diabetic choroidopathy

Diabetic Choroidopathy

Light and Electron Microscopic Observations of Seven Cases

AHMED A. HIDAYAT, MD, BEN S. FINE, MD

Abstract: The choroid of seven young patients (ages 20-29 years), who had had diabetes mellitus for many years (14-23 years) was studied by light and electron microscopy. The eight enucleated eyes were blind and painful as a complication of diabetes mellitus. Histopathologically, the choriocapillaris and other small choroidal blood vessels disclosed marked basement membrane thickening of their walls. Periodic acid-Schiff-positive homogeneous acellular nodules were present and resembled those of diabetic glomerulosclerosis (Kimmelsteil-Wilson disease). Some choroidal arteries were arteriosclerotic. Choroidal compromise was suggested by luminal narrowing of the capillaries, capillary dropout, and focal scarring. Choroidal neovascularization with subretinal fibrovascular membranes occurred in two patients at the midperiphery and periphery, and resembled those of retinitis proliferans. Leakage of proteinaceous fluid into the choroidal stroma and beneath the focally detached pigment epithelium was suggested by the electron microscopic observations. Choroidal vasculopathy in diabetes mellitus is similar to much of what has been described in other tissues of the eye and body, and suggests an important role in the pathogenesis of diabetic retinopathy since the outer retinal layers are largely dependent on the choroid for their nutrition and oxygenation. [Key words: basement membrane, choroidal neovascularization, diabetes mellitus, diabetic choroidopathy.] Ophthalmology 92:512-522, 1985

Diabetic microangiopathy has been described in various organs and tissues throughout the body_ 1-10 Its complications . are well-known, particularly in the kidney4.5 and retina,6-1O but very little has been mentioned about the choroid, a well vascularized structure containing the choriocapillaris that provides nutrients and oxygen to the outer retinal layers and foveola where visual function is most acute. II ,12 As early as 1969

Yanoff8 directed attention to the choroid in diabetic patients_ He pointed out the increased incidence of arteriosclerosis and deposition of periodic acid-Schiff (PAS)-positive material in the thickened walls of arterioles and capillaries_ There has been little emphasis on the diabetic choroidal vasculature since.13 In this report, we have limited our study to young patients (Type I diabetics) in order to avoid confusion with arteriosclerotic or other senile changes that may be present in elderly individuals_ The main purpose of this report is to document the histopathologic changes and complications of the choroid in diabetes mellitus and compare them with the changes previously described in other tissues of

From the Department of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington, DC.

Supported in part by Research Grant EY-03060 from the National Eye Institute, National Institutes of Health, Bethesda, Maryland.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

Reprint requests to Ahmed A. Hidayat, MD, Armed Forces Institute of Pathology, Washington, DC 20306.

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the eye and body _ .

MATERIALS AND METHODS

The choroid of six surgically enucleated eyes and two eyes obtained at autopsy from seven young patients

HIDAYAT AND FINE • DIABETIC CHOROIDOPATHY

Table 1. Clinical Data on Seven Cases of Diabetic Choroidopathy

Patient No.! Sex/Age Duration of (years) Disease (years) General Condition

1/M/20 15 Unknown 2/M/26 Many Diabetic nephropathy,

chronic renal failure; blood pressure slightly elevated

3/M/29 Many Diabetic nephropathy, chronic renal failure

4/F/27 17 Diabetic nephropathy chronic renal failure, renal transplant, nephrotic syndrome, severe arteriosclerosis of aorta and coronary arteries

5/M/24 14 Diabetic nephropathy, chronic renal failure, blood pressure 160/80

6/F/29 20 Good, blood pressure 120/70

7/F/26 23 Diabetic nephropathy, renal transplant; blood pressure 120/70

(aged 20-29 years), who had had insulin dependent diabetes mellitus for many years (Type I diabetics) were studied by light and electron microscopy. Hematoxylineosin, PAS with and without prior treatment with diastase, Movat's and Masson trichrome stains were used in all cases. For electron microscopy, the choroid of the 10% formalin-fixed eyes was sampled at the foveomacular and parafoveal areas in seven eyes, midperiphery in four, and periphery in four. The tissues were processed according to a previously described technique. 14

RESULTS

CLINICAL FINDINGS

The clinical data are summarized in Table 1. The young patients ranged in age at the time of enucleation from 20 to 29 years (median age, 26 years). The four men and three women who had diabetes mellitus were insulin dependent, and the duration of their disease ranged from 14 to 23 years. In three cases (cases 1, 2, 4), the disease was poorly controlled. In one (case 7), it was well controlled, while in the remaining three the control status of the disease was unknown. The six surgically enucleated eyes (cases 1-3, 5-7) were blind and painful as a late complication of diabetes mellitus with proliferative retinopathy, total retinal detachment, intraocular hemorrhage, and secondary neovascular glaucoma. The two autopsy eyes (case 4) showed retinitis proliferans, vitreous hemorrhage, and rubeosis iridis. Five patients had had renal failure as a result of diabetic

nephropathy and were either on renal dialysis or received a kidney transplant. One patient had slightly impaired kidney functions (case 6). In the remaining patient (case 1), the status of renal function was not known. The blood pressure was elevated in three individuals (cases 2,4, 5), normal in two (cases 6, 7) and unknown in the remaining two (cases 1, 3). Except for one patient, case 4, no retinal photocoagulation was done.

PATHOLOGIC STUDIES

Light microscopy. The histopathologic changes in the chorioc?pillaris were quite irregular (Figs 1-5). Some capillaries appeared normal while others had narrow lumens and walls focally or diffusely thickened by a homogeneous PAS-positive diastase-resistant material that in some instances completely obliterated the capillary lumen. Similar PAS-positive material was occasionally present in the thickened walls of larger blood vessels such as arterioles and small arteries. At the level of the choriocapillaris and the underlying stroma, there were a few small nodules composed of acellular eosinophilic amorphous material that stained positive with PAS stain and were resistant to diastase. These nodules varied in size and shape and were located mainly at the posterior pole and juxtapapillary areas in five patients. They closely resembled the PAS positive nodules in the renal glomeruli in patients with diabetic glomerulosclerosis (Kimmelsteil-Wilson disease). In many instances, there was dropout of the capillaries with or without fibrosis throughout the choroid (Fig 5). Neovascularization was present in two patients. In the first patient (Fig 6), it was present at the periphery near the ora serrata where delicate vascular channels associated with a fibrous component grew out of the choroid through the disrupted Bruch's membrane and pigment epithelium into the subretinal space, and resembled the histopathologic process of retinitis proliferans. In the second case, the small delicate blood vessels were present between the pigment epithelium and Bruch's membrane near the mid-periphery. In both patients with choroidal neovascularization, the retina was totally detached with blood present in the subretinal space and choroid. There was no history of retinal photocoagulation in either case.

Small foci of hyperplasia (Fig 7) and/or atrophy of retinal pigment epithelium (Fig 8) were present. Small drusen were also present. Some of the choroidal arteries were arteriosclerotic with thickened hyalinized walls, intimal proliferation, and narrowed lumens (Fig 9). In two eyes, there was focal hemorrhage beneath the detached pigment epithelium (Fig 10). Proliferative retinopathy was far advanced in all patients, and in six of eight cases, the atrophic retina was totally detached with massive proteinaceous exudate, sometimes admixed with blood in the subretinal space.

Electron microscopy. Normal eyes have a choriocapillaris with wide lumens and a fenestrated endothelium completely surrounded by a thin basement membrane (basal lamina).12 The diabetic eyes showed widespread and more extensive thickening of the choriocapillaris

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OPHTHALMOLOGY • APRIL 1985 • VOLUME 92 • NUMBER 4

Fig l. Top left . foveomacula. Diffuse thickening of choroidal vessel walls by periodic acid-Schiff-positive material. The choriocapillaris is prominently involved and occluded on the right. Pigment epithelium absent here (periodic acid-Schiff, X630; AFIP Neg. 83-10258). Fig 2. Top righl. papillomacular bundle. Periodic acid-Schiff-positive thickening of choriocapillaris and feeder vessel are apparent. Adjacent periodic acidSchiff positive nodules are present in the plane of the choriocapillaris. Bruch's membrane is not significantly thickened (periodic acid-Schiff, X630; AFIP Neg. 83-10259). Fig 3. Center left, juxtapapillary choroid nasal to disc. Large periodic acid-Schiff-positive nodules are present in the choriocapillaris layer as well as deeper on the choroid (periodic acid-Schiff, x 630; AFIP Neg. 83-10260). Fig 4. Center right, foveomacula. Diffusely thickened periodic acid-Schiff-positive walls of choriocapillaris are apparent. The lumina are compromised and the intercapillary spaces are enlarged (periodic acid-Schiff, X630; AFIP Neg. 83-10257). Fig 5. Bollom left. papillomacular region. There is widespread loss of the choriocapillaris, with replacement by collagenous tissue (Masson trichrome, X400; AFIP Neg. 84-5061). Fig 6. Bottom right, peripheral choroid. There is neovascularization of the choroid (arrows) and rupture through Bruch's membrane and pigment epithelium into the subretinal space by the newly formed fibrovascular tissue (Masson trichrome, X157; AFIP Neg. 83-10255).

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Fig 7. Focal hyperplasia of retinal pigment epithelium at midperiphery with adjacent atrophic area (hematoxylin-e~sin, X400; AFIP Neg. 84-7807).

Fig 9. Severe arteriosclerosis of a choroidal artery with luminal obliteration. The adjacent choriocapilIaris is also obliterated (hematoxylin-eosin, X400; AFIP Neg. 84-7808).

basement membrane either focally or diffusely, that appeared in various forms including homogeneous, multilaminar, ordered banded, and disordered banded varieties (Figs 11-15). The location of abnormal basement membrane materials corresponded to the homogeneous PAS-positive material in the capillary walls and other larger blood vessels as seen by light microscopy.

Frequently, basement membrane thickening was more prominent along the outer wall (scleral side) of the choriocapillaris near the pericytes (Figs 11, 13, 14). The lumens of many capillaries were significantly narrowed (Figs 11-14) and occasionally completely obliterated (Fig 15) by excessive basement membrane material corresponding to the PAS-positive homogeneous nodules. The widened intercapillary spaces also contained abnormal basement membrane material.

On rare occasions, capillary lumens were markedly narrowed by hypertrophy and hyperplasia of the lining endothelial cells. Throughout the choroid, there was

Fig 8. Atrophy of retinal pigment epithelium at midperiphery. (hematoxylin-eosin, X400; AFIP Neg. 87-7810).

Fig 10. The distorted retinal pigment epithelium is separated from the irregularly folded Bruch's membrane (B) by blood (arrow). Blood is also present in the congested choroid (Movat pentachrome, X60; AFIP Neg. 84-7809).

drop-out of the capillaries with replacement by many collagen fibrils or excessive basement membrane material (Fig 15). Some larger choroidal blood vessels also showed thickening of their walls by accumulating abnormal basement membrane materials (Fig 11).

Increased amounts of fibrin within the lumens of some capillaries and other blood vessels was observed in four patients (Fig 16). Leakage of proteinaceous exudate into the choroidal stroma and beneath the focally detached retinal pigment epithelium was suggested by the presence of minute electron dense particles that were quite similar to the particles of plasma protein within the adjacent blood vessel lumens (Fig 17). The detached retinal pigment epithelium showed degenerative

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M

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Fig 12. Region of choriocapillaris (CH), foveomacula. Thin basement membrane (arrows) of pigment epithelium (P Ep) is unaltered. Focal hyperproduction of choriocapillaris homogeneous basement membrane has occurred along the inner capillary wall ("drusen" of choriocapiUaris). Segments of ordered banded basement membrane are present within the choriocapillaris drusen. Adjacent, to the left, are myriad fragments of disordered banded basemen! membrane (DB). The outer capillary basement membrane (BM) is also focally thickened. (X 15,000; AFIP Neg. 84-9641).

changes with intracellular and intercellular edema, loss of melanin pigment, and presence of cytoplasmic microfilaments. Occasional macrophages engulfing melanin granules were present in the subretinal pigment epithelial spaces. Bruch's membrane including the basement membrane of the retinal pigment epithelium was of normal thickness (Figs II-IS).

DISCUSSION

One of the characteristic features of diabetic microangiopathy is basement membrane thickening of the capillary wall in various tissues throughout the body includ-

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ing the kidney, retina, and muscle.2,4,7,9,13,15-17 In similar fashion, this abnormality was present in the choriocapillaris and other small choroidal blood vessels where basement membrane thickening was so marked as to cause significant luminal narrowing of many capillaries throughout the choroid. The capillary wall was either focally or diffusely thickened. The excessive basement membrane accumulation was often more localized to the outer (scleral) side of the choriocapillaris where the pericytes are normally present. These findings suggest that the pericytes share with the endothelial cells in producing the excessive basement membrane materials that frequently appeared by electron microscopy as homogeneous or multilaminar or both. In addition, other abnormal morphological forms of basement mem-

Fig II. Inner choroid, foveomacula. Segment of choriocapiJlaris (CH) is small. Thickening of the basement membrane is most apparent along the outer capillary wall. Masses of disordered banded basement membrane form the intercapillary columns. Masses of multilaminar (M), homogeneous (H), and disordered banded (DB), basement membrane lie along the inner wall of a deeper choroidal vessel. A moderately thickened basement membrane (arrows) lies along the vessel outer wall. PE = pigment epithelium; bm = normally thin basement membrane of pigment epithelium (X 10,500; AFIP Neg. 84-9638).

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Fig 13. Choriocapillaris, foveomacula. F1attened red blood cell occupies lumen of shrunken choriocapillaris. Outer basement membrane (BM) mostly homogeneous, is thickened. Thin basement membrane (arrows) of pigment epithelium (P Ep) is unaltered (X7,500; AFIP Neg. 84-9639).

brane were present including the ordered and disordered banded varieties. 12,13

Although basement membrane thickening is a consistent finding in diabetes mellitus, it has been described in a variety of pathologic conditions ranging from the metabolic to the neoplastic and from the inherited to the immunologic. 13,17 Therefore, although characteristic, it should not be considered as a pathognomic finding. It is interesting to note that the eosinophilic homogeneous nodules in the choroid at the posterior pole and juxtapapillary region in many of our patients were similar to those described in the renal glomeruli I in the nodular variant of diabetic glomerulosclerosis (Kimmelsteil-Wilson disease).4 At both sites, these nodules are PASpositive and diastase resistant. The choroidal nodules are not to be confused with drusen, which are focal deposits of varieties of basement membrane produced by the retinal pigment epithelium. Drusen are also PASpositive and diastase resistant. Electron microscopic studies of these choroidal nodules revealed excessive accumulation of an abnormal basement material some-

( Fig 14. Choriocapillaris, parafovea, Segment of choriocapillaris is markedly shrunken and completely encircled by multilaminar basement membrane. A calcific spherule (Ca), mostly lost, is present in the outer basement membrane. Thin basement membrane (arrows) of pigment epithelium is unaltered (original magnification X9900; AFIP Neg. 84-9649).


Fig 15. Inset: parafovea. Two nodules (arrows) of almost homogeneous material are present in the plane of the choriocapillaris (paraphenyJene-diamine, X252; AAP Neg. 84-7811). A portion of one nodule is seen in the electron micrograph. The endothelial cell (EN) is enveloped by some multilaminar (M) basement membrane and more abundant homogeneous (H) basement membrane. Aggregates of disordered banded (DM) basement membrane are also present. Bruch's membrane and the thin basement membrane (arrows) of the pigment epithelium are normal (X8800; AFIP Neg. 84-9640).

times with trapped endothelial cells (Fig 15) at the sites of degenerated capillaries and other small blood vessels. To the best of our knowledge, similar PAS-positive nodules have not been previously described in other ocular disorders. Therefore, it is reasonable to assume that their presence in the choroid is characteristic of diabetes mellitus.

In our patients, choroidal compromise was strongly suggested by capillary drop-out with and without fibrosis and the significant luminal narrowing of the capillaries by basement membrane accumulation or less commonly by endothelial hypertrophy in the eyes with far advanced disease. Choroidal compromise could have an adverse effect on the retina where its outermost layers largely depend on the choroid for oxygenation and nutrition. The retinas of six patients in this report showed marked

atrophy and gliosis of all layers in addition to the presence of proliferative retinopathy. Only in one patient, whose eyes were obtained at autopsy, did the retina show proliferative retinopathy without significant atrophy or gliosis.

It is well known that in diabetes mellitus microaneurysms and neovascularization of the retina and kidney occur.4

- 9 In this report, we have 'documented a similar process in the choroid in two patients who were not treated by retinal photocoagulation. In the first patient, the newly formed small blood cells were located between the pigment epithelium and Bruch's membrane at the midperiphery. In the second patient, choroidal neovascularization occurred at the periphery near the ora serrata where multiple delicate choroidal vascular channels coursed through the ruptured Bruch's membrane

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Fig 16. Parafovea. Vessel in plane of choriocapillaris. Fibrin is present in vessel lumen. Dark fragments outside of vessel wall represent segments of ordered banded basement membrane (see enlarged inset). Thin basement membrane (arrows) of pigment epithelium is not altered. CH = choriocapillaris (X 10,500). Inset compares intravascular fibrin (FJ) (200A banding) with extravascular ordered banded basement membrane (08) (lOOOA banding) at higher magnification (X2S,000; AFIP Neg. 84-9641).

and pigment epithelium into the subretinal space and were associated with a fibrous component closely resembling ,the process of proliferative diabetic retinopathy (Fig 6). By analogy, such a process might be called "proliferative choroidopathy". In both patients, the choroid was hemorrhagic, and the atrophic retina was totally detached with proteinaceous exudate containing red cells in the subretinal space. Clinically, diabetic

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patients develop breakdown of the blood-retinal barrier in the eye and proteinuria the latter being the most constant and often earliest clinical manifestation of kidney involvement.4 Similarly, our electron microscopic studies were highly suggestive of excessive leakage of proteinaceous exudate into the choroid and beneath the pigment epithelium (Fig 17). It is quite possible that the proteinaceous exudate in the subretinal space, which


Fig 17. Foveomacula. Retinal pigment epithelium detached and a few red blood cells (RBe) with associated proteinaceous exudates are present. Bruch's membrane is grossly altered, being recognizable by a few remaining masses of ordered banded (OB) basement membrane and disordered banded (DB) basement membrane. The vessel lumen contains a proteinaceous material that appears identical with the proteinaceous extravascular material in the choroidal stroma as well as in the subpigment epithelial space (X8300; AFIP Neg. 84-9643).

was often seen in our patients by light microscopy, was at least partially caused by excessive leakage from the choriocapillaris.

Our morphologic observations of increased amounts of fibrin (Fig 16) within the lumens of some capillaries and larger blood vessels are compatible with previous reports in which biochemical and immunofluorescent studies indicated its presence. 18, J9

Although foci of hyperplasia and atrophy of the retinal pigment epithelium were encountered in our young diabetic patients, its normally thin basement membrane was not thickened and the remainder of Bruch's membrane was also of normal thickness.

The choroidal changes described in this report are related to advanced diabetes. It would be important, however, to know the condition of the choroid at earlier stages of the disease, but it is difficult to obtain such material. It is also difficult to evaluate the condition of the diabetic choroid by routine ophthalmoscopic examination. Perhaps, more detailed scrutiny of early

phase fluorescein angiograms would be helpful in the clinical assessment of choriocapillaris and/or choroidal integrity and function in this disease at an early stage.

We conclude from this study that choroidal vasculopathy in diabetes is similar to much of what has been described in other tissues of the eye and body. It also suggests that choroidal vasculopathy may play a larger role in the pathogenesis of diabetic retinopathy than has been considered to date.

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