technique for obtaining fluorescence excitation and emission spectra in vivo. Photochem Photobiol 1986;44:679–687.
281
