Pearls for managing diabetic retinopathy in pediatric patients

Insulin pumps, digital technology and outcome analyses are useful tools

Diabetes mellitus (DM) is a metabolic disease of high glucose levels or poor glucose utilization that leads to significant morbidity, particularly kidney, eye, heart, and cerebrovascular disease, and premature mortality.1-3 Type 1 diabetes is one of the most common chronic diseases in children and represents a global public health challenge;4,5 the prevalence of type 2 diabetes ranges from 1 to 51 per 1,000.6,7

Although children and adolescents with type 1 diabetes are threatened daily with acute complications of hypoglycemia and ketoacidosis, it is the long-term microvascular and macrovascular complications of the disease that place them at the greatest risk of serious morbidity and early mortality.8

Diabetic eye disease in the young

DM can affect any ocular tissue, although the retinal microvascular changes of diabetic retinopathy (DR) are thought to be the most important long-term complication.1,2 DR, which can occur in all types of DM, can have a debilitating effect on visual acuity and ultimately lead to blindness in some cases.1-3,9

The risk for and time to develop DR is variable, but it may already be present at the time of DM diagnosis. A Danish prospective cohort study that followed children and adolescents with type 1 DM for 8 years reported the prevalence of any level of DR as 17.7% in children aged 12–15 years and 45.4% in the 16–20 years age group, increasing to 67.6% after 20 years.10 Recent reports from the UK11 and Canada12 confirmed that DR was variable but uncommon before 12 years of age.

Specifically, mild DR occurred in 10% of UK children at 12–13 years; only 0.17% had sight-threatening DR.11 A multicenter study based in northwest England reported a DR prevalence of 11% in children with T1 DM.11,13 Of these, 44% had background DR while 56% had pre-proliferative DR, with early age at diagnosis and poor metabolic control as independent risk factors.13

Shibeshi et al. reported a DR prevalence in children in Ethiopia of 4.7% including two individuals who had maculopathy associated with vision loss.14 A recent study from the United States in young people reported an incidence of DR in 20.1% and 7.2% over a median period of 3.2 years in type 1 diabetes and 3.1 years in type 2 DM.15

DR risk depends on age at DM onset or diagnosis, duration of disease16,17, and glycemic control.10,18,19 A population-based study from Australia reported that 24% of children and adolescents with type 1 diabetes developed DR after 6 years of DM;16 a similar study in Sweden reported a DR incidence of 27%20 after 13 years of DM. Prepubertal DM duration is strongly associated with the development of DR.10

GENERAL MANAGEMENT

The general management of DM in young patients has improved recently, supported by advancing technology. The development of insulin pumps, digital technology, and outcome analyses have led to significant improvements in glycemic control.21

Control of blood pressure and serum lipids is also necessary. Close working with diabetologists as well as renal pediatricians is important in achieving the best outcomes.

SCREENING

The current UK guidance is for annual screening from 12 years and above, based on the low prevalence of DR in younger children.22 A close check should be kept on patients aged younger than 12 years by the diabetologist and appropriate referrals to the Eye Clinic affected as necessary.

The American Academy of Ophthalmology recommends that annual eye examinations in children should start 3–5 years after the diagnosis of type 1 DM.23 The International Diabetes Federation/International Society for Pediatric and Adolescent Diabetes guideline from 2017 recommends that eye examinations for children with type 1 DM commence at 11 years of age and after 2 years of DM duration; in children with type 2 DM, screening should commence from diagnosis.24

In populations where DR onset is earlier or more common in children, screening programs should be appropriately directed at the vulnerable population. Evaluation for other eye changes may be initiated by pediatric diabetes teams as appropriate.

Color fundus photographs have traditionally been used to document DR. Optical coherence tomography (OCT) and OCT angiography (OCTA) are non-invasive state-of-the-art imaging techniques that are very useful in evaluating the status of the macula and specifically in quantifying diabetic macular edema (DME).25,26 Recently, the advent of spectral-domain OCT has allowed diabetic neurodegeneration to be identified, which is thought to precede clinical DR detection.25-27

TREATMENT

Unfortunately, the literature on treatment of DR in the young is limited because clinical trials for DR treatments recruit participants aged 18 years or older. The standard treatment for focal DME located more than 500 microns from the foveal avascular zone edge is focal laser photocoagulation, as per the ETDRS protocol. However, laser photocoagulation should be avoided in diffuse edema.

Where the DME is diffuse, or patient cooperation unlikely, pharmacotherapy is more appropriate. Vascular endothelial growth factor (VEGF) blockage through intravitreal injections of anti-VEGF agents is now well established as a treatment for DME in adults,28 although its safety and efficacy have not been established in children and adolescents. Some limited data on the use of ranibizumab (Lucentis, Genentech/Roche) for the treatment of choroidal neovascularization in patients between the ages of 12 and 17 years showed that it was well tolerated.29

Similarly, no data exist for use of intravitreal steroids in DMO in the young, although non-randomized study data exist for dexamethasone in non-infectious uveitis in a similar age group.30-32 As intravitreal steroids are cataractogenic, their use in young diabetic patients is best avoided. However, it may be reasonable in older children if the DME is unresponsive to other therapies, or if a young diabetic patient has to undergo cataract surgery.

It has been suggested that blockage of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors even in the absence of hypertension may slow progression of DR,33 although this was not supported in a study of adolescent diabetics.34 In summary, as there are limited trial data to guide treatment decisions in young patients, treatments for DR in this patient group should be individually tailored.

References
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Winfried Amoaku, FRCS, FRCOphth, PhD, AFHEA
E: winfried.amoaku@nottingham.ac.uk
Amoaku is an associate professor/reader in Ophthalmology and honorary consultant ophthalmologist, based in Academic Ophthalmology and Visual Sciences, Division of Clinical Neurosciences, in the Faculty of Medicine and Health Sciences at the University of Nottingham, UK. He has no financial disclosures related to the content of this article to report.