International clinical disease severity scale for diabetic retinopathy [14].
\r\n\t- BMD measurement technology
\r\n\t- Osteoporosis and fracture risk
\r\n\t- Bone growth and remodeling
\r\n\t
\r\n\tThe submission is also open to any other original study related to these research topics.
The prevalence of diabetes is endemic in the United States and developed countries. According to the 2018 reports it is estimated that the United States has more than 31 million adults diagnosed with diabetes [1]. Diabetes prevalence remains underestimated with approximately one in four individuals that have diabetes are undiagnosed [1]. There are various forms of diabetes and individuals with Type 2 diabetes (T2DM) account for 90–95% of all cases of diabetes within the US [1]. The incidence of diabetes is also likely to increase with 88 million individuals are diagnosed to be pre-diabetic who have potential ongoing subclinical damage [1]. The prevalence of diabetes mellitus in the US is predicted to reach 36 million by the year 2045 and will continue to pose a significant global health problem [2].
Nearly half a billion people are currently living with diabetes globally, and the total number of cases is projected to surge by 25% (578 million) in 2030 [3, 4] and to 700 million by the year 2045 [3, 4, 5]. Diabetes is severely underdiagnosed condition with one in two people (50.1%) currently living with the condition are unaware [3, 4] . The International Diabetes Foundation estimates the socioeconomic burden of diabetes to be USD 760 billion and potentially increase to USD 845 billion by 2045 [2]. The global estimates of socioeconomic burden are predicted to rise in response to the increasing prevalence of diabetes, improved survival rates (longer life expectancy with the condition), and consequently prolonged duration of diabetes mellitus [3, 4, 6, 7, 8].
Diabetic retinopathy (DR) is characterized by the hallmark feature of retinal capillary degeneration that could lead to, significant visual impairment. The natural history of unmanaged or poorly managed diabetic retinopathy leads to proliferative retinopathy (PDR) and/or macular edema [9, 10]; contingent upon the disease-severity, these complications may arise individually or simultaneously. DR affects roughly one in three individuals with diabetes and its severity is closely linked to both the duration of diabetes and the glycemic load [5, 6, 11, 12]. It is estimated that 4.1 million individuals in the US are afflicted with DR, and 899,000 of which are affected by vision-threatening retinopathy [1]. The global prevalence of DR is estimated to affect 146 million adults and projected to reach 191 million by 2030 [3, 4, 8]. Currently, DR remains a leading cause of irreversible, yet preventable, vision loss among adults and is associated with a poorer quality of life, increased susceptibility for developing further complications, and considerable rise in healthcare expenditures [5, 12].
Clinically, retinopathy is routinely graded upon its presenting clinical features during ophthalmic examination in accordance with the International Clinical Disease Severity Scale for DR [7, 10, 13, 14, 15, 16]. The five-stage disease severity classification system (Table 1) was created using prior clinical trials: the Early Treatment Diabetic Retinopathy Study (ETDRS) and the Wisconsin Epidemiological Study of DR (WESDR) [14, 15, 16, 17]. The stages of non-proliferative diabetic retinopathy (NPDR) are based on the severity of microvascular abnormalities limited to the surface of the retina; in addition to reflecting the patients’ risk of developing more advanced, vision-threatening retinopathy. Examination of NPDR by ophthalmoscopy may reveal the presence of microaneurysms, hard exudates, intraretinal hemorrhages (“dot and blot” shaped), and intraretinal microvascular abnormalities (such as tortuous sinus shunt vessels) [14, 15, 17].
Disease Severity Scale | Clinical Features |
---|---|
No apparent retinopathy | No fundus abnormalities |
Mild NPDR | Microaneurysms only |
Moderate NPDR | More than just MAs, but less than severe NPDR |
Severe NPDR | Any of the following: (with no signs of PDR) extensive DBH in each of 4 quadrants (+20/quadrant), venous beading in at least 2 quadrants, and/or IRMA in at least 1 quadrant |
PDR | One or more of the following: neovascularization, tractional retinal detachment, or vitreous/preretinal hemorrhage |
International clinical disease severity scale for diabetic retinopathy [14].
Progressive oxidative injury in NPDR is evident within the vasculature, by the presence of acellular capillaries and endothelial apoptosis. This injury is further exaggerated within local tissue by the onset of capillary nonperfusion and vascular occlusion that may develop in the disease [13, 18, 19]. The resultant retinal injury due to ischemia further exacerbate pro-oxidant and pro-inflammatory mechanisms by compromising oxygenation of the metabolically demanding retinal neurons. This in turn promotes angiogenesis through the release of vascular endothelial growth factor (VEGF) [13, 18, 19, 20]. The retinal neurodegeneration induced by hypoxia can be observed by the presence of abnormal fluffy white patches known as cotton wool spots, upon fundoscopic examination [19]. The ensuing retinal neovascularization indicates the clinical progression of NPDR into the advanced-stages of PDR. These aberrant new blood vessels are fragile and ineffective in restoring tissue perfusion because they grow from the retinal surface and towards the posterior pole of the vitreous cavity [7, 10, 13, 16]. Thus, subsequent risk of acute vision loss is evaluated on the extent of neovascular proliferations, particularly on/near the optic disc, which perniciously emanate from the steady vasculature of the retina.
Diabetic macular edema (DME) develops when fragile or damaged capillary beds leak and cause thickening of macula due to fluid accumulation. Alterations in the microvasculature such as endothelial cell proliferation and retinal pericyte necrobiosis gradually enhance the vascular permeability, which ultimately causes the breakdown of the blood-retinal barrier [13, 18]. The progressive deposition of fluid and proteins can amass on or under the macula which can be clinically examined by optical coherence tomography (OCT), identifying areas of diffuse retinal thickening or hard exudates, indicating the extent of focal leakage [21, 22]. Alternatively, onset of macular edema can occur during any stage of retinopathy (NPDR or PDR) leading to vision loss [6, 13].
Traditionally, diabetic eye disease has largely been considered to be a microvascular end-organ complication of diabetes mellitus. The severity of retinopathy correlates with the susceptibility of further complications such a peripheral neuropathy, nephropathy and cardiovascular disease [6, 11, 12, 23, 24, 25]. It is established that chronic hyperglycemia promotes oxidative injury in the highly-susceptible retina; in part due to high metabolic demands and constant light exposure [26, 27]. However, a growing body of evidence strongly implicates retinal neurodegeneration is potentiated by pro-oxidant and pro-inflammatory processes during the early pathogenesis of DR. Indications of retinal dysfunction that can be detected in diabetic patients even prior to manifestation of clinical signs of retinopathy [6, 12, 19, 25, 27, 28, 29, 30, 31]. Appropriately, the American Diabetes Association defines DR as a highly tissue-specific neurovascular complication and has identified several modalities of management of disease and its progression [7, 11, 28].
The body’s inherent defense against oxidative damage, involving the neutralization of reactive oxygen species (ROS), relies upon the interplay between both endogenous and exogenous antioxidants to maintain redox homeostasis [27, 32]. The interdependence between hyperglycemia, oxidative stress, and changes in redox homeostasis are essential facets in the pathology of diabetic retinopathy [26, 32]. In particular, exogenous antioxidants such as vitamin C, vitamin E and xanthophyll carotenoids (including lutein, zeaxanthin and
Recently, the onset of diabetes in experimental murine models consistently demonstrated a significant increase in pro-oxidant and pro-inflammatory molecules, such as malondialdehyde, oxidatively damaged DNA, and VEGF [37, 38, 39, 40, 41, 42, 43, 44, 45]. Importantly, administration of antioxidants including lutein and/or zeaxanthin was demonstrated to effectively prevent, and in some cases reverse, the hyperglycemia-induced changes in oxidative stress and inflammation [37, 38, 39, 40, 41, 42, 45]. The beneficial effects of lutein and zeaxanthin were shown to augment the endogenous antioxidant defense system by improving retinal concentrations of glutathione (GSH) and glutathione peroxidase (GPx) [37, 38, 39, 42]. The antioxidant and anti-inflammatory effects of lutein and zeaxanthin were also shown to attenuate the microvascular abnormalities that characterize DR pathology, in addition to protecting the retina against accelerated vasoregression that may proceed alterations in the vasculature [37, 38, 39, 40, 41, 42, 43, 44, 46].
To date, only a limited number of observational [26, 32, 47, 48, 49, 50, 51, 52, 53], and randomized-controlled trials [35, 54] have investigated the association of macular pigment optical density (MPOD) levels in diabetic eye disease. Generally, the evidence suggests that MPOD levels are lower in individuals with diabetes when compared to healthy controls [48, 51], and some studies indicate MPOD status may differ between types of diabetes (type 1 and type 2) [26, 32, 50]. MPOD depletion was also negatively correlated with the presence of retinopathy in T2DM [26, 32, 50] and may be attributed in part due to oxidative stress [49]. These findings are promising and begs for additional investigation to substantiate the beneficial role of carotenoid vitamin therapy in the management of diabetic eye disease.
Sensible, relatively inexpensive techniques to evaluate the status of macular carotenoids can serve as important biomarkers in monitoring retinal health in individuals with diabetes and increased risk of retinal neurodegeneration. Biomarkers serve as important tools with significant potential for innovating novel drugs and substantiating the safety and efficacy of available therapies [55, 56]; however, their application is not limited to clinical research and extends into improving clinical practice and establishing public health guidelines. The concept of biomarkers is delusively simple, with which a single biomarker may satisfy the criteria for several different purposes; therefore, it is critical to establish scientific justification how a particular biomarker will be defined according to its situation-specific application. Thus, several categories of biomarkers have been established by the FDA-NIH’s “Biomarkers, EndpointS, and other Tools (BEST)” resource, described in more detail elsewhere [55, 57]. Moreover, by establishing the context of use, this directly expounds the nature, objective and methodology intended for utilizing a biomarker within a particular setting [55, 57, 58].
Advancements in retinal imaging modalities have allowed MPOD status to serve as a biomarker in multiple settings for diabetic retinal disease, including: (1) prognostic biomarker for screening individuals with sub-clinical disease with no overt retinopathy; (2) identification of surrogate biomarkers for the prediction of low MPOD in T2DM; and (3) monitoring biomarker for evaluating the efficacy of carotenoid supplementation on DR. The depletion of MPOD in diabetes has been consistently reported in a number of cross-sectional studies, and some suggest that low MPOD may be a potential clinical feature of T2DM [26, 32, 48, 49, 50, 51]. Studies have demonstrated significant correlations between MPOD and central subfield thickness, retinal volume, and photoreceptor outer segment length in diabetic and healthy controls [59, 60, 61]; thus, clinical measurements of MPOD levels may serve an important role in early-detection of retinal neurodegeneration and prognosticating treatment outcomes. Furthermore, one study identified possible surrogate biomarkers including smoking status, hypertension, and vitamin D insufficiency, that may predict low MPOD in T2DM [32]. Alternatively, serial MPOD measurements have been used as a monitoring biomarker to assess the benefits of the antioxidant micronutrients on visual performance and features of NPDR in Type 1 (T1DM) and T2DM [35]. Based on the systematic review conducted MPOD is found to be a prognostic, surrogate and monitoring biomarker as defined by the FDA-NIH [55].
The macular pigment is comprised of three lipid-soluble carotenoids: including lutein, zeaxanthin, and
Macular carotenoids are quantified by the macular pigment optical density (MPOD) and are associated with maintaining retinal health and optimal visual performance; suggesting that MPOD levels may serve as an important biomarker in health and diseased states [63, 65, 69, 72]. Research suggests that carotenoids serve to protect the retina, specifically the macula, via two proposed methods: 1) they act as a filter against blue light, and 2) they reduce oxidative stress and inflammation in the retinal tissue [63, 69, 72, 73, 74, 75, 76]. The macular pigment attenuates the amount of blue light that reaches the photoreceptor cells, due to the peak wavelength of MPOD’s absorption spectrum (peak ~460 nm) which lies within the range of blue light on the visible light spectrum (400-500 nm); and may provide some preservation and improvement in visual function [62, 76, 77]. Short wavelengths of blue light are of high energy, which can prompt the formation of ROS and induce oxidative injury; causing damage to the lipid bilayer of cell membranes, proteins and DNA, and cause mitochondrial dysfunction leading to cellular necrosis [63, 74, 75, 76, 77, 78]. Thus, the neuroprotective capabilities of the macular carotenoids in the retina, namely MPOD levels, have led researchers to further investigate the role of MPOD levels and its depletion in various ocular diseases.
Techniques to quantify MPOD levels may also serve as susceptibility/risk biomarkers for diabetic eye disease, prior to indications of retinopathy that become clinically evident. Meanwhile, more expensive and advanced imaging modalities such as OCT, can play a more significant role in prognosticating outcome or determining course of treatment [79]. Several methods have been described aiming to effectively quantify levels of MPOD non-invasively in clinical settings; categorized by either psychophysical (subjective) or objective techniques [65, 69, 80]. In brief, these techniques are differentiated by patient-response, or participation required from the individual being evaluated, and requiring minimal participant-involvement to collect measurements, respectively [65, 69, 80, 81].
The clinical measurements of MPOD levels are primarily heterochromatic flicker photometry (HFP) [65, 69, 80, 82, 83, 84]. HFP technology is based on a stimulus of light, alternating between two wavelengths, that differ according to the retinal absorption spectrum of macular pigments (400-540 nm); a short-wavelength blue light maximally absorbed by the pigments, and a longer-wavelength (green) stimuli with minimal absorption [65, 69, 81]. Briefly, current HFP devices collect measurements in the fovea by adjusting the intensity of the target-stimuli, which is perceived as flickering light, according to the participant’s involvement indicating the appearance of flickering light; estimating the level of MPOD as the difference in responsive sensitivity (of blue- and green-wavelength flicker) required at the fovea [65, 69, 81, 83, 85, 86, 87]. Thus, individuals with higher MPOD would require greater intensity blue light (perceive less blue light) at foveal measurements as a result of higher concentrations of macular pigment in the fovea [65, 69, 81, 88].
Objective techniques such as reflectometry [89, 90, 91, 92, 93, 94], fundus autofluorescence [95, 96, 97] and resonance Raman spectroscopy [66, 98, 99], are all non-invasive,
The topic of debate for more than three decades, each technique exhibits unique advantages along with clinical limitations that have been discussed in more detail elsewhere [80, 95, 96, 100, 102]. The heterochromatic flicker photometry is the current gold standard of MPOD measurement.
A systematic review was performed and published articles on the topic were identified using database searches from PubMed and Web of Science indexes. We identified all relevant publications which reported on the association between diabetic retinopathy and MPOD/carotenoids (lutein and/or zeaxanthin and/or
The therapeutic benefits of macular carotenoids have been documented in diabetic murine models, investigating the molecular mechanisms underlying the onset of hyperglycemia-linked retinopathy; in particular, the protective effects of lutein (L) and/or zeaxanthin (Z) on the progression of retinal neurodegeneration [37, 38, 39, 40, 41, 42, 43, 44, 45]. Data from these reports are consistent in providing further evidence that administration of L and Z may delay or prevent the onset of DR by counteracting the proposed causative factors including oxidative stress (by attenuating ROS production with a concomitant regeneration of endogenous antioxidants), in addition to ameliorating inflammation and augmenting neuroprotection of retinal tissue. Administration of the drug Alloxan or Streptozotocin (STZ), which are toxic glucose-analogs that preferentially amass within the pancreatic beta cells that produce insulin, are commonly used for inducing diabetes mellitus in mice and rats, which will later develop retinopathy [37, 38, 39, 40, 41, 42, 43, 105, 106, 107]. Genetic murine models, including the leptin-receptor deficient (db/db) mice, spontaneously develop hyperglycemia and obesity at 4–8 weeks of age [44, 45, 106, 107]. A summary of the experimental animal models evaluating the effects of carotenoids administration on diabetic eye disease is outlined in Table 2.
Study | Design (DM induced by) | L and/or Z | Effect of L/Z on Outcomes |
---|---|---|---|
Arnal et al. [37] | Rats (STZ) | L | prevented loss of retinal thickness |
Kowluru et al. [39] | Rats (STZ) | Z | ameliorated rise in 8-OHdG |
Kowluru et al. [40] | Rats (STZ) | L and Z | significantly reduced total ROS levels |
Muriach et al. [42] | Mice (A) | L | restored levels of GSH and GPx |
Sasaki et al. [43] | Mice (STZ) | L | prevented cell loss in GCL & INL |
Tang et al. [44] | Mice (db/db) | L and Z* | improved central retinal thickness |
Yu et al. [45] | Mice (db/db) | L and Z* | enhanced mitochondrial biogenesis |
Effects of carotenoids lutein and/or zeaxanthin in experimental animal models for diabetic eye disease.
DM = diabetes mellitus; L = lutein; Z = zeaxanthin; STZ = streptozotocin; A = Alloxan; db/db = leptin-receptor deficient; 8-OHdG = oxidatively modified DNA; ROS = reactive oxygen species; GSH = glutathione; GPx = glutathione peroxidase; GCL = ganglion cell layer; INL = inner nuclear layer.
* = Wolfberry.
Hyperglycemia-induced oxidative damage has been strongly considered the causative factor in the onset and development of diabetic retinopathy; resulting from the proliferation of pro-oxidant stressors if left untreated. Following the onset of diabetes in mice and rats, there was a significant increase in retinal markers of oxidative stress including: malondialdehyde, lipid peroxide, oxidatively-modified DNA (8-hydroxy-2’deoxyguanosine, 8-OHdG), and nitrotyrosine [37, 38, 39, 40, 42]. However, reports were consistent in demonstrating that administration of antioxidants (L and/or Z) ameliorated the diabetes-induced increase in these markers of oxidative stress, comparable to levels observed from control animals. Furthermore, one study evaluated the effects of an AREDS-based formula containing antioxidant micronutrients which were shown to attenuate the rise in expression of oxidative stress-related genes modulated by chronic hyperglycemia [38, 40, 108, 109]. Similarly, two clinically distinct features of early-stage retinopathy, microvascular lesions and retinal capillary degeneration, were prevented following treatment with alpha-lipoic acid, a micronutrient with antioxidant properties commonly included in carotenoid supplements for clinical use, such as the EyePromise Diabetes Visual Function Supplement Study (DVS; DiVFuSS) formulation by ZeaVision (MO, USA) [33, 38, 110, 111, 112]. Supplementation treatment with L and Z prevented increase in total retinal ROS levels in rats, suggesting they may prevent the continuation of superoxide free radical production caused by hyperglycemia and subsequent progression of retinopathy [41, 108, 113].
The supplementation of L and Z also attenuates retinal expression of endoplasmic reticulum stress biomarkers like BiP (binding-immunoglobulin protein), PERK (protein kinase RNA-like ER kinase), ATF6 (activating transcription factor 6), and activate caspase-12, in diabetic mice [42, 44]. The administration of L and Z also prevented diabetes-induced dysfunction of the mitochondria and damage to mitochondrial DNA (mtDNA), which was confirmed by enhanced expression of mtDNA-encoded proteins of the electron transport chain [41]. Wolfberry, a traditional Asian fruit containing large amounts of diester forms of L and Z protected against mitochondrial stress and markedly enhanced retinal expression of proteins involved in mitochondrial biogenesis [44, 45, 114]. Thus, L and Z reduced oxidative injury on retinal mitochondria by possibly restoring the effective transfer of electrons during oxidative phosphorylation and attenuating mitochondrial dysfunction.
The metabolic correlates of diabetes, such as insulin resistance, insulin deficiency, hyperglycemia and hyperlipidemia have been linked with inhibition of the endogenous antioxidant defense system, caused by overwhelming generation of pro-oxidant stressors and compromised antioxidant capacity. Restoration of endogenous antioxidant levels, such as GSH, GPx and manganese superoxide-dismutase (MnSOD) are essential for nutrient metabolism, regulation of gene expression, free radical neutralization and inhibition of pro-inflammatory pathways [115, 116, 117, 118, 119, 120]. In the diabetic retina, regeneration of GSH is compromised by reduced GPx activity and redox cycle [121, 122]; however, L and/or Z reversed the hyperglycemia-induced impairment in GSH and GPx activity in the retina [37, 38, 39, 42]. Similarly, diabetic impairment of total antioxidant capacity was sufficiently prevented with supplementation of L and Z [41] along with restoration of MnSOD activity and mRNA expression following administration of AREDS-based micronutrient formula [39, 40, 44].
Carotenoids may prevent the development of DR by suppressing pro-inflammatory pathways activated by overexpressed superoxide free radicals and oxidative injury which are significant contributors in this low-grade chronic inflammatory condition [115, 116, 118]. Metabolic and oxidative insults associated with hyperglycemia can promote induction of inflammation, and concurrently, inflammatory processes can induce oxidative stress. Administration of antioxidants (including L and Z) has been demonstrated to inhibit increased-activation of retinal redox-sensitive nuclear transcriptional factor-B (NF-kB), an important transcriptional regulator of cytokines and growth factors [38, 41, 42, 123, 124, 125, 126]; in addition to suppression of pro-inflammatory cytokine, interleukin-1β [41, 124]. Increases in pro-angiogenic factors such as VEGF, which significantly contribute to the neovascularization of PDR, were effectively prevented by L and Z in both rats and mice [39, 41, 45, 126]. However, increased levels of VEGF also play a significant role in the early-stages of retinopathy, by enhancing cell permeability of vascular and non-vascular retinal cells [116, 118, 119, 120, 126, 127]. Impaired glutamate metabolism in glial cells, resulting from diabetes, may lead to vascular instability in adjacent blood vessels [128, 129]; these changes in glial cell permeability often occur rapidly as a result of hyperglycemia, contributing to neural degeneration and may result in DME [127, 128, 129]. Thus, the protective effects of L and Z are effectual in attenuating multiple inflammatory response pathways and may preserve the retina from adaptive changes in microvasculature.
Clinical findings of early-stage retinopathy are currently characterized by pathogenic alterations in retinal vasculature, represented by microvascular abnormalities like vasoregression, along with choroidal occlusion and leakage [127, 130]. However, there is growing evidence in animal models that alterations in non-vascular cells (such as Mullers, bipolar, amacrine, and photoreceptor cells) are evident prior to the development of vascular abnormalities [131, 132]. The effects of L in retinal ischemic/reperfusion injury, a clinical feature of PDR, demonstrated improvements in cell viability and enhanced survival of Muller glial cells [133, 134]. Meanwhile, accelerated decline of total retinal thickness, including the inner nuclear layer (INL), outer nuclear layer (ONL), inner plexiform layer (IPL) and ganglion cell layer (GCL; thickness and cell number) were sufficiently prevented by L and/or Z in experimental murine models [37, 43, 44]. Significant thinning of the photoreceptor layer (inner segment and outer segment) and structural abnormalities (nuclear distribution) of the ONL were prevented by L and Z (wolfberry) in db/db mice [44]. The alterations in retinal histology, caused by diabetes mellitus, are closely linked with apoptotic oxidative injury in vascular cells; observed in humans and animals. Prevention of capillary cell apoptosis, determined by terminal deoxyribonucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-staining, and increases in degenerative (acellular) capillaries, was achieved by L and/or Z; regarded as a surrogate endpoint for DR-therapeutic development and hallmark sign of early-stage NPDR, respectively [37, 38, 39, 40, 41, 43, 111, 112]. Thus, the neuroprotective potential of L and Z in maintaining the retina, an integral part of the central nervous system, is essential in preventing neural degeneration and irreversible vision loss.
Visual performance dysfunction caused by retinal degeneration, observed by electroretinogram (ERG) in the inner retinal layers, show a decrease in oscillatory potentials (OPs; OP3 and total OPs) in diabetic mice [43]; similar functional impairment observed clinically in early-stage retinopathy [135, 136, 137]. Similarly, the neuroprotective effects of L and Z were observed in ERG recordings which indicated the preservation of b-wave latency and a-wave/b-wave amplitudes, restoring retinal dysfunction induced by diabetes [37, 41, 42, 43]. Synaptophysin, a synaptic vesicle protein that plays an important role in neuronal synaptic network activity, is also reduced in diabetic retina [43]; which is caused by chronic activation of pro-oxidant extracellular signal-regulated kinase (ERK) [138, 139]. In the retina of hyperglycemia-induced mice, administration of L preserved synaptophysin protein and suppressed ERK activation. This provides evidence of neuroprotective potential of L to help maintain synaptic activity [43, 137]. Furthermore, supplementation of L demonstrated enhanced preservation of neural activity by restoring expression levels of retinal neurotrophic factor, BDNF (brain-derived neuronal trophic factor) [43]; an important mediator of synaptic network activity and cell survival in the inner retinal and ganglion cell layers [140, 141, 142, 143]. The neuroprotective benefits of L and Z observed in animal models may be explained by supporting cell survival and increased viability and thus, enhancing overall visual function.
There are some limitation to the findings from animal models. Briefly, lack of studies on the effects of L and Z in non-murine models, restricts the translative potential for clinical use due to species differences between humans and rodents; namely, absence of the macula in these animals [144, 145]. Retinal preservation and neuroprotection with L and/or Z were observed in some [38, 42, 43, 44, 45] but not all [37, 39, 40, 41] studies, independent of any change in hyperglycemic status and thus, interpretation of these findings must be exercised with prudence. Moreover, the dosage of L and Z tested in experimental models is typically inflated to significantly higher amounts than those observed in clinical application to achieve a dose-dependent effect, which may prompt the necessity for renewed clinical trials to determine safety and toxicity of these carotenoids in larger amounts. It is not an exaggeration to conclude that these animal model experiments of diabetes provide substantial evidence in support of the putative anti-angiogenic and anti-inflammatory benefits of carotenoids lutein and zeaxanthin in protecting against retinal neurodegeneration.
To date, a limited number of studies have examined the complex association of macular carotenoids levels and diabetic eye disease in individuals with type 1 and type 2 diabetes [26, 32, 35, 47, 48, 49, 50, 51, 52, 53, 54]. Studies evaluating the relationship between serum levels of L and Z and DR demonstrated that: (1) serum concentrations of L and Z were lower in patients with DR when compared to healthy controls; (2) higher plasma concentrations of non-pro-vitamin A carotenoids (including lycopene, L and Z) were associated with lower risk of developing or progression of retinopathy in T2DM, after adjusting for potential confounders; (3) supplementation with carotenoid vitamin therapy may improve visual function and features of macular edema in patients with DR [47, 54]. It is known that carotenoid levels in the plasma are positively correlated with concentrations in the macular pigment [71, 146]. However, there are limitations when measuring serum levels to evaluate the effects of L and Z on DR, namely that their concentrations are almost entirely dependent upon relatively-recent dietary-behaviors; fluctuations that can occur in response to dietary intake of high-glycemic index foods and/or sugar-sweetened beverages [147, 148, 149, 150]. Moreover, these dietary habits, similar to those in the Western diet, have been attributed largely to the prevalence and onset of the metabolic syndrome [147, 148, 149, 151, 152].
Several studies investigated the putative role of L and Z in attenuating the pathogenesis of DR by evaluating levels of MPOD in cohorts that included both type 1 and type 2 diabetes [26, 32, 35, 48, 49, 50, 51, 52, 53]. The findings from these reports suggest the following: (1) MPOD levels are lower in patients with diabetes, in particular T2DM, than healthy individuals; (2) in T2DM, MPOD was inversely associated with several behavioral, anthropometric, and novel serum biomarkers such as vitamin D insufficiency; (3) MPOD levels can be augmented with dietary supplementation in patients with diabetes (type 1 and 2) [26, 32, 47, 48, 49, 50, 51, 52, 53]. Generally, reports are consistent suggesting MPOD levels are significantly lower in individuals with diabetes, and a negative correlation has been indicated between severity of diabetic maculopathy and level of macular carotenoids [48, 49, 51]. The type of diabetes also had a statistically significant difference on MPOD when accounting for other covariates (including history of smoking, hypertension and bodyweight) [26, 32, 50]. Current smoking status and increased adiposity are potential predictors of low MPOD in diabetes [26, 32] and concomitantly, one study found low serum vitamin D (≤50 nmol/L; P = 0.006) was significantly correlated with MPOD in T2DM after multivariate regression analysis [32]. The DiVFuSS study demonstrated that carotenoid supplementation, which included antioxidant micronutrients such as alpha-lipoic acid and vitamin D3, can significantly improve MPOD levels (mean increase of 27% in participants on active supplement) and measures of visual function in patients with diabetes (with no retinopathy) and those with mild to moderate NPDR [35, 109, 153].
Evidence suggests that the MPOD depletion may be a clinical feature of T2DM, however, the proposed causal mechanisms may elucidate distinct contributing factors in the development of diabetic retinopathy; mechanistic associations with MPOD status that may differ between type 1 and type 2. Metabolic comorbidities observed in T2DM including increased adiposity and dyslipidemia, primarily characterized by reduced high-density lipoprotein (HDL) and hypertriglyceridemia, may substantially compromise the bioavailability of dietary carotenoids. Thus, diminished transport and assimilation of serum L and Z into the macular pigment may be directly represented by low MPOD levels [154, 155, 156, 157, 158, 159, 160, 161]. Not surprisingly, L and Z are regularly deposited into visceral and subcutaneous adipose tissue, major body sites for carotenoids, which may make them less available to retinal tissue. In fact, reports have demonstrated higher percentages of body fat and body mass index (BMI) are inversely associated with MPOD levels [155, 158, 162, 163, 164]. Adipose concentrations of macular carotenoids vary according to the body site, coordinated by the hormonally-regulated deposition and mobilization of fatty acids, with demonstrably elevated levels in abdominal fat [164, 165, 166]; which may also explain sex-based differences observed in MPOD levels [154, 161]. Metabolic correlates like dyslipidemia may further contribute to low MPOD in T2DM by compromising the transport of plasma carotenoids to the retina in consequence of increased serum triglycerides to HDL (TG/HDL) ratio concurrent with worsening insulin resistance [166, 167, 168]. Furthermore, evidence suggests that serum carotenoids are predominantly transported by HDL particles and retinal absorption of L and Z is mediated by a ‘piggy-back’ mechanism involving scavenger receptor class B type-1 (SR-1B) in the RPE [157, 159, 169].
The depletion of MPOD in T2DM or poorly controlled T1DM is likely dependent upon the complex interplay between the development of metabolic perturbations including increased adiposity, dyslipidemia, insulin deficiency and hyperglycemia and the oxidative stress and inflammation induced by diabetes mellitus. Traditionally, adipose tissue has mainly been considered in the context of energy storage, however, they produce a variety adipocytokines and inflammatory mediators and has been suggested to function like a metabolically-active immune organ [170, 171]. In fact, increased intra-abdominal fat is a crucial determinant of the atherogenic lipid profile in T2DM with obesity, and research indicates visceral adipose tissue may be the principal mediator of inflammation associated with diabetes [172, 173, 174]. Therefore, this chronic low-grade inflammatory disease in turn exacerbates oxidative injury, causing a positive feedback loop between oxidative stress and inflammation, which may lead to compounding depletion of macular pigment concentrations [35, 115, 152, 175, 176, 177]. The elevated serum concentrations of a marker for total systemic oxidative stress
Results from these [26, 32, 35, 48, 49, 50, 51, 52, 53] clinical studies that have investigated the implications of MPOD on diabetic eye disease are promising, but not without limitations: (1) with one exception [26], individuals with T1DM and T2DM were evaluated and analyzed homogeneously in comparison to controls; (2) only a limited number of studies evaluated cohorts based on status of DR; (3) relatively small and unequal sample sizes (of individuals with diabetes and controls) in multiple studies; (4) with one exception [35], studies were only observational in nature. Additional research is necessary to further elucidate the potentially different associations that may exist between MPOD status and T1DM and T2DM.
Diabetic retinopathy is the most common microvascular complication of diabetes mellitus and DR remains the leading cause of preventable blindness in developed countries among working-age adults. It appears chronic hyperglycemia has significant deleterious effects on the endogenous defense systems, resulting in the depletion of macular carotenoids lutein, zeaxanthin and
The authors would like to thank the Assessment & Public Relations Librarian from Western University of Health Sciences, Rudy Barreras for his counsel in conducting the systematic review.
Drake W. Lem none. Dr. Pinakin Davey is a consultant and has received research grants from ZeaVision and Guardion Health Sciences. Dr. Dennis L. Gierhart is an Employee, Chief Scientific Officer for ZeaVision manufacturer of various nutritional supplements including the DVS.
White spot lesion (WSL) is the demineralization of the enamel surface and subsurface that is devoid of cavitation [1, 2, 3]. They are a result of the imbalance between mineralisation and demineralization, which if not intervened, may further lead to irreversible damage [1, 2]. In early lesions the mineral content in the affected area is reduced, which in turn affects the translucent feature of the enamel, and the colour of these areas appear more opaque white, hence, they are termed as white spot lesions. They are the first visible findings in caries formation and are considered as initial lesions by many clinicians. However, it should be remembered that, for demineralization to be visible, it must have a minimum depth of 300–500 μm implying that a considerable amount of damage to sound tooth structure has already begun [4, 5, 6, 7].
These lesions are commonly associated with poor oral hygiene and increased plaque accumulation. In addition to the above other risk factors such as poor dietary habits, high DMFS (Decayed, Missing or Filled Surfaces) index, and lack of preventive measures during orthodontic treatment always prevail.
A white spot may be intrinsic or extrinsic in origin [2], enamel defects such as fluorosis, hypomineralisation, hypomaturation of enamel, hypoplastic defects can lead to noncarious intrinsic white spots of the enamel. These developmental anomalies are greatly influenced by genetic aberrations, environmental variations, metabolic diseases, drug abuse, use of chemicals, radiation and trauma [4]. The differential diagnosis is imperative to the treatment plan.
An early enamel lesion can easily be identified as a white opaque spot when air-dried and is the most efficient way to detect it [5]. What may appear to be a smooth, shiny, non-carious lesion under light may be a rough, opaque and porous lesion on cleaning and drying [6]. It is challenging for a clinician to detect these in a regular check-up, and the diagnosis can only be established subjective to the clinician. Since these discolorations may be a result of several factors, it is usually challenging to arrive at an accurate diagnosis for the same.
WSL usually has a multifactorial manifestation. It is vital to ascertain the causes, before planning and providing treatment options to the patient. This is because the results of the treatment will vary depending on the substructure available [8, 9, 10, 11, 12].
Causes of WSL include,
high fluoride intake in childhood
complications in pregnancy
trauma
poor oral hygiene
During the phase of enamel mineralisation, if there is excessive fluoride exposure, and as a result the enamel would become hypomineralized, leading to a condition called fluorosis. Studies conducted by McKay and Black [11] conclude, that fluoride can be beneficial or harmful depending on certain factors, like the age, dosage, and health of the patient [13]. In preventive measures, many times a dentist uses fluoride to reinforce the enamel, hence a controlled dosage is required to make the use of fluoride extremely beneficial (Figure 1).
Mild fluorosis.
It is observed that fluorosis generally appears symmetrically and can present itself in 3 ways i.e., white spots, brown spots or pitting. In milder cases, it presents itself as narrow white lines, following the perikymata, cuspal snow capping or snowflaking whereas, in severe cases the brown discoloration is apparent due to the infiltration of chromophoric proteins [3] (Table 1). In any case, WSL and fluorosis are two different entities and can be differentiated as follows [14]:
Classification | Criteria—description of enamel (teeth not air-dried) |
---|---|
Normal | No evidence of fluorosis |
Questionable | Enamel discloses slight aberrations from the translucency of normal enamel, ranging from a few white flecks to occasional white spots. This classification is utilised in those instances where a definite diagnosis is not warranted and a classification of ‘normal’ not justified |
Very mild | Small, opaque, paper-white areas scattered irregularly over the tooth involving up to 25% of the tooth surface. Frequently included in this classification are teeth showing up to 1–2 mm of white opacity at the cusp tips of the premolars or second molars |
Mild | More extensive white opaque areas in the enamel of the teeth involving up to 50% of the tooth surface (Figure 1) |
Moderate | All enamel surfaces of the teeth are affected and are at risk of attrition. Brown stain is frequently a disfiguring feature |
Severe | All enamel surfaces are affected and the hypoplasia affects the general form of the tooth. The major diagnostic sign of this classification is discrete or confluent pitting. Brown stains are widespread and teeth often present with a corroded-like appearance |
Dean’s fluorosis index [12].
Occurs due to the hypomineralization of enamel.
Surfaces appear translucent when the tooth surface is moist and, opaque white when the surface is air-dried.
The surface of WSL is softer and rougher with easy dental plaque formation.
Occurs due to hypomineralization because of excessive incorporation of fluoride during the formation of enamel.
In the early phase, the surfaces have convergent horizontal white lines leading to a “Parchment-like” appearance along with irregular chalky areas. Then the colour changes to brown, due to the infiltration of exogenous chromophoric proteins.
Histopathologically, fluorosis occurs on the sub-surface of the external third of enamel.
It is not unusual to find white spot lesions due to trauma in the primary dentition stage. An incidence rate of 74.1% is seen [15] following which the succeeding tooth may be hypoplastic, or display discoloration (Figure 2).
Traumatic hypomineralization.
Traumatic hypomineralization is usually asymmetric in presentation and involves a single tooth with unusual patches.
Physical trauma such as a break or fracture of the tooth or chemical trauma such as a periapical infection of the primary tooth can cause a severe periapical inflammation which disturbs and influences the underlying mineralisation of the tooth, resulting in accelerated deposition of minerals. These are commonly seen as punctiform lesions of the dental crowns or the incisal one thirds [16].
Enamel demineralization is a complication associated with poor hygiene during orthodontic treatment. When there is prolonged and excessive plaque accumulation, in the course of treatment, WSLs are seen along the appliance margins at various sites. 46–73% is the prevalence rate of demineralization following orthodontic treatment and this poses a grave challenge to the clinicians [17]. The subsurface demineralization is a predisposing factor to caries formation and is commonly seen around the bracket attachments and underneath the molar bands.
These areas are mostly noticed in orthodontic patients who are unable to adequately clean the tooth surface with the toothbrush which later appears as white spots. They are white chalky in appearance and unusually located (Figure 3).
Demineralization with braces.
Weerheijm et al. introduced the term molar-incisor hypomineralization (MIH) [18], wherein they defined it as a hypomineralization of systemic origin, which presented itself as a demarcated, qualitative defect of the enamel of 1–4 first permanent molars, frequently associated with enamel opacities. In these cases, due to the qualitative defects, the teeth exhibit post-eruptive breakdown of the enamel. This causes rapidly progressive caries and severe sensitivity of the teeth.
The causes of MIH are still not clear, it is thought that there is a systemic disruption of amelogenesis which includes, malnutrition, hypoxia, common childhood illness and use of antibiotics before the age of 3 years that causes this effect [16].
Clinically they are seen as white-creamy or yellow-brown opacities, usually larger than 1 mm and post-eruptive breakdown of at least one first permanent molar.
A history of illness in the first three years, difficulty during birthing, or prenatal illness helps with the diagnosis.
The clinical manifestation of WSL starts as early as 4 weeks in case of orthodontic treatment. Unnoticed WSL can lead to the disintegration of enamel surface followed by carious lesion which may require aesthetic restorations or in more advanced cases a prosthodontic intervention. This is more commonly seen in high caries risk individuals. In people with low caries activity, the repair mechanisms help in the potential healing of the lesion.
Hence, it is important to plan the treatment according to the caries activity in individuals after a proper diagnosis. The emphasis given to new technologies has made it possible to detect initial lesions before they turn into irreversible cavitation [19].
The ideal method for the detection of WSLs should have a high level of sensitivity (the ability to detect disease when present) and specificity (the ability to confirm that disease is absent).
The conventional methods of diagnosing WSLs are visual examination, tactile examination with probing and digital photographic examination. These methods are simple to use, inexpensive, and clinically valid.
For visual examination, the tooth surface must be air-dried for at least 5 s after cleaning with pumice under adequate light to visualise the WSLs. The opacities on the enamel surface will not be visible and the lesion cannot be distinguished the enamel gets wet. Because the micro pores in the surface are filled with water and the refractive index of enamel becomes 1.33, which is close to that of healthy enamel. On the other hand, after the air drying, the pores within the lesion will be filled with air, which has a refractive index of 1.0. Hence, the opaque enamel lesions become evident and distinct from the healthy enamel surface [20].
The recommended specifications for taking intraoral images are 100 mm macro lens with a small aperture of 25. While taking a photograph the teeth should be inaccurate axial position i.e. the occlusal plane should be parallel to the horizontal plane. Although, these methods are useful in the detection, they do not quantify the depth of the lesions [21].
They are more consistent and enhanced sensitivity towards lesion diagnosis when compared to the conventional methods. This can be classified as:
An intact enamel surface is a good electrical insulator due to its high inorganic content. Demineralization causes loss of minerals, resulting in increased porosities filled with saliva, this acts as a conductive pathway for electric current. The electric conductivity is directly proportional to the amount of demineralization [22].
E.g., Electrical Caries Monitor, Caries Meter L, CarieScan Pro.
The autofluorescence of tooth tissue decreases as the demineralization activity increases .This could be attributed to protoporphyrin, a photosensitive pigment present in demineralized dental tissues that are generated due to bacterial metabolic activity [23].
E.g., Fibre-Optic Transillumination (FOTI), Digital imaging Fibre-Optic Transillumination (DIFOTI), Near-infrared digital imaging transillumination (NIDIT), Laser fluorescence (LF), Quantitative light-induced fluorescence (QLF), and Multiphoton imaging
The concept of transillumination for the detection of WSL is based on the refractive index of different tooth structures [23]. The refractive index will vary when light is passed through different tissues. The demineralized enamel appears as a grey hue whereas dentin gives an orange-brown or a bluish hue. Due to the intra and inter-observer disparity, Digital imaging FOTI (DIFOTI) was developed in the 1990s. In DIFOTI the images are captured and stored by a CCD camera. Another advanced method is near-infrared digital imaging transil-lumination (NIDIT). In this technique two near-infrared laser diodes are used, which allows superior light to spread into the dental tissues and get better picture quality than visible light [23].
LF uses a red wavelength of 655 nm for caries detection [23]. It is based on the principle when light is applied to the tooth surface, the caries-related changes in the tooth tissues lead to an increase in fluorescence. This can be translated into numeric values, which can vary from 0 to 99.
For example, in DIAGNOdent pen scores from 0 to 10 are interpreted as healthy, while scores above 30 indicate a lesion that requires restorative treatment [23].
It measures the percentage of fluorescence change in demineralized enamel. This technique allows us to detect the lesion activity as well as to predict the lesion progression. Since demineralized tissue has limited penetration of light, it gives a dark image in QLF [24].
Unlike conventional fluorescence imaging, it uses two infrared photons simul¬taneously to excite a fluorescent compound in the tooth. Caries will appear as a dark form within a bright fluorescing tooth. It also helps to collect information from carious lesions up to 500 μm of depth [25].
The concept of thermography for the detection of early enamel caries has been discovered by Kaneko in 1999. It measures the lesion activity rather than its presence or absence. This is based on the principle of change in thermal radiation energy that occurs when fluid is lost from a lesion by evaporation just as in WSLs [25].
E.g., Infrared thermography, Frequency-domain infrared photothermal radiometry and modulated luminescence (PTR/LUM).
Terahertz parametric imaging (TPI) has great potential in the diagnosis of WSL [25]. Terahertz radiation is located between the high-frequency microwave and long-wavelength infrared region of the spectrum. This helps identification of infected tissue inside the tooth followed by 3D plotting which can be applied to obtain the depth of the demineralized tissue. It can also be used to measure the remineralization of enamel [25].
It works on the principle of difference in the optical behaviour inside the tooth. The probe when placed on the tooth surface emits 635–880 nm wavelength and the light reflected from the surface of the tooth converts it to electrical signals [25].
It is a novel, non-irradiative, non-invasive imaging technique. The concept of OCT is based on the differences in the optical absorption and scattering properties of the dental tissue. It uses infrared light to produce a real-time cross-sectional image of dental tissue. Demineralized tissue can be distinguished from sound tissue based on the following principles:
Increased light scattering in porous demineralized tissue and
Depolarization of incident light by demineralized tissue.
Enamel caries appear brighter on grayscale OCT images whereas dentin caries gives the image a continuous bright area throughout the enamel into the dentin [26].
Conventional methods: [21]
Visual examination: on visual examination, if the lesion is active or inactive can also be determined. If the tooth surfaces are chalky and rough, it indicates active lesions. If the tooth surfaces are smooth and shiny, it indicates inactive lesions. Different methods are used for evaluation on clinical examination. They include:
Ekstrand assessment scale (1995)
The Nyvad system (1999)
The Dundee Selectable Threshold Method for Caries Diagnosis (DSTM in 2000)
The International Caries Detection and Assessment System (ICDAS in 2004) [26].
The scores are given in Table 2.
Photographic examination: for the evaluation on photographic examination, frontal and lateral photos are taken and it’s done using the Gorelick index. The scoring is done on the labial surfaces of incisors, cuspids and buccal surfaces of premolars. The inference is given in Table 3.
Ekstrand system | Nyvad system | DSTM system | ICDAS system |
---|---|---|---|
0—no/slight changes in enamel translucency after prolonged air dry (5 s) | 0—healthy tooth | G—healthy tooth | 0—sound |
1—opacity/discoloration distinctly visible after air drying, hardly on wet surfaces | 1—active (intact) | W—white spot lesion | 1—first visual change in enamel |
2—opacity/discoloration distinctly visible without air drying | 2—active (surface discontinuity) | B—brown spot lesion | 2—distinct visual change in enamel |
3—localised enamel breakdown in opaque or discoloured enamel and/or greyish discoloration from the underlying dentine | 3—active (cavitated) | E—enamel cavitation | 3—localised enamel breakdown |
4—cavitation in enamel exposing the dentine | 4—inactive (intact) | D—dentine lesion (non-cavitated) | 4—underlying dark shadow from dentine |
5—inactive (surface discontinuity) | C—dentine cavity | 5—distinct cavity with visible dentine | |
6—inactive (cavity) | P—pulp involvement | 6—extensive distinct cavity with visible dentine | |
7, 8, 9—presence or absence of caries which might be active or inactive in the filling or restorations | A—arrested dentinal decay F—filled surfaces contiguous with the upper types of lesions |
Different systems for evaluation on clinical examination.
Score | Inference |
---|---|
0 | No lesion |
1 | Thin rims of white spot lesion |
2 | Thick bands of white spot lesion |
3 | Cavitation due to white spot lesion |
Gorelick index scoring.
Electrical conductance measurement (Caries meter L):
The tooth surface is inserted with conducting gel and is gently air-dried. Every tooth surface is dampened between the measurements to establish proper contact between the electrode and tooth surface. The device has colour codes to indicate the extent of caries as given in Table 4.
Quantitative light fluorescence (QLF):
According to Rodrigues et al. in 2011, there are two devices used in QLF. They are DIAGNOdent device and DIAGNOdent pen. The device consists of a laser diode, photo diode and a long pass filter [27]. A tip is placed on the tooth surface at a certain angle and fluorescence values are calculated as in Table 5.
Light-emitting diode fluorescence:
LED fluorescence is based on the principle of difference in optical property. There are two available systems: Midwest caries (MID) and Vista Proof (VP). MID probe is a small battery-operated device with a portable handpiece and a probe [27]. When the probe touches the demineralized tooth surface there is an audible signal with a colour change from green to red as given in Table 6.
Frequency-domain infrared photothermal radiometry and modulated luminescence (PTR/LUM) [21]:
A recent technology called the Canary system has been introduced in the year 2011. This system consists of a laser tip along with an intra-oral camera. The laser tip is placed on the tooth surface that has to be examined and the WSL is recorded based on the scoring from 0 to 100 on the digital display. The scores and inferences are given in Table 7.
Colour | Inference |
---|---|
Green | No caries |
Yellow | Caries in enamel |
Orange | Caries in dentine |
Red | Caries reaching pulp |
Colour codes and inference of caries meter L.
Readings | Inference |
---|---|
0–14 | Absence of caries |
15–20 | Caries present in enamel |
21–99 | Caries present in dentine |
Scoring of DIAGNOdent device.
Score | Inference |
---|---|
0 | Green light without any signal indicates healthy tooth |
1 | Red light with medium signal indicates enamel caries |
2 | Red light with rapid signal indicates dentinal caries |
Scoring of Midwest caries device (LED fluorescence).
Score | Inference |
---|---|
0–20 | Healthy tooth |
21–70 | Demineralization and caries |
71–100 | Advanced caries |
Scores and inference of PTR/LUM.
The pathophysiology of dental caries is a continuous process of demineralization and remineralization wherein a net mineral gain is required to prevent lesion progression. To achieve this, the balance between the pathological factors such as fermentable carbohydrate ingestion, salivary function inhibition, acidogenic bacteria and protective factors like antibacterial agents, composition and rate of flow of saliva, fluoride and diet needs to be maintained [28]. Fermentation of carbohydrates leads to formation of organic acid by acidogenic bacteria that cause diffusion of calcium and phosphate ions out of the tooth leading to the formation of white spot lesions at an early stage, which further progresses to cavitation if the process continues [5]. This can be prevented by remineralization or mineral gain which is defined as the process whereby calcium and phosphate ions are supplied from a source external to the tooth to promote ion deposition into crystal voids in demineralized enamel [29].
Saliva is the major source of these minerals consists of calcium (Ca), phosphate (P), fluoride (Fl) ions in addition to salivary proteins such as proline-rich proteins, statherin, histatins which increases the concentration of calcium ions and salivary enzymes such as lysozymes and peroxidases. Normally the saliva is supersaturated with calcium and phosphate ions but when the pH decreases (<5.5) due to the fermentation of carbohydrates, as mentioned above, this equilibrium is lost and demineralization starts. To prevent this, saliva acts as a remineralizing agent by providing Fl ions to regain homeostasis and thereby acts by preventing demineralization, promoting remineralization and having an antibacterial effect. Therefore, a variety of treatment modalities are available to treat initial carious lesions also known as white spot lesions based on the above theory, which will be discussed in the upcoming treatment modalities [30].
There are various treatment options available to treat WSLs depending on their extent and severity [31] (Table 8).
White spot lesion | Presentation | Treatment options |
---|---|---|
Fluorosis | Can vary from symmetrical lesions, presence of white lines, ‘snowflake appearance’, to pitting and mottling in severe cases |
|
Traumatic hypomineralisation | Presents as a punctiform lesion on the incisal 3rd of the crown, usually asymmetrical |
|
MIH | Condition where there is hypomineralised permanent first molars along with or without the incisors, presenting yellowing of the teeth, mottling and post eruptive breakdown of molars |
|
Demineralisation | Presents as faint white lesions around the orthodontic brackets |
|
WSL (natural) | Presents itself as isolated white spots with a diameter less than 0.5 mm on the incisors |
|
Various WSLs and their treatment options.
Micro-abrasion is the application of an acidic and abrasive compound to the surface of the enamel. The micro abrasion process removes small amounts of surface enamel but also leaves a highly polished enamel surface. The micro-abraded enamel surface does not have the ideal enamel surface appearance as interprismatic spaces would be absent.
The micro-abrasion process abrades surface enamel while compacting calcium and phosphate into the interprismatic spaces. This polished surface reflects light differently than natural enamel. Therefore, a portion of the whitened enamel is removed and a portion is camouflaged by the highly polished surface.
Following this procedure, a 4-min 2% sodium fluoride treatment is recommended. If the micro-abrasion technique does not produce optimal aesthetic results, and if the whitened enamel is still prominent, vital tooth bleaching should be considered [32].
Also known as vital tooth bleaching or bleaching. It is the process of lightening the colour of enamel. To date, there are two techniques of tooth whitening that have been prescribed:
Ambulatory—that requires an intraoral device/tray to apply a gel of peroxide, which can be done at home and is more cost-effective. It must be kept in mind that major changes are not observed before the 7th day.
In-office method, which requires a professional to perform the procedure, uses photoactivation, where the changes of colour in the enamel can be witnessed from the first session [33].
Also known as an ICON (infiltration concept) was designed as a minimally invasive resin infiltration system for treating incipient caries in patients of all ages. The low viscosity unfilled resin, developed by the company DMG (Germany) camouflages white spots using optical manipulation, and no tooth tissue removal is strictly necessary (Figure 4).
ICON treatment: pre and post treatment.
The clear resin flows into the demineralized enamel, and has similar optical properties (similar refractive index) to the enamel, therefore reflecting light to match the tooth’s natural shade [34, 35].
CPP-ACP (Casein Phosphopeptide-Amorphous Calcium Phosphate) also known as the stabilised ACP, was developed based on the idea that CPP being saliva biomimetic solubilises the nano complexes readily, and creates a diffusion gradient that allows them to localise in supragingival plaque [36].
Low pH conditions that arise during a cariogenic attack, facilitate the release of Ca and P ions, inhibiting demineralization and favours the remineralization of the incipient lesions by precipitation of the released ions. This subsurface remineralization pattern produced by CPP-ACP has shown significant improvement in the aesthetics, and strength of the remineralized white spot lesion [29]. Some of the commercially available products are GC tooth mousse, flouride varnish, nanohydroxyapatite system and bioactive glass.
Dental restorations also known as dental fillings are treatments used to restore the function, integrity and morphology of the missing tooth structure. Dental restorations include glass ionomer cement, composites (light-cured, chemically cured or dual-cure), giomers, compomers and veneers.
Restorations are done in cases where aesthetics is of major concern and when there are lesser chances of reversing the damage. Restorations are also considered as a permanent solution [37].
Without a doubt, enamel decalcification/demineralization is a major clinical problem. Once the lesions are established, it is hard to achieve complete remineralization. Fluoride is a major ingredient that is cariostatic and is capable of arresting the lesion. Hence judicious use of fluoridated toothpastes and mouthwashes are advocated. Newer agents like CPP-ACP, hydroxyapatite systems, bioactive glasses are also being experimented [2]. Optimal oral hygiene is necessary to evade white spot lesions. Regular dental visits and the use of oral prophylactic aids are not negotiable. Patients undergoing fixed orthodontic treatment are required to maintain their oral hygiene and use oral hygiene products that would help in remineralizing the demineralized enamel.
Prevention of enamel demineralization is of utmost importance. Should enamel demineralization occur (white spot lesions), early diagnosis and intervention are appropriate. Improved brushing with fluoridated dentifrice and over-the-counter fluoride rinses would be the first recommended intervention.
Patients may also develop demineralized enamel during orthodontic treatment, which exhibits itself as white spot lesions adjacent to brackets and the free gingival margin area. As previously discussed, topical fluoride therapy is appropriate to be sure remineralization of enamel has occurred. Mild whitened enamel can often be camouflaged by bleaching with standard tray-based whitening systems used overnight or with the hydrogen peroxide-impregnated polyethylene strips. If 2 to 4-week bleaching with these regimens is ineffective at camouflaging this whitened enamel, microabrasion followed by bleaching is recommended.
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