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Diabetic retinopathy is microvascular complication of diabetes mellitus (Mohamed et al., 2007). Being one of the leading causes of blindness in the people of working age in UK and US, the prevalence of diabetic retinopathy is alarming (Mohamed et al., 2007). It is estimated that approximately 4,200 people are blind from diabetic retinopathy in UK and this number is increasing at incident of approximately 1,280 per annum.
The prevalence of diabetic retinopathy is reported to increase with the duration as well as the type of diabetes (Mohamed et al., 2007, Qian and Ripps, 2011). It affects nearly all persons with type 1 diabetes and more than 60% of type 2 after duration of 20 years (Mohamed et al., 2007). Several epidemiologic studies have revealed the major risk factors for having diabetic retinopathy which are; hyperglycemia, hypertension, hyperlipidemia, pregnancy and renal disease (Mohamed et al., 2007). The less consistent risk factors associated with diabetic retinopathy are the obesity, smoking, moderate alcohol consumption and sedentary lifestyle (Mohamed et al., 2007).
In the early stage which known as nonproliferative diabetic retinopathy, changes occur in the retinal vasculature structure in which there is thickening of the capillary basement membrane and the loss of pericytes (Qian and Ripps, 2011) . The weakening of the capillary structure and the changes in its permeability gives rise to small out-pouching of the vessel wall known as microaneurysms (Qian and Ripps, 2011, Antonetti et al., 2012). Further deterioration of the vasculature structure leads to exudative leakage of the lipoprotein, retinal haemorrhage, microretinal infarcts of the nerve fiber layer , vessels collateralization and dilatation of venules and (Antonetti et al., 2012).
The proliferative state of diabetic retinopathy is thought to be the consequences of the tissue ischemia and up regulation of vascular endothelial growth factor (VEGF) which in turns promotes the neovascularization of the inner retina (Antonetti et al., 2012). The neovascularization could arise on the optic disk or elsewhere at the site of nonperfused retinal vessel junctions (Antonetti et al., 2012). The vision could remain undisrupted throughout the disease progression unless there is macular involvement or vitreous haemorrhage.
To date, the most common management of nonproliferative diabetic retinopathy is intensive glycemic control. Similar findings was observed in DCCT and UKPDS in which the incidence and progression of diabetic retinopathy reduced significantly in group of patient receiving intensive as compared to conventional therapy (Mohamed et al., 2007). Tight blood pressure control on the other hand is found to be major modifiable risk factor of incidence and progression of diabetic retinopathy (Mohamed et al., 2007). Other management of diabetic retinopathy includes the medical interventions such as antiplatelet agents and protein kinase C inhibitors as well as the anti VEGF namely ranibizumab and bevacizumab (Mohamed et al., 2007).
The severe nonpoliferative and proliferative stage of retinopathy required more aggressive treatment in order to halt further progression and undesirable outcome. It has been reported that untreated neovascularization will lead to vitreous haemorrhage through vitreous contraction force and progress to traction retinal detachment through series of event (Dowler, 2003, Antonetti et al., 2012) Historically, it was first treated by mean of pituitary ablation though it is discontinued later due to hypopituitarism complication (Antonetti et al., 2012). Later, the laser and surgical interventions were established as an option to manage proliferative diabetic retinopathy.
2.2. LASER TREATMENT FOR DIABETIC RETINOPATHY
For more than 30 years, laser photocoagulation remains as the accepted treatment for PDR and diabetic macular oedema (DMO). The laser treatment for PDR is warranted when the other feasible primary treatment is inadequate to stop the progression. The therapy takes the form of Pan- Retinal Laser Photocoagulation (PRP) in which the laser burns are placed over the entire retina whilst sparing the central macula to persevere the central vision (Mohamed et al., 2007). Meanwhile in DMO where the vision is disturbed, the therapy can take form of focal or grid macular laser (Dowler, 2003, Mohamed et al., 2007).
In PDR, the laser burns are responsible to reduce the calibre of new vessels (Dowler, 2003). Traditional view postulated that the reduction of the new vessels is brought by the destruction of the oxygen-consuming photoreceptors brought by thermal mechanism (Roider et al., 1999, Muqit et al., 2010b). Several studies have confirmed the effectiveness of the PRP in stopping the angiogenesis. Two randomized controlled trials in the 1970s and 1980s namely Diabetic Retinopathy Study (DRS) and Early Treatment Diabetic Retinopathy Study (EDTRS) provide the strongest support evidence (Mohamed et al., 2007). In DRS, 1758 patients with PDR in at least 1 eye or bilateral severe PDR were randomized to either receive PRP or serve as control by receiving no treatment (1978, 1981). At 2 years interval, the results showed severe visual loss in 6.4%of treated vs 15.9% of untreated eyes (1978, 1981). Furthermore, they also observed greatest advantage in eyes with high risk characteristics which having new vessels at the optic disc or vitreous haemorrhage with new vessels elsewhere by reduction of severe visual loss by 50% (1978, 1981).
In ETDRS study, 3711 patients with less severe DR and visual acuity greater than 20/100 were randomized to receive either PRP treatment immediately or deferral (1991). It was observed that the early PRP treatment of patient with less severe DR decreased the risk of high- risk proliferative DR by 50% as compared to deferral group (1991). Nevertheless, the incidence of visual loss was low for both groups of early treatment or deferral (2.6% vs 3.7%)(1991).
In DMO, macular laser is gently applied to areas of central retinal thickening to resolve the oedematous tissue and consequently improve vision (Dowler, 2003). Despite the still poorly understood exact biological mechanism which leads to the therapeutic effects, Bresnick 1983 hypothesized that the effect is associated with the restoration of new retinal pigmented epithelium (RPE) barrier (Bresnick, 1983). As the PRP, laser treatment also reported to be effective to persevere vision in DMO eyes (Mohamed et al., 2007). The EDTRS study randomized 1490 eyes with DMO to receive either focal laser treatment or just being observed (Early Treat Diabetic Retinopathy Study Res, 1985). At 3 years, the laser treatment proved to significantly reduce moderate visual loss in as compared to observation group. The greatest benefit was observed in the eyes with clinically significant macula oedema (Early Treat Diabetic Retinopathy Study Res, 1985).
The view of adequate laser burns applied to the retina especially in PDR changes over time. In 1989, Aylward concluded that the use of more extensive treatment is necessary for the elimination of new vessels and thus should be continued until regression of new vessels occurs. Furthermore, EDTRS also recommends up to 2000 visible end point (VEP) photocoagulation burns on the retina using the long pulse duration (100-200ms) for both DMO and PRP (Early Treat Diabetic Retinopathy Study Res, 1985). While the laser burns application was reported to be effective against neovascularization, the adverse side effects are still controversial (Muqit et al., 2009). Aylward 1989 stated the argon laser photocoagulation is associated with angle closure, macular oedema, foveal burns, loss of peripheral VF and reduced colour discrimination. The conventional laser scar expansion also associated with photoreceptor loss, RPE hypertrophy and subfoveal fibrosis, loss of night vision and decreased contrast sensitivity in numbers of patients (Hudson et al., 1998, Ulbig et al., 1994). It is said that the thermal energy produced by the laser light at the level of RPE can transmit to the adjacent retinal layers and therefore producing damage which cause the unwanted side effects (Yu et al., 2005). Considering to that effects, a new photocoagulation technique was developed to treat the RPE and reducing damage to photoreceptor at the same time (Roider et al., 1999).
Micropulse technique and non VEP photocoagulation was introduced and has been reported to produce comparable visual outcome to long pulse photocoagulation (Moorman and Hamilton, 1999). The micropulse reported to produce more localized photocoagulation of the RPE and photoreceptors due to short duration feature of laser energy which limits the degree of thermal spread to the absorption site (Mainster, 1999, Roider et al., 1999). In our study, pattern scanning laser (Pascal) system (532nm) was used. It was first introduced in 2005 mainly for retinal photocoagulation (Blumenkranz et al., 2006). Shorter treatment delivery times in Pascal were brought by semi- automated brief pulse duration along with rapid raster scan application of multiple spots (Muqit et al., 2010a).
2.3. LASER HEALING RESPONSE
The new advancement of laser technology has open new window for more studies to be conducted. While the photoreceptor deaths contributing to lower oxygen consumption is still the leading hypothesis of how PRP regress the neovascularization, the researchers nowadays are more enthusiastic to explore new possibility of the healing response to occur using micropulse technique. The healing response is said possible by using photocoagulation that selectively targeting the RPE with minimal photoreceptor loss and followed by repopulation of the RPE and photoreceptor (Paulus et al., 2008). However, the newest laser technology of minimizing the damage could possibly suffer from disadvantage of lack of long term therapeutic effects (Muqit et al., 2010a).
Autofluorescence imaging (AF) and Fourier domain optical coherence tomography (FD-OCT) were used to evaluate the laser-tissue interaction and healing responses in various studies (Muqit et al., 2010a, Framme et al., 2002). The AF is used as a non-invasive tool to evaluate the laser tissue interaction on the RPE metabolism (Muqit et al., 2009). It is used as an alternative of the established invasive procedure of fluorescent angiography. The autofluorescent signal was reported to become hyperautofluorescent for up to 3 years after the laser treatment therapy even though lack of autofluorescent were observed for the first 1 hour (Framme et al., 2002). Meanwhile, Muqit 2012 was able to detect the Pascal burns at all-time demonstrating the reliability of this method regardless of the visibility of the laser burns ophthalmoscopically. The FD-OCT on the other hand allows the non-contact in vivo visualisation of the retina up to an axial resolution of 5Âµm by using high acquisition speeds (25000 A-scan/s) initiating the possibility of evaluating the alteration of retinal architecture in depth (Muqit et al., 2009).
In a study by Muqit on the laser-tissue interactions and healing responses, 24 eyes were assigned to either receive 20- or 100- millisecond Pascal RPE and further evaluated by AF and FD-OCT. The results showed an increase in autofluorescence with the increased of pulse duration as well as the significant difference of greatest linear diameter (GLD) (Muqit et al., 2010a). At 4 weeks, all the burns were observed to correspond to the defects at the junction of inner and outer segments of photoreceptors. After 4 weeks, there is reduction of GLD of 20-milisecond burn by 35% (p<0.01) as opposed to no difference observed in 100- millisecond burns. Thus, it suggested the novel healing response localized to inner and outer segments of photoreceptors in 20- millisecond burns as it progressively reduce in size(Muqit et al., 2010a). On the other hand, 100- millisecond burns showed no healing responses as it develops larger defect presumably due to thermal diffusion and collateral damage(Muqit et al., 2010a). In another study, a healing of photoreceptors inner segment/outer segment was also observed using 20- millisecond laser burns as compared with 100- and 200- millisecond laser burns showing the healing response predominantly occur in short pulse duration laser therapy (Muqit et al., 2011). In a study using animal, the RPE was shown to photocoagulated and later regenerate with survival of adjacent photoreceptor in healing period when treated with short laser pulse (Roider et al., 1993). The healing response on the other hand was not observed in conventional laser burns due to irreversible photoreceptors damage. Thus, it is shown that the healing response is actually possible using new laser technology even though the exact underlying mechanism is still yet unclear.
2.4. RETINAL OXYGENATION LEVEL PRE AND POST LASER TREATMENT
The diabetic retinopathy is one type of ischemic disease in which the oxygenation of the retina plays a substantial role for the progression. The damage to the retinal capillaries gives rise to capillary non perfusion and subsequently causing the retinal hypoxia (Hardarson and Stefansson, 2012). The ischemic retina in turns stimulates the production of the cytokines specifically VEGF causing the formation of new blood vessels and oedema. The conventional laser treatment stop the neovascularization by mean of reducing oxygen consumption brought by the destruction of the high oxygen consuming photoreceptors and therefore creating the balance between oxygen supply and demand.
A study by Hardarson comparing the retinal oxygen saturation between normal and diabetic eyes showed that the oxygen saturation is significantly higher in diabetics rather than in control (Hardarson and Stefansson, 2012). The result was in agreement with Hammer et al who also found that the saturation increased with the severity of retinopathy (Hammer et al., 2009). The high oxygen saturation in diabetic retinopathy could represent the maldistribution of oxygen in which the oxygen is not efficiently delivered to the retinal cells contributing to the hypoxic cells and hyperoxic venular blood (Hardarson and Stefansson, 2012). The large and dilated capillaries in diabetic retinopathy causing an increase in the blood flow velocity resulting in poor oxygen uptake by the cells and trigger the hypoxic effect (Hardarson and Stefansson, 2012). Another reason of inefficient oxygen delivery from the blood to the retinal cell is the thickening of the capillary walls which cause an increase of diffusion distance from the vessels to the tissue (Hardarson and Stefansson, 2012). Thus, the evidences show that the oxygen perfusion is impaired in diabetic retinopathy as compared with normal creating retinal hypoxia. Concerning the effect oxygenation on the vessel diameter, it were reported to dilate during hypoxia and constrict when the oxygenation increase (Stefansson, 2001). The significant correlation was found between the vasoconstriction and the regression of neovascularization (Richard and Kreissig, 1985). On the other hand laser photocoagulation were also reported to produce retinal vasoconstriction in macular oedema and branch retinal vein occlusion (Arnarsson and Stefansson, 2000). In short, it is clear that the retinal oxygenation is disturbed in diabetic patients while the laser photocoagulation could reduce the diameter of vessels by increasing oxygenation.
Stefansson postulated that the changes in the oxygen flux after the conventional laser treatment is responsible to reduce the hypoxic tissue. Instead of supplying mostly the high metabolic photoreceptors, the oxygen flux from choriocapillaris could now reach the inner retina in absence of photoreceptors following the conventional laser treatment (Stefansson et al., 1981, Stefansson, 2001). According to him, such physiology works provided if the laser energy used is mild and therefore only damage the outer retina without damaging the inner part (Stefansson et al., 1981). As a result, the oxygen tension increased in the inner retina and hypoxia elevated (Pournaras, 1995). The corrected hypoxia will then decrease the production of VEGF and reduce the vascular permeability.
A considerable amount of studies using animals and diabetic patients were conducted supporting the increase of oxygen tension in the inner retina following laser treatment. It was first shown in 1981 by Stefansson in which he found that the retinal oxygen tension is much higher in areas treated by laser as compared to untreated areas in the same retina in rhesus monkey. A study done in miniature pigs also found a clear increase in oxygen tension in the photocoagulated regions (Molnar et al., 1985). Furthermore, Pournaras and co-workers found that the retinal hypoxia induced by branch retinal occlusion is reversible using laser treatment (Pournaras et al., 1985). Laser treatment also reported to be effective against macular oedema showing the effect of laser photocoagulation has on the retinal oxygenation (Arnarsson and Stefansson, 2000).
Despite unclear underlying mechanism of how the new micro pulse laser technology treats the PDR, some studies were done to see the oxygenation level afterward. Yu et al. measured the intraretinal oxygen distribution in pigmented rabbit using an oxygen sensitive microelectrodes. They found that the subthreshold micropulse can produce increase in intraretinal oxygenation level and reduce tissue oxygen consumption (Yu et al., 2005). Similarly, a study by Muqit et al. also demonstrated healing responses which occur along with improved tissue oxygenation at the location of laser burns and surrounding retina using 20- miliseconds laser (Muqit et al., 2011). They also noted that spatial oxygenation increased with the longer duration of laser pulse but resulted in more collateral tissue damage over time (Muqit et al., 2011). Though the amount of oxygenation to amend the consequences of retinal ischemia is still unknown, these findings suggested a benefit of partial destruction and thereby lessening the degree of scotoma produced by the laser treatment (Yu et al., 2005). In this study, we aim to measure the retinal oxygenation level of diabetic retinopathy patients after treated with the Pascal laser using multispectral imaging.
2.5. MEASUREMENT THE RETINAL OXYGENATION
To date various methods have been developed and introduced to measure the retinal oxygenation level. However, the methods of measuring retinal oxygenation were invasive traditionally limiting majorities of the studies done on experimented animals. These can be seen in studies by Stefansson and co workers, Yu et al and Molnar et al in which the animals recruited were rhesus monkey, pigmented rabbits and miniature pigs respectively (Stefansson et al., 1981, Yu et al., 2005, Molnar et al., 1985). The oxygen tensions in those studies were measured by using oxygen-sensitive microelectrodes as a function of retinal depth which were inserted through a small hole at the pars plana and thus demanding the animals to be anesthetized (Molnar et al., 1985, Yu et al., 2005). Regardless of the invasive nature, few studies have used this method to measure the oxygen effect of laser treatment in patients undergoing vitrectomy (Stefansson et al., 1992).
In clinical setting whereby the measurement of retinal oxygenation is difficult to be done, fluorescein angiography is often used to detect any subclinical signs of retinal ischemia. Unlike the invasive method as previously described, the fluorescein angiography does not give any value of retinal oxygenation. Instead, the level of retinal ischemia is interpreted by the angiogram produced by photographing the circulatory filling of the fluorescein as the dye injected to the systemic circulation. Despite regarded as the standard method to detect the ischemic region, the fluorescein angiography is yet invasive, might be unpleasant to the patients, time consuming and may be associated with adverse allergic reaction (Nourrit et al., 2010). Thus, a non-invasive method to measure the retinal oxygenation would definitely be an advantage and favourable as an alternative to fluorescein angiography as well as windows to further researches progress.
Various approaches has been undertaken to measure the oxygen saturation in blood and retinal tissue non-invasively using the retinal oximetry. The basic principles of oximetry involved the application of spectroscopy that uses the spectral information to deduce the oxygen saturation in the blood (Allaboud, 2009). It manipulates the difference in light absorption between oxygenated and deoxygentated haemoglobin using multiple wavelength reflectance oximetry (Allaboud, 2009). The measurement of retinal haemoglobin oxygen saturation using spectrophorometric was first initiated by Hickam et al. (1963). In their study, two vessel wavelength images were captured using standard photography and oxygen densities later analysed. The techniques were further refined using multiple spectral combinations as illustrated by Pitmann and Dully (1975) and Delori (1988) whom used three wavelengths of interest. Pitman and Dully choice of wavelengths comprises of two isobestic wavelengths to eliminate the scattering contribution from the optical model and employ more sophisticated algorithm analysis (Alboud,Pitman and Dully). In the latter study by Delori, the three wavelengths were narrowly spaced which further eliminate the light scattering effect by erythrocytes (Delori, 1985). Further advancement in retinal oximetry has seen to involve multiple wavelengths as illustrated by Schweitzer et al. (1999) whom used four wavelengths ranging from 510 to 586 nm rendering more accurate results. Despite of several studies attempted to quantify retinal oxygenation level, the accurate measurement is still an issue as inferior sensitivities might arise from the use of limited spectral wavelengths (Schweitzer, 1999). To cater this problem, multispectral imaging (MSI) was introduced to detect hypoxic change more accurately by gathering more information to account for confounding influences in the retina (Alabboud, 2009)Recently, most of the spectral cameras manipulate the use of multiple wavelengths of more than five to be able to quantify the retinal oxygenation which is so called multispectral or hyperspectral imaging. In our study, we use MSI with modified fundus camera to measure the retinal oxygenation level of diabetic retinopathy patients post treated with laser photocoagulation.
Beside the methods previously discussed, some researchers have attempted to noninvasively measure the retinal oxygenation response using MRI (Trick et al., 2006). In this MRI oxymetry, change in signal intensity between T1-weighthed MRI images during normal air room breathing and those obtained in either oxygen or carbon inhalation challenge is regarded as retinal oxygenation response. The results which exhibited a significant increase in retinal oxygenation response in diabetic patients as compared to normal was in agreement with studies who found out an altered retinal oxygenation in diabetics (Hardarson and Stefansson, 2012). Trick et al. further observed that the retinal oxygenation response in type 1 diabetic patients were also significantly supernormal even before the retinopathy appearance suggesting the novel possibility of MRI to monitor therapeutic efficacy in human trials (Trick et al., 2006). The drawbacks of this method are the discomfort in the magnet and artefacts created by the excessive head movements as well as still lacking literatures (Trick et al., 2006).
2.6. MULTISPECTRAL IMAGING FOR MEASURING RETINAL OXYGEN LEVEL
Advancements in the optical technology namely the more sensitive camera and high speed filters have enabled the multispectral imaging with high spatial resolution (Nourrit et al., 2010). MSI or hyperspectral imaging has gained numerous attentions in detecting retinal disease as well as quantifying retinal oxygenation level (Nourrit et al., 2010). With respect to detecting retinal diseases, MSI offer advantages of having both high spatial resolution as well as keeping wide ranges of spectral information over others fundus imaging techniques (Nourrit et al., 2010). Nouritt et al. (2010) demonstrated in his study that some retinal features are more visible at certain wavelength, ie the retinal nerve fibre layers are more visible at 496nm and less visible at 586nm while abnormal blood vessels is best observed at 580nm. This advantage is brought by the nature of light propagation in which the light penetrates to different depths of retina as the wavelength change (Alabboud, 2009). The light illuminates the retinal background and vessels at wavelengths 530-580nm and it starts to penetrate the vessels to reach choroid at more than 640nm (Alabboud, 2009). In addition, the non-invasive nature of MSI is a further advantage over the established procedure of fluorescein angiography in diagnostic field.
There are two different strategies of acquiring multispectral images; simultaneous and sequential (Gautam). In the first technique, the recording of the spectral and spatial information is done simultaneously by either imaging on a series of monochromatic images or separating spatial and spectral information by posterior rather on the sensor (Gautam). In the latter technique, the spectral images are recorded sequentially through various approaches. The retina is illuminated with monochromatic light either from monochromatic source or using white light source filtered monochromatically (Gautam). The sequential technique provides advantages of relative optical simplicity, flexibility and versatility in which the selection of wavelength and exposure time could be adjusted independently (Nourrit et al., 2010). The MSI in our study is manipulating the sequential technique in which 250W lamp filtered by a fast tunable liquid crystal filter (Varispec VIS 07 to 20 STD; Cambridge Research Instrumentation, Cambridge UK) (Muqit et al., 2011). Due to the longer acquisition time in sequential technique, some extra post processing is required to compensate for the eye movement (Nourrit et al., 2010).
The oximetry maps were generated using a standard Beer-Lambert law model; A(Î»)= c1 x Îµ1 (Î») + c2 X Îµ2 (Î») + c3 X Îµ3 (Î») with A(Î») being absorbance and c1,2.3 are the contribution of oxyhemoglobin (Îµ1), deoxyhemoglobin (Îµ2) and tissue scattering (Îµ3) (Alabboud, 2009, Nourrit et al., 2010). The generated maps calculated by Beer-Lambert law were represented pixel-by-pixel with the brighter areas indicate higher oxygenation while the darker areas indicate lower oxygenation (Nourrit et al., 2010, Muqit et al., 2011). Fig. 1 represents an example of oxygenation map obtained in our study.
In reviewing the literature, there is still few study attempted to research the role of MSI in measuring the retinal oxygenation in the vessels or tissue. A pioneer study by Beach et al. (1999) using dual wavelengths reported a significant decrease in retinal venous of blood oxygen saturation during hyperglycaemia (Beach et al., 1999). In another study by Mordan et al. using hyperspectral imaging of wavelengths between 556-650nm using patients with branch retinal artery occlusion, they identified lower oxygen saturation values at the location of occluded arteriole. Their method however suffers main disadvantage of long acquisition time of approximately 10-15 minutes and cumbersome subsequent analysis (Mordant et al., 2011). McNaught et al. on the other hand tried to research the feasibility of MSI techniques (sequential and simultaneous) on measuring oxygen saturation in both normal and people affected by retinovascular disease. They found that both methods provided accurate estimation of vessel oxygen saturation as validated with model eye system. They further observed significantly higher oxygen saturation in retinal venules adjacent to new vessels than in normal.
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