|Year : 2021 | Volume
| Issue : 4 | Page : 401-407
Diabetic retinopathy and the principles of screening
Department of Ophthalmology, Istanbul Florence Nightingale Hospital; Turkish Diabetes Foundation; Department of Ophthalmology, Faculty of Medicine, Demiroglu Bilim University, Istanbul, Turkey
|Date of Submission||05-Apr-2021|
|Date of Decision||27-Sep-2021|
|Date of Acceptance||13-Jul-2021|
|Date of Web Publication||12-Jan-2022|
Dr. Sehnaz Karadeniz
Istanbul Florence Nightingale Hospital, Izzetpasa Mah., Abide-I Hurriyet Cad., No. 166, Sisli 34381, Istanbul.
Source of Support: None, Conflict of Interest: None
Diabetes-related eye problems are a growing eye health concern globally, and diabetic retinopathy (DR) is one of the leading causes of preventable blindness. Ideally, people with diabetes should have an initial comprehensive eye examination, including fundus examination through dilated pupils, and then followed up with recommended intervals. However, in reality, this cannot be achieved because of the limitations in the human resources and health facilities, among others. On the other hand, fundus screening for DR justifies the suggested principles for screening for combating a disease. DR screening programs at the local/regional/national level can serve as an effective way for the diagnosis and treatment of vision-threatening DR in people with diabetes. These programs need to be tailored according to the human resources and the infrastructure of the community; they will serve, and they should have a monitoring system in place, as well. The availability, accessibility, and affordability of the treatment should also be ensured for people with vision-threatening DR.
Keywords: Diabetes mellitus, diabetic eye disease, diabetic retinopathy, screening
|How to cite this article:|
Karadeniz S. Diabetic retinopathy and the principles of screening. J Diabetol 2021;12:401-7
| Introduction|| |
Globally, we are going through difficult times because of the COVID-19 pandemic, which disrupted health services worldwide besides our day-to-day life. This pandemic should not suspend our fight against diabetes and the related burden any further.
As the overall life expectancy of people with diabetes has increased, and their numbers are skyrocketing, so are the number of people with DR.,, At present, we are unable to definitely prevent or cure DR; therefore, there remains the following three main strategies in combating the retinopathy burden:
- - prevention of diabetes in order to decrease the number of susceptible people by identifying the risk groups and intervening mainly by lifestyle modification;
- - delaying the development or slowing down the progression of DR by good metabolic control and control of other risk factors in people with diabetes;
- - timely treatment of vision-threatening disease by early diagnosis and regular follow-up.
Hence, the key is, to identify the disease in its earlier stages before it causes any visual impairment through effective screening.
The importance of disease prevention has already been put into words by Huangdi, the Yellow Emperor, back in 2600 BC. He is considered one of the legendary rulers of Chinese civilization. In his textbook Huangdi neijing (Canon of Medicine), the principle of “prevention is better than cure” was put forward.,
Prevention of a disease needs a proactive approach, especially in noncommunicable diseases such as diabetes. Screening is at the center of this approach in order to find out the cases with the disease or those who are susceptible to the disease. This is unlike other medical interventions where the foremost purpose is to respond to a sign, symptom, or diagnosis.
Back in 1968, the WHO published a Public Health Paper on screening to set out the principles and practices of screening for a disease as they recognized that communicable diseases are becoming less important than noncommunicable diseases as killers. Wilson and Jungner had set the principles of screening as follows:
- The condition sought should be an important health problem.
- There should be an accepted treatment for patients with the recognized disease.
- Facilities for diagnosis and treatment should be available.
- There should be a recognizable latent or early symptomatic stage.
- There should be a suitable test or examination.
- The test should be acceptable to the population.
- The natural history of the condition, including development from latent to declared disease, should be adequately understood.
- There should be an agreed policy on whom to treat as patients.
- The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.
- Case-finding should be a continuing process and not a “once-and-for-all” project.
After more than 50 years, the question is to what extent do these principles justify retinopathy screening in people with diabetes and which of them can be considered a strong or moderate argument for retinopathy screening.
Diabetic retinopathy is an important health problem
According to the International Diabetes Federation estimates in 2019, there are 463 million adults (20–79 years) with diabetes, worldwide. More importantly, one in two adults living with diabetes are unaware that they have the condition that makes them more prone to complications.
In a pooled analysis of 35 studies (1980–2008) around the world, the overall prevalence of DR was 34.6% and that of vision-threatening DR (VTDR) was 10.2%.
In another review of 32 studies published between 2015 and 2019 utilizing retinal images for assessment, the global prevalence of any retinopathy was 27%.
Based on these and other studies, it is estimated that approximately one-third of the people with diabetes have DR with, or without, any visual symptoms. If they would be living in the same country, it would be the twelfth most populous country in the world.
A further one-third of the people with retinopathy have vision-threatening disease. This is again a huge number of affected individuals, and DR is still one of the leading causes of avoidable moderate-to-severe vision loss in the working-age population worldwide.
The projections for the number of people with diabetes and with DR in the coming decades are even worse.
There is an accepted treatment for patients with recognized retinopathy
DR is an end-organ response to a systemic disease. Besides good metabolic control and control of other risk factors, there are also evidence-based local treatments for VTDR––proliferative DR (PDR) and diabetic maculopathy (mostly diabetic macular edema [DME]).
The DME with center involvement is the leading cause of moderate-to-severe visual impairment, generally in people with diabetes. In addition, intraocular hemorrhage due to PDR is the leading cause of sudden vision loss in people with diabetes.
At least, for three decades, laser photocoagulation has been the effective approach, in the treatment of sight-threatening retinopathy.
The strongest evidence came from two randomized controlled trials in the 1970s and the 1980s––the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS).
The DRS showed that panretinal laser photocoagulation reduces the risk of severe vision loss significantly, at least by 50% at five years in patients with severe nonproliferative or proliferative retinopathy. In the presence of proliferative retinopathy with high-risk characteristics, prompt treatment is advised. After so many decades, panretinal laser photocoagulation is still the first-line treatment in proliferative retinopathy. There is also a discussion on the use of intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents alone or in combination with laser photocoagulation in proliferative retinopathy.
The ETDRS Group demonstrated that focal laser treatment reduces the risk of moderate visual impairment due to clinically significant DME, and focal/grid laser has been used as the first-line treatment for decades. However today, anti-VEGF agents are considered the first line of treatment in center-involving DME.
In 2012, the FDA approved an anti-VEGF, ranibizumab, for the treatment of DME. Another anti-VEGF, aflibercept, for intraocular use in DME, has also been approved in 2014 by the FDA. Yet another anti-VEGF, bevacizumab, is still used as an off-label drug. Other molecules are also on the way.
Steroids have also been extensively evaluated as a treatment for center-involving DME, as there is a significant inflammatory component in its etiology. Intravitreal steroids are mainly used in unresponsive cases and in patients with pseudophakia, because of its related complications such as cataract and glaucoma.,,
Klein et al. examined the changes in visual impairment prevalence in people with type 1 diabetes mellitus (T1DM) diagnosed before the age of 30 years by the period of diagnosis of diabetes as part of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The age of diagnosis of T1DM was grouped as <1960, 1960–1969, 1970–1974, and 1974–1979. The prevalence of visual impairment was lower in those people diagnosed more recently than in those diagnosed earlier for most durations of diabetic groups. They concluded that this is likely because of better glycemic control, resulting in a decrease in the incidence of PDR and clinically significant macular edema, and more timely intervention for vision-threatening disease.
Facilities for diagnosis and treatment are available
The availability, accessibility, and affordability are keys to eye health outcomes in people with diabetes. Unfortunately, there is a deep inequality in resource allocation for health between the countries and the households within the country.
Approximately 79.4% of the diabetic population lives in low- and middle-income countries where the governments may have more limited resources to deal with the overwhelming numbers of people with diabetes and related complications.
Cost of care and treatment, insurance coverage, and timely access are still a serious problem in today’s world, as about 10% of the world’s population lives in extreme poverty, as defined by the international poverty line with an income of less than US$1.90 a day.
Screening can be done with different equipment according to the different resource settings, such as using direct ophthalmoscopy if nothing else is available, having its low sensitivity and specificity in mind.
As to the treatment options in low-resource settings, the WHO facilitated the access to anti-VEGF agents by including bevacizumab to its WHO Essential Medicine List. This enables people to have access to an anti-VEGF agent at all times in sufficient amounts, although it is used off-label.
There is a recognizable latent or early symptomatic stage
DR is one of the long-term complications of diabetes.
Patients with DR (including DME) may not have any complaints even till the late stages of DR such as VTDR.
An additional threat is that center-involving DME develops gradually; therefore, the patient may become aware of his/her visual impairment when her/his day-to-day life is affected. The DME may develop both during the nonproliferative and proliferative stages of DR.
Intravitreal hemorrhage due to PDR causes a sudden vision loss. Its severity depends on the extent of the intraocular bleeding.
On the other hand, there are well-recognized guidelines for the timing of the initial ophthalmological examination in people with diabetes.
People with T1DM should have their initial eye examination within five years after the onset of diabetes, provided they are ≥11 years or puberty has started, whichever is earlier. People with type 2 diabetes mellitus (T2DM) should have their initial eye examination at the time of diagnosis. Thereafter, they should have yearly follow-up examinations in the absence of DR. Screening every two years can be considered if no retinopathy is present in one or more annual examinations and glycemia is well controlled. In the presence of DR, more frequent eye examinations will be considered according to the severity and progression of the disease.,,
Women with preexisting T1DM or T2DM should preferentially have their eyes examined when pregnancy is planned, or latest during the first trimester. Then, they should be closely followed up during the pregnancy and at one year postpartum.
There is a suitable test or examination
At present, the diagnosis and grading of DR are done according to the observed lesions at the back of the eye. These depend on the extent and severity of the retinal hypoxia and increased vascular permeability, irrespective of the underlying mechanisms.
It has been about 170 years, when scientists were excited about the newly developed ophthalmoscope by Helmholtz and the opportunities provided.
In 1911, the Swedish ophthalmologist Allvar Gullstrand presented the earliest version of the slit lamp, but it was not until 1916 that the slit lamp was truly realized. Slit-lamp examination using contact/noncontact lenses is still the key tool for fundus examination in ophthalmological practice.
The introduction of the fundus camera for retinopathy screening and further advances in fundus imaging in the 2000s paved the way for mass screening programs in the diabetic population with remote reading by experts or the use of a validated assessment tool. This way, screening is more accessible in areas where ophthalmologists (or optometrists if licensed in the country) are not available, and also costs for screening are reduced.
However, retinal screening using the fundus camera is not a substitute for comprehensive eye examination that should be performed ideally in all people with diabetes at least initially and thereafter at intervals as needed.
Traditional fundus cameras need to be based in a clinic because of their bulkiness and be used by skilled personnel. The modern tabletop fundus cameras are mostly nonmydriatic cameras; however, they are again office based, and most of them are expensive, which limits their application in primary health-care or other screening facilities. Modified handheld digital fundus cameras operating in a point-and-shoot manner are lightweight and a portable alternative, but the absence of fixation targets on the camera for proper focusing and the artifacts in images limit their use. The integrated adaptor-detector-based handheld ophthalmic cameras and smartphone-based ophthalmic cameras may serve as lightweight and easy-to-use options, but they need to be validated in clinical settings.,
In a study by Piyasena et al. to assess the diagnostic test accuracy of a handheld nonmydriatic retinal camera used by general physicians, 43.4% of the images could not be graded, which decreased to 12.8% after pupil dilation. After excluding the ungradable images, they detected no significant difference in diagnostic test accuracy by pupil status as compared with a clinical reference standard.
Moreover, in this past decade, the discussions around the use of artificial intelligence (AI) are growing exponentially. Back in 2018, the FDA approved the first AI-based device for marketing to detect greater than a mild level of DR in adult patients. In 2020, the FDA cleared another AI technology for autonomous detection of more than mild retinopathy and also of VTDR.
However, there are medical, ethical, technical, and legal challenges with the use of semiautomated or autonomous AI systems that need to be overcome in future.
Most importantly, our human laws have been built around the assumption that people, and not AI, make decisions. Therefore, legally and ethically, there are several blind spots such as the medical malpractice and product liability, the intellectual property, the patient privacy, the storage of data, and the patient’s consent for use of their data.,,,
The pace of laws and regulations for the use of AI should catch up with increasing interest in its use in medical care.
Some of the other issues are: AI-based systems are expensive, there is a need for at least one trained staff to operate the system, and there should be a human grader for validation not only for semiautomated systems but also for automated systems, if needed.
Both the physicians and the patients should be aware that the system is not failsafe; therefore, the liabilities of the physicians, AI providers, and patients should be well defined, which again points out to the urgent need of laws and regulations for the use of AI in medicine.
All these tests are acceptable to the population
Ophthalmoscope, slit-lamp examination using noncontact/contact lenses, and fundus photography are already in use in day-to-day practice of ophthalmology for fundus screening in people with diabetes.
The natural history of the condition, including development from latent to declared disease, should be adequately understood
DR remains one of the most complex, heterogeneous, and multifactorial disorders. Today, we more and more define DR as a highly specific neurovascular complication of diabetes. Moreover, we do the screening and the staging of the disease according to the observable changes during the fundus examination.
Continued research in this field will undoubtedly offer new insights for its prevention and treatment.
There should be an agreed policy on whom to treat as patients
Patients with VTDR should be treated in order to save the sight in people with diabetes. There are well-established evidence and widely recognized recommendations/guidelines on when, how, and whom to treat.,,
The cost of case-finding (including diagnosis and treatment of patients diagnosed) is economically balanced in relation to possible expenditure on medical care as a whole
Diabetes is an expensive disease mainly because of the direct and indirect costs of its related complications. The direct cost includes not only the medical ones but also the nonmedical ones such as travel expenses for obtaining the care and the treatment and the cost of the caregivers. The indirect costs include productivity losses by patients and their caregivers and absenteeism.
Lee et al. from the United States compared the direct and indirect costs of employees with DR to employees with diabetes but without retinopathy. Data were obtained from an administrative database of more than five million privately insured individuals, who received medical services from 1999 to 2004. The study revealed a significant difference among the costs of the groups. The mean annual total costs of the employees with DR were US$18,218 (indirect = US$3,548) compared with US$11,898 among the control group (indirect = US$2,374).
Some other studies also investigated the cost-effectiveness of screening and treatment of DR.
Javitt et al. analyzed the medical and economic implications of alternative screening strategies at 6-, 12-, and 24-month intervals in people with T1DM. They calculated potential savings from screening and treatment from the amounts paid by the federal government for blindness-related disability. They estimated a net annual saving of 62.1 to 108.6 million US$ to the federal government, and between 71,474 and 85,315 person-years of sight and 76,886 and 94,705 person-years of reading vision could be saved with all the studied strategies.
Later, Javitt et al. explored the cost-effectiveness of the screening and treatment of retinopathy also in people with T2DM. They predicted that the net savings would exceed 472.1 million US$ and 94,304 person-years of sight, if all patients with T2DM receive the recommended care.
Unfortunately, there are only a few studies exploring the cost-effectiveness of screening and treatment in low- to middle-income countries.
Several studies from these countries have shown that increasing the screening intervals in patients with low risk, and including tele-screening services using fundus cameras, will improve the cost-effectiveness of the screening.,
A study from Chennai, India, has used the WHO-suggested threshold (1–3 times the Indian gross domestic product) to define cost-effectiveness. From a health provider perspective, screening up to a frequency of once every two years would be considered cost-effective because of a reduction in progression to sight loss among treated patients. When considering the sum of the health provider and household costs––the societal perspective, tele-screening once every five years was cost-effective but not more frequently.
There may be other programs/studies on this subject published in some local/national journals that are not accessible by mostly used academic search engines.
However, existing studies leave no room for doubt about the cost-effectiveness of screening and treatment in people with diabetes, tailored according to the health provider and societal costs in that setting.
Case-finding should be a continuing process and not a “once-and-for-all” project
Establishing a national/regional/local screening program is a fundamental part of the strategy to combat diabetes-related vision loss.
A good example is the regular screening for diabetic eye disease in the community of Laxå in Sweden. The diabetes register for T2DM was established in the mid-1970s and is being continuously updated, and retinopathy screening has been practiced since 1983. They found no significant difference in the visual acuity between the diabetic group and the control group. Only one of the 276 patients with T2DM was legally blind from DR.
In Iceland, the first-known national program for DR screening was established in 1980. Approximately 90% of the people with insulin-dependent diabetes mellitus (DM) and about a fifth of the people with T2DM received annual eye examination and fundus photography. Kristinsson et al. reported the prevalence of legal blindness from DR in people with insulin-dependent DM as 0.5% in 1994 compared with a reported prevalence of 1.8% in people with T1DM from Iceland in 1982. The percentage of legal blindness was 1.6 in people with T2DM.,
Countrywide population-based retinopathy screening programs were developed in Wales and England at the beginning of the 2000s. Liew et al. analyzed the national database of blindness certificates to find out the changes in the leading causes of blindness in adults in 1999–2000 in comparison to 2009–2010. Although DR was the leading cause of blindness certification in 1999–2000 with 17.7%, it decreased to 14.4% in 2009–2010. They concluded that this improved outcome in people with diabetes may be because of the introduction of nationwide screening programs and improved metabolic control.
| Outlook|| |
The effect of diabetes on eyes can range from simple refractive changes to permanent vision loss, mainly due to the advanced stages of DR, including DME. There is a wide spectrum of diabetic complications that may be seen in every ocular tissue, such as corneal changes, cataract, diabetic papillopathy, and extraocular palsies. Diabetes may also be associated with increased risk of some other eye diseases, such as glaucoma and nonarteritic anterior ischemic optic neuropathy.,,,,
Therefore, ideally, all people with diabetes should have an initial comprehensive eye examination, including fundus examination through dilated pupils.,, Moreover, follow-up examinations should be tailored according to the fundus findings and other eye problems.
However in reality, the limitations in human resources and the equipment, access to, and availability of the health facilities for comprehensive eye care are major barriers even in high-resource settings. Moreover, in addition to the barriers related to health-care system and health-care professionals, there are also patient-related barriers such as inadequate health literacy and negligence that delay the diagnosis and treatment of VTDR.
Therefore, the organization of local/regional/national retinopathy fundus screening programs is of utmost importance in preventing moderate-to-severe vision loss due to DR in the diabetes community. Such screening for DR justifies all the screening principles that are set by Wilson and Jungner more than 50 years ago and that are still valid today.
To be effective, they should be structured according to the available resources and infrastructure of the community that the program will serve. And, most importantly, they should have a monitoring scheme in place as well.
The availability, accessibility, and affordability of the treatment for people with VTDR will be decisive for the ultimate success of the screening program.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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