Br J Ophthalmol 1998;82:407–409 407

Diabetic retinopathy in Down’s syndrome Br J Ophthalmol: first published as 10.1136/bjo.82.4.407 on 1 April 1998. Downloaded from

Tim Fulcher, Margaret GriYn, Seamus Crowley, Richard Firth, Robert Acheson, Niall O’Meara

Abstract currently 6000 active attenders. All patient Aim—To determine the prevalence of dia- data are recorded on a computerised database, betic retinopathy in patients with Down’s which is updated annually. In Ireland, diabetes syndrome and diabetes mellitus. care is hospital based. Thus, this group is Method—Nine patients with Down’s syn- probably representative of the population of drome and diabetes mellitus were as- diabetics at large. Information about all sessed. Factors recorded included type patients with Down’s syndrome and diabetes and duration of diabetes, level of diabetic mellitus was retrieved from the database, and control, blood pressure, urinalysis, and patients were invited to attend for an ophthal- results of ophthalmological examination. mological assessment. The group in this study Results—The duration of diabetes ranged represents the entire population of patients from 8 to 41 years (mean 17.6 years). All with Down’s syndrome and diabetes from our had satisfactory glycaemic control and unit. blood pressure measurements on the low The ophthalmological examination included side of normal (mean 106.6/70 mm Hg). orthoptic assessment, refraction, slit lamp One patient had early background dia- examination, funduscopy with a direct oph- betic retinopathy. The remainder had no thalmoscope, 90 dioptre lens, and fundus pho- evidence of diabetic retinopathy. tographs for cooperative patients. Conclusion—The low prevalence of dia- Other factors recorded included: type of betic retinopathy in these Down’s syn- diabetes, duration of diabetes, mean glyco-

drome patients, despite the long duration, sylated haemoglobin (HbA1c) over the previous is an interesting finding. It suggests some 5 years, most recent blood pressure inherent protective factor against the measurement, and the presence of proteinuria development of diabetic retinopathy in (measured by dipstick analysis and 24 hour this patient subgroup. urinary collection when positive). (Br J Ophthalmol 1998;82:407–409)

Results Diabetes is an important cause of blindness in There were nine patients included in the study, developed countries. The precise cause of dia- eight females and one male. The ages ranged http://bjo.bmj.com/ betic retinopathy in patients with diabetes mel- from 25 to 44 years (mean 37.2 years). Seven litus has not been defined. Definite contribut- had insulin dependent diabetes mellitus ing factors include chronic hyperglycaemia1–4 (IDDM) and two had non-insulin dependent and the duration of diabetes.5 The presence of diabetes mellitus (NIDDM). The duration of coexisting hypertension67 and hormonal diabetes in the group with IDDM ranged from changes associated with puberty and preg- 8 to 41 years (mean 20 years). In the two

nancy may also contribute. By contrast, certain patients with NIDDM the duration was 9 and on September 25, 2021 by guest. Protected copyright. factors may be protective including glaucoma,8 10 years respectively. myopia,910 and ipsilateral carotid artery The ophthalmic clinical features are summa- disease.11 rised in Table 1. Four patients had esotropia, Department of Down’s syndrome (trisomy 21) is a chromo- four had blue dot lens opacities, and one had Ophthalmology, Mater somal anomaly characterised by moderate to keratoconus. Refraction showed that four Misericordiae severe mental retardation and a characteristic patients were myopic (ranging from −6 to −9 Hospital, Dublin, physical appearance. Ocular problems are dioptres), two were emmetropic, and three had Ireland T Fulcher frequently encountered including an increased compound hypermetropic astigmatism. On R Acheson incidence of strabismus, keratoconus, cataract, funduscopic examination, no evidence of and refractive errors. diabetic retinopathy was present in six out of Department of Diabetes appears to be associated with seven (85.7%) patients with IDDM. The Endocrinology, Mater Down’s syndrome, but few data exist on remaining patient had minimal background Misericordiae microvascular complications in such patients. diabetic retinopathy, with only a few micro- Hospital, Dublin, Ireland In this study, we attempted to determine the aneurysms being present. Neither patient with MGriYn prevalence of diabetic retinopathy in a group of NIDDM had any diabetic retinopathy. S Crowley nine patients with Down’s syndrome and The patient characteristics are summarised N O’Meara diabetes mellitus. in Table 2. Blood glucose control was assessed R Firth by the mean glycosylated haemoglobin (HbA1c) Correspondence to: Patients and methods during the previous 5 years. Mean HbA1c levels Mr T Fulcher, Institute of All patients with Down’s syndrome and ranged from 6.4% to 9.1% (normal range Ophthalmology, 60 Eccles diabetes mellitus who attend the diabetic unit 4.2% to 6.2%). Street, Dublin 7, Ireland. in the Mater Misericordiae Hospital were Systolic blood pressure measurements ranged Accepted for publication included in this study. The diabetic unit has from 90 to 130 mm Hg (mean 106.6 mm Hg). 28 October 1997 been established for over 30 years. There are Diastolic blood pressure measurements ranged 408 Fulcher, GriYn, Crowley, et al

Table 1 Ocular features of patients in this study about 55% in the conventionally treated group. In our study, only one patient out of nine Br J Ophthalmol: first published as 10.1136/bjo.82.4.407 on 1 April 1998. Downloaded from Patient no Retinopathy Cataract Keratoconus Strabismus Refraction developed any signs of diabetic retinopathy 1 Absent Yes No Yes Hyperopic astigmatism despite a mean duration of 17.6 years. 2 Present No No No Emmetropic Hypertension has been associated with an 3 Absent No No Yes Hyperopic astigmatism 4 Absent Yes No No Myopic increased incidence of severe diabetic 5 Absent No No Yes Myopic retinopathy.6 12–15 In patients with IDDM this is 6 Absent No No Yes Hyperopic astigmatism reported to be associated with an elevated 7 Absent Yes No No Emmetropic 8 Absent No No No Myopic diastolic blood pressure above the 75th 9 Absent Yes Yes No Myopic percentile.16 In the same study it was shown that an increased incidence of retinopathy also Table 2 Systemic features of patients in study occurred in patients with high/normal blood pressure. Other studies have shown a signifi- Type of Duration of Blood cant association between systolic blood pres- Patient no DM DM pressure Mean HbA Urinary protein Retinopathy 1c sure (above 140 mm Hg) and an increased 1 IDDM 24 years 110/70 9.1% Negative Absent prevalence of retinopathy.17–19 This eVect of 2 IDDM 8 years 100/70 8.2% Positive Present 3 IDDM 13 years 110/70 7.5% Negative Absent increasing blood pressure on the subsequent 4 IDDM 41 years 130/80 7.9% Negative Absent development of diabetic retinopathy, may be 5 IDDM 24 years 110/70 7.9% Positive Absent mediated through the accompanying increase 6 IDDM 18 years 90/60 8.5% Negative Absent 7 IDDM 12 years 110/70 6.6% Negative Absent in retinal blood flow in a setting where the nor- 8 NIDDM 9 years 110/70 6.4% Negative Absent mal autoregulatory responses to changes in 9 NIDDM 10 years 90/70 7.4% Negative Absent blood pressure are impaired.19 20 In the patients DM = diabetes mellitus; IDDM = insulin dependent diabetes mellitus; NIDDM = non-insulin with Down’s syndrome in this study, all blood dependent diabetes mellitus. pressure measurements were on the low side of normal. Mean systolic pressure was 106.6 mm from 60 to 80 mm Hg (mean 70 mm Hg). Hg and mean diastolic pressure was 70 mm Mean arterial pressures ranged from 70 to 97 Hg. This may be significant in protecting this mm Hg (mean 82 mm Hg). group from developing diabetic retinopathy. Urinalysis was negative for protein on all The absence of hypertension may also reflect occasions in seven of nine patients (77.7%). the absence of clinical nephropathy in our The remaining two patients had positive patient group. dipstick analysis and subsequently had 24 hour Myopia has been shown to be protective urinary collections for protein. One had against diabetic retinopathy.910 The study by non-significant proteinuria (0.22 g/24 hours), Rand 10 showed that patients with HLA-D the other had significant proteinuria (0.48 g/24 et al group antigen markers of IDDM and no hours). Interestingly this latter subject was the significant refractive error had 3.74 times the single patient who had mild background risk of developing proliferative retinopathy diabetic retinopathy. when compared with patients with HLA-D group antigen markers of IDDM and myopia http://bjo.bmj.com/ Discussion of 2 dioptres or more. Four patients in our The prevalence of diabetic retinopathy was study had myopia ranging from −6.0 dioptres reported in the Wisconsin Epidemiologic to −9.0 dioptres. None had diabetic retino- Study of Diabetic Retinopathy as 97% in those pathy. who had diabetes for 15 or more years, when Short stature is a characteristic feature of the age at diagnosis of diabetes was less than 30 Down’s syndrome. AVected children have 5 years. In our current study, diabetes mellitus severe postnatal growth arrest which can be on September 25, 2021 by guest. Protected copyright. was diagnosed in eight patients with Down’s partially reversed by growth hormone syndrome before the age of 30 years and at 34 therapy.21 Furthermore, growth hormone defi- years in the remaining patient. The mean ciencies have been described in some but not duration of diabetes in those diagnosed before all series of cases of Down’s syndrome.22 23 the age of 30 years was 18.75 years. Only one There are extensive data in the literature impli- patient had any signs of diabetic retinopathy. cating growth hormone in the pathogenesis of This suggests a protective factor against the diabetic retinopathy24 and the absence of development of retinopathy in Down’s syn- diabetic retinopathy has previously been re- drome patients. ported in a group of sexual ateliotic dwarfs Chronic hyperglycaemia is an important risk with poorly controlled diabetes.25 It is possible factor in the development of diabetic retin- that abnormalities in growth hormone secre- opathy. The Diabetes Control and Complica- tion or responsiveness in Down’s syndrome tions Trial (DCCT) proved conclusively that could account for the low prevalence of tight blood glucose control reduced the risk of diabetic retinopathy noted in this study. developing retinopathy by 76% over a 6.5 year In conclusion, the development of diabetic period.4 In that study the mean glycosylated retinopathy, while driven by hyperglycaemia,

haemoglobin (A1c) in the intensively treated may be modulated by a number of other

group was 7.2 %. In our study, the mean HbA1c factors. The low prevalence of retinopathy in was 7.72 % (SD 0.86%). This is between the Down’s syndrome patients with diabetes sug- intensively and conventionally treated range of gests such factors may be operational here. the DCCT and indicates satisfactory control. Their relatively low blood pressures may be an However, after 9 years the percentage of important protective factor. Other unidentified patients who developed retinopathy was about factors may also play a role, including the 15% in the intensively treated group, and possibility of growth hormone deficiencies in Diabetic retinopathy in Down’s syndrome 409

Down’s syndrome patients. The observations 11 Gay AJ, Rosenbaum AL. Retinal artery pressure in asymmetric diabetic retinopathy. Arch Ophthalmol 1966;75: Br J Ophthalmol: first published as 10.1136/bjo.82.4.407 on 1 April 1998. Downloaded from in this study may further aid our understand- 758–62. ing of the pathogenesis of diabetic retinopathy 12 Blankenship GW, Skyler JS. Diabetic retinopathy: a general survey. Diabetes Care 1978;1:127–37. in aVected individuals. The results should also 13 Szabo AJ, Stewart AG, Joron GE. Factors associated with be confirmed in a multicentre clinical study. increased prevalence of diabetic retinopathy. Can Med Assoc J 1967;97:286–92. 14 Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. The The authors would like to thank Dr Mary Codd for her advice Wisconsin Epidemiologic Study of Diabetic Retinopathy. during the preparation of this manuscript. IX Four year incidence and progression of retinopathy when the age at diagnosis is less than 30 years. Arch 1 Dahl-Jorgenson K, Brinchman-Hanson O, Hanssen KF, Ophthalmol 1989;107:237–43. Sandvik L, and the Aker Diabetes Group. Rapid tightening 15 Klein R, Klein BEK, Moss SE, DeMets DL. Blood pressure of blood glucose control leads to transient deterioration of and hypertension in diabetes. Am J Epidemiol 1985;122:75– retinopathy in insulin-dependent diabetes mellitus. The 89. Oslo study. BMJ 1985;290:811–5. 16 Chase HP, Garg SK, Jackson WE, et al. Blood pressure and 2 Kroc Collaborative Study Group. Blood glucose control and retinopathy in type 1 diabetes. Ophthalmology 1990;97: the evolution of diabetic retinopathy and albuminuria. N 155–9. Engl J Med 1984;311:365–72. 17 Lewis JM, Jovanovic-Peterson L, Ahmadizadeh I, et al. The 3 Lauritzen T, Larsen HW, Frost-Larsen K, Deckert T, and Santa Barbara County diabetic retinopathy screening feasi- The Steno Study Group. EVect of 1 year of near-normal bility study: significance of diabetes duration and systolic blood glucose levels on retinopathy in insulin dependent blood pressure. J Diabetes Complications 1994;8:51–4. diabetics. Lancet 1983;i:200–4. 18 Cignareeli M, DeCicco ML, Damato A, et al. High systolic 4 DCCT Research Group. The eVect of intensive treatment blood pressure increases prevalence and severity in of diabetes on the development and progression of NIDDM patients. Diabetes Care 1992;15:1002–8. long-term complications in insulin dependent diabetes 19 Kohner EM, Patel V, Rassam SMB. Role of blood flow and mellitus. N Engl J Med 1993;329:977–86. impaired autoregulation in the pathogenesis of diabetic 5 Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. The retinopathy. Diabetes 1995;44:603–7. Wisconsin Epidemiologic Study of Diabetic Retinopathy. 2 20 Patel V, Rassam S, Newsom R, Wiek J, Kohner E. Retinal Prevalence and risk of diabetic retinopathy when age at blood flow in diabetic retinopathy. BMJ 1992;305:678–83. diagnosis is less than 30 years. Arch Ophthalmol 1984;102: 21 Anneren G, Gustafsson J, Sara VR, Tuvemo T. Normalised 520–6. growth velocity in children with Down’s syndrome during 6 Knowler WC, Bennett PH, Ballintine EJ. Increased growth hormone therapy. 1993; : incidence of retinopathy in diabetics with elevated blood J Intellect Disabil Res 37 pressure: a six-year follow-up study in Pima Indians 381–7. .N Engl 22 Barreca A, Rasore-Quartino A, Actis MS, Assessment JMed1980;302:645–50. et al. 7 Kornerup T. Studies in diabetic retinopathy: an investiga- of growth hormone insulin like growth factor-1 axis in tion of 1,000 cases of diabetes. Acta Med Scand 1955;153: Down’s syndrome. J Endocrinol Invest 1994;17:431–6. 81–101. 23 Castells S, Torrado C, Bastian W, Wisniewski KE. Growth 8 Becker B. Diabetes and glaucoma. In: Kimura SJ, Caygill, hormone deficiency in Down’s syndrome children. J Intel- WM, eds. Vascular complications of diabetes mellitus. St Louis: lect Disabil Res 1992;36:29–43. Mosby Yearbook, 1967:43–8. 24 Alzaid AA, Dinneen SF, Melton LJ, Rizza RA. The role of 9 Jain IS, Luthra CL, Das T. Diabetic retinopathy and its rela- growth hormone in the development of diabetic retin- tion to errors of refraction. Arch Ophthalmol 1967;77:59– opathy. Diabetes Care 1994;17:531–4. 60. 25 Merimee TJ. Comparative metabolic and clinical studies of 10 Rand LI, Krolewski AS, Aiello LM, et al. Multiple factors in sexual ateliotic dwarfs and diabetics in Camerini. Vascular and the prediction of risk of proliferative diabetic retinopathy. N neurological changes in early diabetes. New York: Academic Engl J Med 1985;313:1433–8. Press, 1978:207–13. http://bjo.bmj.com/ on September 25, 2021 by guest. Protected copyright.