Sudanese Journal of Ophthalmology

REVIEW ARTICLE
Year
: 2014  |  Volume : 6  |  Issue : 2  |  Page : 43--48

Ocular problems in diabetes mellitus


Galal Mohamed Ismail 
 Department of Neuroscience, Faculty of Optometry and Visual Science, Elneelain University, Khartoum, Sudan

Correspondence Address:
Galal Mohamed Ismail
College of Health Sciences, University of Buraimi, Buraimi, Sultanate of Oman
Sudan

Abstract

Diabetes Mellitus (DM) is an important health problem affecting wide population band globally. According to the World Health Organization (WHO) considerable numbers of individuals were diagnosed with DM, however, notable numbers are still undiagnosed due to diverse reasons. All diabetics are at risk of developing pathological complications in particular ocular complications seemed to appear early and might lead to blindness at late stages. The screening and routine medical eye care programs helped in detecting early the ocular problems allowing best possible remedy. Monitoring of such ocular problems has significant role in reducing advance stages that might lead to blindness. In an attempt of listing possible ocular problems due to DM, the author reviewed what would be most seen in practice across the ocular and visual components structurally and functionally. Assuming the article might be used as a quick reference by the clinicians involved in seeing diabetic patients.



How to cite this article:
Ismail GM. Ocular problems in diabetes mellitus.Sudanese J Ophthalmol 2014;6:43-48


How to cite this URL:
Ismail GM. Ocular problems in diabetes mellitus. Sudanese J Ophthalmol [serial online] 2014 [cited 2019 Jun 19 ];6:43-48
Available from: http://www.sjopthal.net/text.asp?2014/6/2/43/150992


Full Text

 INTRODUCTION



Diabetes mellitus (DM) is an important cause of visual impairment. It affects most of the ocular and visual components in different ways, structurally and functionally. Diabetic retinopathy and diabetic cataract are the main causes of visual loss in DM, although other complications certainly exist. [1] Some of these complications are of a subtle nature, and it may require a very detailed eye examination to reveal some of them. In the areas of screening, monitoring and management of diabetes the diabetic care team is concerned with the relationship between the level of glycemia and complications. It is widely believed that excellent blood glucose control decreases the risk of the diabetic complications. [2],[3],[4]

This article meant to address briefly the different effects of DM on the ocular structures highlighting the most possible complications and suggestion of means of protection.

 ORBIT



Orbito-rhino-mucormycosis is the most dreaded orbital infection caused by mucor fungus. It develops in patients with severe acidosis and poor metabolic control. [5] The clinical signs noted are ptosis, edema, ophthalmoplegia, unilateral proptosis, pain, headache and possibly, a deterioration or drop in visual acuity. [1]

 LIDS



Ptosis is observed in diabetics, and it occurs as a result of isolated palsy of the third nerve. [6] The degree of the lid closure is influenced by duration of diabetes, particularly in type I patients in whom retinal changes are present. [7] Xanthelasma, which are orange-yellow elevated plaques on and around the eyelids, have been reported to occur in patients with poor control. [8] Blepharitis is observed in diabetic patients, perhaps reflecting general proneness to infections. [5]

 EXTRAOCULAR MUSCLES



Diabetes is one of the most frequent causes of an acquired palsy where the onset of sudden diplopia is the main sign. The basic pathology is occlusion of the blood supply to the nerves, inflammation within the trunk of the nerve and involvement of intraneural vessels of the nerve. [9] The neuropathy that results may cause paralysis of the third, fourth and sixth nerves. The diplopia occurring as a result can be treated by patching, prisms or surgery in the event of failure of the first two methods.

 LACRIMAL APPARATUS



There are conflicting reports on the tear secretion of diabetic patients. Schultz et al. (1981) reported a reduction in tear secretion, [10] while others have found no significant difference in secretion in type I with or without retinal involvement. [11] Rubinstein (1987) reported that tear secretion reduction is only present in type II patients; however, the effect of age has to be taken into consideration. [12] Diabetics, who have developed autonomic neuropathy, are more likely to show a decrease in tear secretion rates. Shortened tear break up time and increased tear glucose concentrations are also reported in diabetes. [13],[14],[15]

 AQUEOUS



Hayashi et al. (1989) reported a decreased rate of aqueous formation that was not associated with the degree of retinopathy, duration of diabetes or glucose levels. [16]

 IRIS



Rubeosis iridis is a known complication occurring due to the frequent occlusion of small vessels. New vessels develop from the iris stroma and spread across the iris surface, possibly causing a blockage to the drainage leading to an increase in the intra ocular pressure and may eventually end in neovascular glaucoma. [17] Rubeosis is common in patients with advanced diabetes who invariably have proliferation of blood vessels in the retina. It has been estimated that <5% of patients with milder retinal involvement will develop Rubeosis. However, one to two-thirds of patients with a retinal proliferation who are not laser-treated may develop it also. [18] Pigment deposits, leading to iris melanosis, are reported in diabetes. There is an overgrowth of the posterior pigment epithelium that extends over the edge of the pupil in the margin area forming an apron known as ectropion uveae. The condition is normally a sequel to iris neovascularization.Vacuolization of the iris pigment epithelium loads the cells with glycogen and makes them very fragile. These cells may degenerate and release pigments into the anterior chamber. Pigments may be cast into the aqueous and formed on the corneal endothelial surface. The floater pigments may precipitate extending to the trabecular meshwork leading to pigmentary glaucoma.The pupillary dysfunctions in diabetes are closely related to the duration of diabetes and are accounted for by either myopathy or neuropathy, or both. Sluggish reaction to light has been noticed to be slow in response in both onset and course. Excessive miosis or failure to dilate normally in the dark is also noticed in diabetics. Diabetic pupils also dilate poorly with anti-muscarinics but show supersensitivity with sympathomimetic drugs. [19]

 CILIARY BODY



Thickening of the basement membrane of the ciliary processes was noticed in diabetic subjects compared to nondiabetics. [20]

 INTRAOCULAR PRESSURE



Diabetic patients without background retinopathy have been found to demonstrate a slight (1-2 mmHg) elevation in intraocular pressure (IOP). [21],[22] Traisman et al. (1967) found IOP in cases with retinopathy was greater than that of nondiabetics. [23] It has been reported that young insulin-dependent DM (IDDM) patients (7-18 years) with background diabetic retinopathy have IOPs higher than those without retinopathy-means of 19 mmHg and 14 mmHg respectively. [21] It has been suggested that high IOP protects the retina from neovascularization by physical pressure.

 GLAUCOMA



Glaucoma is more common in diabetic patients. Armstrong et al. (1960) estimated the incidence of glaucoma in diabetics to be about 5.9%. Some studies have shown no difference in the frequency of glaucoma in both diabetics and nondiabetic groups. Such studies indicated that abnormally high IOP was not characteristic of diabetics and concluded that the outflow facility of diabetics when measured with tomography was the same as in nondiabetics. [24]

A later study showed that while IOP in young diabetics was comparable to the normal population, the older diabetics of long duration had diminished outflow and elevated tensions. These findings tend to support a possible relationship between diabetes and glaucoma. [25]

Klein et al. (1984a, b) confirmed that diabetic patients have higher values of IOP than nondiabetics. They assumed 21 mmHg as an upper limit of normal. They found IOP is greater by 5.8% than the normal value in the type I whose age was <30 years and by 7.1% of those who were 30 years or older at time of onset. In type II patients, they found 8.1% of those 30-60 years of age and 8.9% of those 65 years of age or older had IOP more than the normal value. They were able to relate the duration of diabetes to IOP only in the type I patients. [26],[27]

On the other hand, there is a three times greater incidence of primary open-angle glaucoma in diabetics compared to the general population. [28] More frequent family history of primary simple open-angle glaucoma is reported in some studies. [29],[30],[31]

 LENS



Diabetes increases cataract formation by 2-4 times in all age groups and increases it in juvenile patients by 15-25 times. [32],[33] The risk of cataract increases with diabetic duration and experience of poor metabolic control. [34],[35] "True" diabetic cataract is thought to be osmotic in origin, clinically described as "a snow flake" opacity. [36],[37] The formation of age-related cataract appears to be accelerated in diabetics. [38],[39] Collected data indicate that between 10% and 15% of patients undergoing cataract surgery are diabetics. [40],[41]

 REFRACTION



With the lens hydration or dehydration refractive shifts can move toward either myopia or hypermetropia. Recent work suggests that hyperglycemia induces a hypermetropic shift. [42],[43] Sorbitol accumulation within the lens secondary to hyperglycemia is proposed as an explanation for the refractive shifts. [44] A decrease in the accommodation ability has been reported in diabetic patients and probably occurs due to glycogen infiltration of the iris, diabetic neuropathy or alteration of the lens substance. [5]

 CORNEA



Diabetes has been shown to be associated with decreased corneal oxygen consumption, abnormal collagen formation, altered glycosaminoglycans metabolism and thickening of the corneal basement membrane. [45],[46],[47],[48] Diabetes possibly causes epithelial keratopathy that is characterized by slow wound repair, increased permeability and fragility, striate keratitis, glycogen and glucose accumulation, microcystic edema and bleb formation. [49],[50],[51] Endothelial permeability is increased in diabetic patients. Activity of corneal endothelial Na/K adenosine triphosphatase has been shown to be decreased in diabetic animals. [52],[53] Poor diabetic control has been reported to bring about increased stromal hydration and decreased ability to recover from contact lens induced edema. Alteration in corneal endothelial function and biochemistry has been proposed to explain these findings. [54],[55],[56] Corneal sensitivity is decreased in diabetics. Demyelination of the nerve secondary to abnormal lipid metabolism and Sorbitol accumulation within the Schwann cell have been proposed to explain the decrease of corneal sensitivity. [5],[12],[46],[53],[54],[57],[58]

 SCLERA



The sclera seems to be the only part of the eye that is free from any diabetic complications. [59]

 CONJUNCTIVA



Subconjunctival hemorrhages are due to the fragility of the blood vessels' walls. [12] Vessel tortuosities are observed. [60] Microaneurysms are more prevalent in diabetics. [61] Conjunctival hypoxia has been noticed in diabetic patients increasingly with severity of retinopathy and being greatest with Rubeosis iridis. [62]

 DIABETIC RETINOPATHY



Diabetic retinopathy makes blindness 25 times more frequent in diabetics than nondiabetics. [63] Retinopathy may exist in some diabetic patients without visual impairment; however, 15% of diabetics have a level of retinopathy more likely to show market visual impairment if left untreated. [64] Palmberg found that diabetic retinopathy to be responsible for about 10% of the new blind registrations at all ages, about 20% of who were between the ages of 45 and 74 years. [65]

More recent population-based studies show that the prevalence rates of diabetic retinopathy could vary between 24% and 70% depending upon the country of origin of data. [66],[67]

Along with the differences due to the age factor, the two main diabetic types are reported to affect the diabetic retinopathy incidences differently. There are big variations in the reported incidence of DR in different studies. In IDDM patients, the incidence is about 40% whereas in non-IDDM (NIDDM) it is 20%. Khan et al. (1974) [68] noted some degree of retinopathy in 97% of insulin-dependent diabetic patients after 15 years of diabetic duration and in about 60% of insulin-treated diabetics. However, the prevalence of retinopathy was noted by this study to be greatest in the insulin dependent diabetic, three to six times greater, up to 80% of all cases, and 60% of proliferative cases were noninsulin-dependent diabetic patients.

Selective loss of retinal capillary perciytes (mural cells) is agreed to be the early anatomical change in diabetics. These cells are thought to control blood flow through the retinal vasculature and may also contribute to the stability of the vessel wall. Abnormalities of the integrity of blood-retinal barrier and the blood flow in retinal blood vessels may exist before any anatomical lesion is evident.

Fluorescein angiography has allowed the breakdown of the blood-retinal barrier to be demonstrated. However, good control of glycemia has been noted to resolve the leakage seen in the retinal vessels. Early leakage of fluorescein into the vitreous was reported to be found, possibly days after the diagnoses of diabetes. [63] This leakage has been taken as evidence of an early damage to the blood-retinal barrier before any other demonstrable abnormalities are found.

A group of elements are recognized as giving the clinical features of diabetic retinopathy. They are: Microaneurysms; venous abnormalities; hemorrhages; edema; exudates; new vessel formation; glial proliferation; vitreoretinal traction. All of these elements appear in the different types according to the development and progression of diabetic retinopathy. The most suitable classification based on the literature survey for diabetic retinopathy is:

Background or nonproliferative diabetic retinopathy.Preproliferative diabetic retinopathy.Maculopathy: Ischemic.

Cystoid.Focal.Proliferative diabetic retinopathy.Advanced diabetic ocular disease: Vitreous hemorrhage.

Detachment traction.Opaque membrane formation.Neovascular glaucoma.In general, the clinical feature of nonproliferative diabetic retinopathy is an alteration in the original retinal vasculature, however, proliferative retinopathy is characterized by neovascularization and fibrous tissues.

Photocoagulation is a useful, however, not curative means of eliminating diabetic retinopathy. Photocoagulation should be attempted early before the development of visual symptoms and retinal traction complications. Regression of the new vessels has been reported to occur in 80% of the treated cases, and 61% fewer eyes become blind in those treated as compared to those untreated. [5]

The more recent elucidation of the role of vascular endothelial growth factor (VEGF) in the pathogenesis of both types of diabetic retinopathy, and the ability to specifically inhibit VEGF effects by the intraocular injection of blocking agents offer new options of nondestructive treatment with better visual outcomes than laser. [69]

 DIABETIC MACULOPATHY



The clinical features of diabetic maculopathy are microaneurysms, hemorrhages, hard exudates and edema, all concentrated at the macular causing central visual impairment. It is more common in elderly type II diabetics soon after diagnosis of diabetes. [70] In Donovan's and Rowbotham (1978) clinical sample out of 23% of patients with diabetic retinopathy, 6.1% were reported to have diabetic maculopathy. [71] Aiello et al. (1981) had observed that macular edema in patients who were <50 years in age was usually associated with preproliferative and proliferative stages of diabetic retinopathy. Different types of diabetic maculopathies are noticed, and each type is related to the extent of the leakage and occlusions in the retina. [72] Diabetic macular edema may also respond to intraocular steroid therapy, and the development of slow-release delivery systems can now provide drug delivery for 3 years from a single injection. The assessment of diabetic macular edema has been revolutionized by noninvasive imaging with ocular coherence tomography which allows microscopic visualization of macular detail and serial quantitative measurement of the structural response to treatment. These new therapeutic options are improving visual outcomes for diabetic macular edema. [69]

 OTHER MISCELLANEOUS DISORDERS



Optic atrophy occurs about 30% more frequently in diabetic eyes than in the general population. Moreover, it occurs in diabetics with long-standing proliferative retinopathy. [73] Retrobulbar neuritis, possibly vascular in origin following widespread ischemic changes, or secondary to peripheral neuropathy is sometimes seen in diabetics. [74] Exophthalmos, rarely due to diabetes, is of acute superlative-mucormycosis form when it occurs. [75] Lipemia retinalis is a rare condition due to an abnormally high lipoid content of the blood. It is characterized ophthalmoscopically by enlarged flat, ribbon like retinal arteries and veins that vary in color from salmon to pink to cream making it difficult to differentiate one from the other. It usually occurs in uncontrolled ketotic young individuals with xanthomata, indicative of long-standing hyperglycemia. [75] Fifteen percent of cases of asteroid hyalitis and synchisis scintillans are observed to be diabetics. [76] Toxic amblyopia has been reported to occur in diabetics and is associated with poor diabetic control. [73] In general, the visual loss in diabetes occurs gradually as a result of cataract, macular edema, toxic amblyopia, glaucoma, optic atrophy and diabetic retinopathy. On the other hand, the visual loss may occur suddenly as in the late stages of diabetic retinopathy or as a result of vascular accident, either retinal or cerebral.The ocular problems due to diabetes are inevitable; however, early detection and medical intervention can make a difference in the progression of such complications.

Clinician continuous clinical training alongside well-designed screening and monitoring programs would count as the key element of quality caring service for the diabetic population which increasing substantially. The facing side to those elements should be attractive educational sessions to pass the knowledge and understanding of DM and its' possible complications to the diabetics and their families. The work needs cooperation of the concerned formal and voluntary organizations to implement agreed strategic plans.

References

1Henkind P. The eye in diabetes mellitus: Signs, symptoms and their pathogenesis. In: Mausolf FA, editor. The Eye and Systemic Disease. St. Louis: CV Mosby; 1980. p. 187-203.
2Cahill GF, Etzwiler DD, Freinkel N. Control and diabetes. N Engl J Med 1976a;294:1004-5.
3Cahill GF, Etzwiler DD, Freinkel N. Blood glucose control in diabetes. Diabetes 1976b;25:237-9.
4Ingelfinger FJ. Debatees on diabetes. N Engl J Med 1977;296:1228-30.
5L'Esperance FA, James WA. The eye and diabetes mellitus. In: Ellengberg M, Rifkin H, editors. Diabetes Mellitus: Theory and Practice. 3 rd ed. New York: Medical Examination Publishing; 1983. p. 727-58.
6Kanski JJ. Clinical Ophthalmology. London: Butterworth's; 1984.
7Bastiaensen LA. Narrowing of the palpebral fissure in diabetes. Doc Ophthalmol 1983;56:5-10.
8Waite JH, Beetham WP. The visual mechanism in diabetes mellitus. N Engl J Med 1935;212:367-443.
9Asbury AK, Aldredge H, Hershberg R, Fisher CM. Oculomotor palsy in diabetes mellitus: A clinico-pathological study. Brain 1970;93:555-66.
10Schultz RO, Van Horn DL, Peters MA, Klewin KM, Schutten WH. Diabetic keratopathy. Trans Am Ophthalmol Soc 1981;79:180-99.
11Andersen J, Baun O, Aamand HE. Tear secretion in juvenile diabetics with and without autonomic neuropathy. Acta Ophthalmol (Copenh) 1985;63:93-6.
12Rubinstein MP. Diabetes, the anterior segment and contact lens wear. Contact Lens J 1987;15:4-11.
13Foulks GN, Thoft RA, Perry HD, Tolentino FI. Factors related to corneal epithelial complications after closed vitrectomy in diabetics. Arch Ophthalmol 1979;97:1076-8.
14Gassett AR, Braverman LE, Fleming MC, et al. Tear glucose detection of hyperglycaemia. Am J Ophthalmol 1968;64:1149-51.
15 Sen DK, Sarin GS. Tear glucose levels in normal people and in diabetic patients. Br J Ophthalmol 1980;64:693-5.
16Hayashi M, Yablonski ME, Boxrud C, Fong N, Berger C, Jovanovic LJ. Decreased formation of aqueous humour in insulin-dependent diabetic patients. Br J Ophthalmol 1989;73:621-3.
17Zirm M. Protein glaucoma - Overtaxing of flow mechanisms? Preliminary report. Ophthalmologica 1982;184:155-61.
18Liang JC. Diabetic eye disease. In: Wilensky JT, Read JE, editors. Primary Ophthalmology. New York: Grune and Stratton; 1984. p. 193-210.
19Huber MJ, Smith SA, Smith SE. Mydriatic drugs for diabetic patients. Br J Ophthalmol 1985;69:425-7.
20Yamashita T, Becker B. The basement membrane in the human diabetic eye. Diabetes 1961;10:167-74.
21Blanksma LJ, Rouwe C, Drayer NM. Retinopathy and intraocular pressure in diabetic children. Ophthalmologica 1983;187:137-40.
22Klein BE, Klein R, Moss SE. Intraocular pressure in diabetic persons. Ophthalmology 1984;91:1356-60.
23Traisman HS, Alfano JE, Andrews J, Gatti R. Intraocular pressure in juvenile diabetics. Am J Ophthalmol 1971;64:1149-51.
24 Armstrong JR, Dialy RK, Dobson HL, et al. The incidence of glaucoma in diabetes mellitus. A comparison with the incidence of glaucoma in the general population. Am J Ophthalmol 1960;50:55-63.
25Safir A, Paulsen EP, Klayman J, Gernsenfield J. Ocular abnormalities in juvenile diabetes. Arch Ophthalmol 1966;76:557-62.
26Klein R, Klein BE, Moss SE, Davis MD, De Mets DL. The Wisconsin epidemiologic study of diabetic retinopathy II: Prevalence and risk of diabetic retinopathy when age at diagnosis is more than 30 years. Arch Ophthalmol 1984a;102:520-6.
27Klein R, Klein BE, Moss SE, Davis MD, De Mets DL. The Wisconsin epidemiologic study of diabetic retinopathy II: Prevalence and risk of diabetic retinopathy when age at diagnosis is more than 30 years. Arch Ophthalmol 1984b;102:527-32.
28Becker B. Diabetes mellitus and primary open-angle glaucoma. Am J Ophthalmol 1971;71:1-13.
29Armaly MF, Baloglou PJ. Diabetes mellitus and the eye. II: Intraocular pressure and aqueous outflow facility. Arch Ophthalmol 1967b;77:493-502.
30Wilensky JT. Glaucoma. In: Peyman GA, Sanders DR, Goldberg MF, editors. Principle and Practice of Ophthalmology. Vol. 1. Philadelphia: W.B. Sanders and Co.; 1980. p. 671-737.
31Aiello LM, Rand LI, Sebestyen JS, Weiss JN, Bradbury MJ, Wafai MZ, et al. The eye and diabetes. In: Marble A, Krall LP, Bradley FR, Christlieb AR, Soeldner JS, editors. Joslin's Diabetes Mellitus. 12 th ed. Philadelphia: Lea and Febinger; 1985. p. 600-34.
32Ederer F, Hiller R, Taylor HR. Senile lens changes and diabetes in two population studies. Am J Ophthalmol 1981;91:381-95.
33Bernth-Petersen P, Bach E. Epidemiologic aspects of cataract surgery III: Frequencies of diabetes and glaucoma in a cataract population. Acta Ophthalmol 1983;61:406-16.
34Schwab IR, Dawson CR, Hoshiwara I, Szuter CF, Knowler WC. Incidence of cataract extraction in Pima Indians. Diabetes as a risk factor. Arch Ophthalmol 1985;103:208-12.
35Klein R, Klein BE, Neider MW, et al. Diabetic retinopathy as detected using ophthalmoscopy, a non-mydriatic fundus camera and a standard fundus camera. Ophthalmology 1985;92:485-91.
36Hiller R, Khan HA. Senile cataract extraction and diabetes. Br J Ophthalmol 1976;60:283-6.
37Varma SD, Richards RD. Aetiology of cataracts in diabetes. Int Ophthalmol Clin 1980;24:93-110.
38White FA, Richert HM. Accelerated bilateral cataract formation in insulin-dependent diabetes mellitus. Diabetes Care 1984;7:186-7.
39Cotlier E, Sharma YR. Senile cataract acceleration by diabetes and deceleration by aspirin. Can J Ophthalmol 1981;16:118-20.
40Gilvarri A, Eustace P. The medical profile of cataract patients. Trans Ophthalmol Soc UK 1982;102:502-4.
41Liang JC. Diabetic eye disease. In: Wilensky JT, Read JE, editors. Primary Ophthalmology. New York: Grune and Stratton; 1984. p. 193-210.
42Feinblum SM. Clinical significance of refractive changes in diabetes. Optom wkly 1972;63:199-206.
43Fledelius HC. Refractive change in diabetes mellitus around onset or when poorly controlled. A clinical study. Acta Ophthalmol (Copenh) 1987;65:53-7.
44 Fledelius HC, Fuch J, Reck A. Refraction in diabetes during metabolic disregulation, acute or chronic. Acta Ophthalmol 1990;68:275-80.
45Graham CR, Richards RD, Varma SD. Oxygen consumption by normal and diabetic rat and human corneas. Ophthal Res 1981;13:65-71.
46Alberti KG, Press CM. The biochemistry of diabetes mellitus. In: Keen H, Jarrett J, editors. The Complications of Diabetes. London: Edward Arnold; 1982. p. 231-70.
47Malthy K, Kurup PA. Metabolism of glycosaminglycans in alloxan induced diabetic rats. Diabetes 1972;21:1162-7.
48Ishii Y, Lahav M, Mukai Y. Corneal changes in diabetic patients and streptozotocin-diabetic rats. Invest Ophthalmol Vis Sci 1981;20 Suppl:154.
49Benson WE, Brawn GC, Tasman W. Diabetes and its Ocular Complications. Philadelphia: W.B. Saunders and Co.; 1988. p. 110-20.
50Friend J, Kiorpes TC, Thoft RA. Diabetes mellitus and the rabbit corneal epithelium. Invest Ophthalmol Vis Sci 1980;21:317-21.
51Friend J, Ishii Y, Thoft RA. Corneal epithelial changes in diabetic rats. Invest Ophthal Res 1982;14:269-78.
52Lass JH, Spurney RV, Dutt RM, et al. A morphologic and flouorophotometric analysis of the corneal endothelium in type I diabetes mellitus and cystic fibrosis. Am J Ophthalmol 1985;100:783-8.
53Herse PR. Corneal hydration control in normal alloxan-induced diabetic rats. Invest Ophthalmol Vis Sci 1990;31:2205-13.
54Busted N, Olsen T, Schmitz O. Clinical observation on the corneal thickness and corneal endothelium in diabetes mellitus. Br J Ophthalmol 1981;65:687-90.
55Olsen T, Busted N. Corneal thickness in eyes with diabetic and nondiabetic neovascularisation. Br J Ophthalmol 1981;65:691-3.
56Drager J. Corneal Sensitivity: Measurement and Clinical Importance. Vienna: Springer-Verlag; 1984.
57Macrase SM, Engerman RL, Hatchell D. Corneal sensitivity and control of diabetes. Cornea 1982;1:223-6.
58Nielsen NV. Corneal sensitivity and vibratory perception in diabetes mellitus. Acta Ophthalmol (Copenh) 1978;56:406-11.
59Block RS, Henkind P. Ocular manifestations of endocrine and metabolic disease. In: Dune JD, Jaeger EA, editors. Clinical Ophthalmology. Ch. 21. Philadelphia: JB Lippincott; 1985. p. 8-9.
60Hampton FR. Ocular Differential Diagnosis. 3 rd ed. Philadelphia: Lea and Febinger; 1984.
61Armaly MF, Baloglou PJ. Diabetes mellitus and the eye. I: Changes in the anterior segment. Arch Ophthalmol 1967a;77:485-92.
62Isenberg SJ, Mcree WE, Jedrzynski MS. Conjunctival hypoxia in diabetes mellitus. Invest Ophthalmol Vis Sci 1986;27:1512-5.
63Marble A. Insulin in the treatment of diabetes. In: Marble A, Krall LP, Bradley FR, Christlieb AR, Soeldner JS, editors. Joslin's Diabetes Mellitus. 12 th ed. Philadelphia: Lea and Febinger; 1985. p. 380-402.
64Kohner EM. Diabetic retinopathy. Br Med Bull 1989;15:148-73.
65Palmberg PF. Diabetic retinopathy. Diabetes 1977;26:703-11.
66Mitchell P. The prevalence of diabetic retinopathy: A study of 1300 diabetics from Newcastle and the Hunter Valley. Aust J Ophthalmol 1980;8:241-6.
67Nielsen NV. Diabetic retinopathy. II: The course of retinopathy in diabetes treated with oral hypoglycaemic agents and diet regime alone. A one year epidemiological cohort study of diabetes mellitus. The island of Falster, Denmark. Acta Ophthalmol 1984;62:266-73.
68Khan HA, Hiller R. Blindness caused by diabetic retinopathy. Am J Ophthalmol 1974;78:58-67.
69Towler HM. A new technologies and drugs in the management of diabetic retinopathy. Pract Diabetes 2014;31:275-80.
70Bodanski HJ, Cudworth AG, Whitelocke RA, Dobree JH. Diabetic retinopathy and its relation to type of diabetes - Review of retinal clinic population. Br J Ophthalmol 1982;66:496-9.
71Donovan JC, Rowbotham JL. Foot lesion in diabetic patients: Cause, prevention and treatment. In: Marble A, Krall LP, Bradley FR, Chirstlieb AR, Soeldner JS, editors. Joslin's Diabetes Mellitus. 12 th ed. Philadelphia: Lea and Febinger; 1985. p. 732-6.
72Aiello L, Rand LI, Briones JC, Wafal MR, Sebestyen JS. Diabetic retinopathy in Joslin clinic patients with adult-onset diabetes. Ophthalmology 1981;88:619-23.
73Bonar JR. Diabetes: A Clinical Guide. London: Henry Kimpton; 1977.
74Rosenberg MA. Neuro-ophthalmology. In: Peyman GA, Sanders DR, Goldberg MF, editors. Principles and Practice of Ophthalmology. Vol. 3. Philadelphia: W.B Sanders and Co.; 1980. p. 1917-81.
75Jampol LM. Ocular manifestations of selected systemic disease. In: Peyman GA, Sanders DR, Goldberg MF, editors. Principles and Practice of Ophthalmology. Vol. 3. Philadelphia: W.B Sanders and Co.; 1980. p. 1633-71.
76Caird FI, Pirie A, Ramsell IG. Diabetes and the Eye. Oxford: Blackwell Scientific Publications; 1969.