Retinal Ischemia in Diabetic Retinopathy George
H.
Bresnick, MD; Guillermo
De
Venecia, MD;
\s=b\ Eight patients with proliferative diabetic retinopathy developed extensive retinal arteriolar and capillary obstruction. Ophthalmoscopy showed many white, thread-like retinal arterioles associated with capillary and venous dilatation. Widespread retinal arteriolar and capillary nonperfusion was demonstrated by fluorescein angiography. Ischemic maculopathy resulted in severe loss of visual acuity in some eyes. The severe degree of retinal ischemia was accompanied by optic disc pallor and neovascularization and a high incidence of rubeosis iridis with neovascular glaucoma. Patients with this variety of diabetic retinopathy have a poor prognosis of retaining useful vision.
(Arch Ophthalmol 93:1300-1310, 1975)
Submitted for publication June 4, 1974. From the Department of Ophthalmology, University of Wisconsin School of Medicine, Madison.
Reprint requests to Department of Ophthalmology, University Hospitals, 1300 University Ave, Madison, WI 53706 (Dr Bresnick).
Frank L.
Myers, MD;
James A.
Harris, MD; Matthew D. Davis,
retinal ischemia is a prom¬ inent feature of diabetic reti¬ nopathy. Atrophy of retinal capillaries, often associated with narrowing or obliteration of precapillary arterioles, has been found in various histological preparations,14 and focal capillary and arteriolar nonperfusion has been demonstrated by fluorescein angiog¬ raphy.5 7 In some cases of diabetic retinopathy arteriolar obliteration is very extensive, involves both small and large order arterioles, and be¬ comes the predominate feature of the retinopathy. This report describes a series of eight such diabetic patients in whom arteriolar obstruction was widespread, advanced rapidly, and caused profound loss of vision. The clinical features shared to some extent by all of these patients may be summarized as follows. Retinal ischemia: Extensive capil¬ lary and arteriolar obliteration is es¬ pecially severe at the posterior pole. Obstructed arterioles may appear as white, thread-like vessels. Capillary and venous dilation: These changes are most prominent bordering ischemie zones. Granular bhod flow: Some of the remaining patent blood vessels on the venous side of the vascular tree may show severe stasis characterized by granular flow. Loss of visual acuity: Macular edema may be present, but the loss of
Focal
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MD
visual acuity is out of proportion to the degree of macular edema. Visual loss may be of sudden onset. Visual field defects: Central and
paracentral
scotomas
correspond
to
of retinal ischemia. Severe con¬ striction of the peripheral visual field may occur with extensive vaso-obliteration. Optic disc pallor and neo¬ vascularization of the optic disc: New vessels occur predominantly on the temporal side of the disc. Rubeosis iridis: Severe rubeosis causes a high incidence of neovascular glaucoma. Bilateral symmetry: Both eyes tend to be similarly involved. Poor visual prognosis: The progres¬ sive capillary and arteriolar closure usually leads to pronounced visual areas
disability.
REPORT OF CASES Five of the eight cases will be reported in detail to illustrate the prominent clini¬ cal features of this variety of diabetic ret¬
inopathy.
Case 1.—A 30-year-old man who had had diabetes for 27 years was first seen in Sep¬ tember 1972 with a six-month history of blurred vision in both eyes. Both parents, a sister, and two maternal uncles were dia¬ betic. His mother had died at age 60 and his sister at age 33, both blind, apparently from diabetic retinopathy. The patient's corrected visual acuity was 20/40 in the right eye and 20/50 in the left
Fig 1.—Top left, Several small arteriolar branches to the (arrows) appear as white threads. Intraretinal hemor¬ rhages and cotton-wool exudates are scattered around posterior pole. Neovascular net seen at superior portion of optic disc (case 1, OD, Sept 18, 1972). Top right, Many sclerotic arterioles. Neo¬ vascularization is seen at temporal aspect of disc and along su¬ perior temporal vein. Note irregular caliber of macular branch of inferior temporal artery (arrow) (OS, Sept 18, 1972). Bottom left, Fluorescein angiogram of early arteriovenous phase. Poor capil¬ lary filling around macula. Note narrowed column of fluorescein macula
Fig 2.—Visual field OS; large central 1973).
scotoma
(case 1, Jan 2,
origin of macular branches of superior temporal artery. One nonperfused arteriole (arrow) shows only residual stump at its origin (OD, Nov 2, 1972). Bottom right, Fluorescein angiogram of arteriovenous phase. Poor perfusion of temporal portion of poste¬ rior pole. Macula appears supplied only by vessels in papillo¬ macular region and few tiny arteriolar twigs of macular branch of inferior temporal arteriole. Note narrowed fluorescein column in this arteriole at its origin (arrow). Fluorescein leaks from disc new vessels (OS, Sept 18, 1972). at
Fig 3.—Fluorescein angiogram of early arteriovenous phase. Small twigs of macular branch of inferior temporal artery fail to perfuse (arrow) (compare Fig 1, bottom right) (case 1, OS, Jan 2, 1973).
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(OD, -6.00 +3.25x180; OS, -5.50 + 2.25 175). There were many white, thread-like
arterioles in the posterior fundus of both eyes. The discs were moderately pale and there were surface new vessels on their temporal aspects (Fig 1, top left and top right). Moderate venous dilatation and tortuosity were present, and granular blood flow was seen in some of the retinal veins. Neovascularization was rebtricted to the disc in the right eye. In the left eye there were three patches of surface new vessels in the temporal quadrants in addi¬ tion to the disc new vessels. A small vitreous hemorrhage was noted inferiorly
in the right eye, but there was none in the left. On examination with the slit lamp and flat contact lens, neither posterior hyaloid detachment nor macular edema could be detected in either eye. Fluorescein angiography was carried out in the left eye on Sept 18, 1972, and in the right eye on Nov 2, 1972. The angiograms showed widespread areas of nonperfusion of the retinal vascular bed in the posterior pole of both eyes (Fig 1, bottom left and bottom right). Many of the medium-sized arteriolar branches that appeared white in color photographs failed to fill in the fluo¬ rescein angiogram, while some filled slowly
and showed a granular filling pattern. In instances there was a small residual stump of fluorescence marking the origin of an arteriole that was obstructed just af¬ ter it arose from the parent vessel. In each eye only a few residual arteriolar branches to the macula remained and there was very poor capillary filling in the distribution of these vessels. In the left eye, the major macular branch of the inferior temporal artery showed an attenuated fluorescein column at its origin and in its early course. In the absence of macular edema, the moderate decrease in visual acuity in each eye was attributed to ischemie involvesome
Fig 4.—Visual field OD; paracentral scotoma in field nasal to fixation (case 1, Jan 2, 1973).
Fig 5.—Left, Eye three weeks following photocoagulation. All major arterioles show narrowed blood column with increased sheathing. Note segmentation of blood column in macular branch of inferior temporal artery. New vessels along superior temporal
vein appear dried up (arrow) (case 1, OS, Jan 22, 1973). Right, Fluorescein angiogram of early arteriovenous phase. Nonperfu¬ sion of macular branch of inferior temporal artery. New vessels on disc still leak fluorescein (OS, Jan 22, 1973).
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Fig 6.—Top left, Multiple white, thread-like arterioles surround posterior pole. Note dilated intraretinal vessels bordering is¬ chemie zone in papillomacular area. Visual acuity is 20/100. (case 2, OD, Feb 28, 1973). Top right, Thread-like arterioles to macula with apparently incomplete blood column. Dilated intra¬ retinal vessels in zone bordering ischemie macula similar to right eye. Visual acuity 20/50 (before photocoagulation) (OS, Feb 2,
Considering the sparsity of patent vessels in the macular re¬ gion, it was surprising that the visual acuity was not even worse. On Jan 2, 1973, the patient returned stating that visual acuity had suddenly become worse in his left eye on the preceding day. Visual acu¬ ity was 20/200. Goldmann perimetry ment of the macula.
showed a dense central scotoma that extended into the nasal field (Fig 2). Fundus examination showed that the macular branch of the inferior temporal artery, in which previously a narrow blood column could be seen, had become com¬ pletely white. Repeat fluorescein angiogra-
1973). Bottom left, Arterioles in nasal quadrants also appear thread-like. Note sheathing of major arterioles around disc. Optic disc is pale (OS, Feb 2, 1973). Bottom right, Eye three weeks fol¬ lowing photocoagulation. Narrowing and increased sheathing of major retinal arterioles (compare Fig 6, bottom left). Visual acuity 3/200 (OS, Feb 28, 1973).
phy (Fig 3) demonstrated further oblitera¬ tion of the arteriolar supply to the macula, providing a plausible explanation for the progression of visual loss. The right eye appeared unchanged by ophthalmoscopy. There was a large paracentral scotoma in the nasal field that did not involve fixation and that was consistent with the better visual acuity in this eye (Fig 4). Photocoagulation was carried out in the left eye with a xenon arc photocoagulator on Jan 3, 1973. A total of 553 moderately intense retinal burns produced with set¬ tings of Green II-III and a three degree field was scattered from the borders of the
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posterior pole out to the equator. In the temporal quadrants, treatment began two disc diameters from the center of the mac¬ ula and in the nasal quadrants one disc diameter from the optic disc. Spacing of approximately the diameter of one burn was left between burns. Dilated intrareti¬ nal capillaries, capillary microaneurysms, and retinal hemorrhages were treated pref¬ erentially, but normal-appearing retina was also photocoagulated in the course of com¬ pleting the scatter treatment. The new vessels in the temporal quadrants were treated directly, but the disc new vessels were
not.
Fig 7.—Left, Fluorescein angiogram of late venous phase. Ab¬ sent perfusion corresponds to distribution of the thread-like arte¬ rioles Leakage of fluorescein from disc new vessels (case 2, OD, Feb 28, 1973). Right, Fluorescein angiogram of arteriovenous
phase. Absent perfusion in entire temporal portion of posterior pole including macula. Dilated intraretinal capillaries border is¬ chemie zone. Fluorescein leakage from persistent disc new ves¬ sels (OS, Feb 28, 1973).
Fig 8.—Visual field OS showing cecocentral and scotomas (case 2, Feb 28, 1973).
Nineteen days later, the visual acuity in the left eye remained 20/200 and disc neo¬ vascularization had increased (Fig 5, left). Repeat fluorescein angiography showed a further decrease in arteriolar filling at the posterior pole (Fig 5, right). The visual acuity in the right eye remained 20/40 and the retinopathy appeared essentially un¬
changed.
During the following year there was a gradually progressive increase in arterio¬ lar obliteration, constriction in visual fields, and decrease in visual acuity in both eyes. On April 14,1974, the corrected visual acuity was 16/200 in the right eye and 7/200 in the left eye.
Patient 1 showed severe retinal arterio¬ lar obliteration at the posterior poles of both eyes. Sudden loss of central visual acuity in the left eye was accompanied by fluorescein angiographie evidence of fur¬ ther obstruction of arteriolar supply to the macula, suggesting an ischemie basis for the visual decrement. In addition, there was angiographie evidence of further arte¬ riolar obliteration at the posterior pole fol¬ lowing the peripheral scatter photocoagu¬ lation therapy. Case 2.—A 32-year-old man whose diabe¬ tes was of 17 years' duration was first seen in February 1973, with a history of pro¬ gressive visual loss for one year in both
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paracentral
one aunt were dia¬ betic. Corrected visual acuity was 20/100 in the right eye and 20/50 in the left (OD, -4.00 +2.00X180; OS, -3.00 +1.00x183). Because of pain in the left eye one week previously, he had seen his local ophthal¬ mologist who found an elevated intraocu¬ lar pressure in the left eye and placed him on a regimen of acetazolamide, 250 mg four times daily, and topically applied dexamethasone, 0.1%. Ophthalmoscopic examination showed many white, thread-like retinal arterioles involving the posterior pole and the nasal quadrants in both eyes (Fig 6, top left, top right, and bottom left). Sheathing of all
eyes. Two sisters and
Fig 9.—Left, Several nonperfused zones along macular branch temporal artery. Stump of one small arteriolar branch supplying ischemie zone is marked by arrow. Most of capillaries around posterior pole appear dilated. Macula well perfused. Vi¬ sual acuity 20/30 (case 3, OS, Sept 14,1971). Right, Pronounced of inferior
of ischemie process. Several stumps along arteriole which correspond to sites of origin of previously patent arteriolar twigs. Retinal capillaries in distribution of these twigs fail to perfuse, including those to inferior macula. Visual acuity decreased to 20/70 (OS, Feb 1, 1972).
progression
are seen,
Fig 10.—Left, Perimacular arterioles re¬ duced to white threads (arrows). Scat¬ tered intraretinal hemorrhages and hard exudates are present in posterior pole (case 4, OD, Aug 8, 1972). Right, Central two-thirds of disc shows NVD. Major arte¬ rioles are focally narrowed (OD, Aug 8, 1972).
Fig
11.—Fluorescein
angiogram
of
phase. Capillary nonperfusion dif¬ fusely involves area temporal to macula and superior temporal quadrant. Dilated capillaries and microvascular abnormal¬ ities are present between macula and disc. Filling of superior retinal vein is markedly delayed (case 4, OD, Aug 8, 1972).
venous
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the major retinal arterioles was present within one disc diameter of the optic disc. The veins were dilated and tortuous and granular blood flow was seen in several of them in the posterior fundus. New vessels were present on the temporal aspect of each optic disc. The color of the disc was normal in the right eye but moderately pale in the left. Mild diffuse macular edema was present in both eyes. Posterior hyaloid detachment was not detected in ei¬ ther eye. There was a cuff of new vessels on the peripupillary iris in each eye, but the intraocular pressure was normal sev¬ eral hours following the most recent dose of acetazolamide (OD, 16 mm Hg; OS, 11 mm
Hg by applanation tonometry).
Because of the disc neovascularization, scatter photocoagulation with a xenon pho¬ tocoagulator was performed in the left eye on Feb 9, 1973, in the same fashion as de¬ scribed previously in case 1. No direct focal treatment was applied to the disc new ves¬ sels. On Feb 28, 1973, visual acuity in the left eye had decreased to 3/200. Venous dila¬ tion and disc new vessels were decreased. The caliber of the visible blood column in the major retinal arterioles had dimin¬ ished, and "sheathing" of the arterioles was more pronounced. There was more pal¬ lor of the optic disc (Fig 6, bottom right). The visual acuity in the right eye remained 20/100 and the fundus appeared un¬ changed. Fluorescein angiography showed widespread obliteration of the retinal vas¬ cular bed at the posterior pole in both eyes (Fig 7, left and right). New vessels were still present on the optic disc of both eyes and along the superior temporal vein in the left eye. Perimetry of the left eye showed severe constriction of the visual field; it was most pronounced in the nasal quad¬ rants (Fig 8). The visual field of the right eye was constricted to a lesser degree. Ophthalmodynamometry (ODM) showed normal, symmetrical values in both eyes (OD, 100/70; OS, 105/66; BP, 128/72 mm
Hg).
The left eye was given additional pho¬ tocoagulation to treat surface new vessels along the inferior temporal and superi¬ or temporal veins in December 1973 and March 1974. The visual acuity in the left
Fig 12.—Top, Markedly beaded retinal veins are present in all quadrants. Hard exu¬ dates are scattered in peripapillary region (case 5, OD, Oct 10, 1972). Center, Foci of in¬ traretinal hemorrhages and hard exudates are present in posterior pole. Inferior tempo¬ ral vein shows extensive beading (OD, Oct 10, 1972). Bottom, Fluorescein angiogram of late venous phase shows no filling of major veins and vessels around macula (OD, Oct 10, 1972).
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eye was 6/200 on March 6, 1974. The visual acuity and retinopathy in the right eye remained unchanged until March 6, 1974, when a vitreous hemorrhage re¬ duced the visual acuity to 12/200. Intraocu¬ lar pressures were OD 24 mm Hg and OS 20 mm Hg with the patient taking no ocu¬ lar medications. Diminished visual acuity in both eyes when the patient was first seen could be explained best on the basis of macular is-
chemia secondary to retinal arteriolar ob¬ struction at the posterior pole. Further se¬ vere loss of visual acuity occurred in the left eye during the three weeks following scatter photocoagulation therapy. Al¬ though pretreatment fluorescein angiogra¬ phy was not performed, the time course of the visual loss and the evidence of ad¬ vanced arteriolar obliteration in the posttreatment angiogram suggest that the scatter treatment exacerbated the vasoobliterative process. Case 3.—The rapidity with which arte¬ riolar obstruction may advance is illus¬ trated in this case of a 29-year-old man with diabetes of 17 years' duration. When first seen in September 1971, visual acuity with best correction was 20/25 in the right eye and 20/30 in the left. (OD, -3.00 -1.50x100; OS, -3.00 +1.25x45) Fluores¬ cein angiography of the left eye revealed focal areas of retinal ischemia and diffuse capillary dilatation around the posterior pole (Fig 9, left). When fluorescein angiog¬ raphy was repeated three and one-half months later, there were numerous nonperfused arteriolar branches along the in¬ ferior temporal artery, including the blood supply to the inferior portion of the macula (Fig 9, right). The patient's visual acuity had decreased to 20/70 in this eye, with no evidence of macular edema by contact lens examination. Direct photocoagulation of new vessels beyond the disc and a scatter treatment of the retina peripheral to the posterior pole were carried out in the left eye with the argon laser on May 30, 1972. Progressive disc neovascularization devel¬ oped with repeated vitreous hemorrhages and tractional detachment of a portion of the retina along the superior and inferior temporal vessel arcade. Visual acuity was 20/200 in the left eye on Aug 8, 1973, and has remained at that level through April 11, 1974. The right eye showed a similar degree of posterior pole ischemia and developed ru¬ beosis iridis with severe neovascular glau¬ coma in October 1972. Treatment with cyclocryotherapy (Oct 3, 1972, and May 18, 1973) together with topical administration of epinephrine and systemic adminis¬ tration of acetazolamide failed to ade¬ quately control the pressure, and the visual acuity in the right eye was reduced to hand motions. Case 4.—A 50-year-old man with diabe¬ tes mellitus of 13 years' duration was seen initially on Aug 8, 1972. Vascular hyper¬ tension had been present for several years, and the patient was taking antihypertensive drugs. Two years previously he had noted a gradual decrease in visual acuity in both eyes. One month previously he had been examined by another ophthalmologist
who recorded a corrected visual acuity of 20/60 in each eye. Ocular examination showed a corrected visual acuity of 2/200 in the right eye and 20/200 in the left. The anterior segments were normal and there was no evidence of rubeosis iridis. Ophthalmoscopic examina¬ tion revealed many white, thread-like arte¬ rioles involving the posterior pole and the nasal quadrants in both eyes (Fig 10, left). Characteristic granular flow was noted in most of the major retinal veins. The right macula was moderately edematous while the left macula showed moderate pigmen¬ tary disturbance. Occasional foci of hard exudates were present in the posterior pole of each eye. Neovascularization involved the central two-thirds of the right optic disc and the central one-third of the left (Fig 10, right). The right disc was of nor¬ mal color, and the left was moderately
pale.
Fluorescein angiography showed dilated retinal capillaries and extensive intrareti¬ nal microvascular abnormalities in a zone around the right disc extending one and a half to two disc diameters from it (Fig 11). Only the nasal half of the perifoveal capil¬ lary network was delineated by the fluo¬ rescein. The temporal half of the peri¬ foveal capillary network and the capillary bed elsewhere were not perfused with fluo¬
rescein, suggesting widespread capillary obliteration. The filling of major retinal
veins was markedly delayed and there was late staining of their walls. Leakage of dye was noted from the new vessels on the disc. Late fluorescein photographs of the left fundus suggested a similar vascular pattern with a much larger area of appar¬ ent
capillary nonperfusion.
When the patient was seen again on Aug 28, 1972, the visual acuity of the left eye had improved to 20/70. Because of neo¬ vascularization of the disc, scatter pho¬ tocoagulation treatment with a xenon photocoagulator was carried out in the right eye in two episodes 24 hours apart. Treat¬ ment was similar to that in case 1, with a total of 720 burns being given. No direct focal treatment was applied to the new vessels on the disc. On Sept 19, 1972, visual acuity was un¬ changed in both eyes. The new vessels on the disc in the right eye showed slight pro¬ gression. Granular flow was still present, involving most of the retinal veins. On Nov 29, 1972 the patient developed neovascular glaucoma in the left eye. He was unable to return for examination be¬ cause of deterioration of his general health. When he was seen on Dec 12, 1972, visual acuity was hand movements in the right eye, and no light perception in the left. In the right eye, examination of the
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anterior segment gave normal results. The severe decrease in visual acuity in the right eye was attributed to progression of retinal ischemia. In the left eye there was severe corneal epithelial edema and exten¬ sive neovascularization on the iris surface and in the anterior chamber angle. The in¬ traocular pressure was 14 mm Hg in the right eye and 60 mm Hg in the left. The patient was admitted to University Hospi¬ tals and topically applied corticosteroid drops every hour and acetazolamide 250 mg four times a day were started. Within 24 hours the intraocular pressure in the left eye fell to 25 mm Hg. The patient was discharged on a regimen of topically given dexamethasone, 0.1% and systemically ad¬ ministered acetazolamide. He died on Nov 4, 1973 of uremia and diabetic acidosis. The profound loss of visual acuity in both eyes during the one-month interval between the patient's examination by the referring ophthalmologist and his initial visit with us appeared to be related to pro¬ gressive retinal ischemia. Scatter pho¬ tocoagulation treatment may have aggra¬ vated the already compromised vascular tree. The total loss of visual acuity in the opposite untreated eye is believed to be in part the result of neovascular glaucoma. Case 5.-A 17-year-old girl had been dia¬ betic since the age of 10. Control of her di¬ abetes had been difficult, and she had been hospitalized on several occasions for ketoacidosis. At age 15 her visual acuity be¬ gan to deteriorate and became progres¬ sively worse until she could only count fingers at two feet. In May 1972, at the age of 17, cataract aspiration was carried out in the right eye. There was no improve¬ ment in visual acuity. On our initial examination of the patient on Oct 10, 1972, visual acuity was hand movements in the right eye and 1/200 in the left. A secondary membrane was pres¬ ent in the right eye and a moderately ex¬ tensive diabetic cataract was present in the left. Although examination of her fundi was difficult because of lens opac¬ ities, very striking beading of the retinal veins was evident in all quadrants in both eyes (Fig 12, top and center). No new ves¬ sels could be seen and the macula did not appear edematous in either eye. Visual field examination showed a 10° to 15° cen¬ tral scotoma with full peripheral field to a large test object. Fluorescein angiography showed essentially no filling of the retinal vessels in the posterior pole in either eye. Filling of the dilated retinal veins was
markedly delayed (Fig 12, bottom). On Dec 26, 1972, neovascular glaucoma
noted in both eyes, with intraocular pressure of 48 mm Hg in the right eye and 58 mm Hg in the left. Cyclocryotherapy was
carried out in the left eye on Feb 20, on March 19, 1973. Subse¬ quently, treatment with acetazolamide, 250 mg four times a day, and 1% epinephrine drops in each eye twice a day was contin¬ ued. Intraocular pressures in both eyes were controlled below 20 mm Hg. Because of increased opacity of the left lens, cata¬ ract aspiration was done on March 4, 1974. On her last visit of April 18, 1974, visual acuity was OD light perception and OS hand movements. The left fundus showed several elevated neovascular patches. was
1973, and again
Diabetes
Patient/Age, yr/Sex
Age at Onset, yr
Duration,
Followup,
yr
mo
1/30/M
27
19
2/32/M
15
17
13
3/29/M
12
17
34
RESULTS
4/50/M
37
13
The clinical data on all eight pa¬ tients are presented in the Table. Only 15 eyes will be considered. The right eye of patient 7 could not be evaluated for ischemie retinopathy because vitreous hemorrhages shortly after his first visit prevented visual¬ ization of the fundus. Character¬ istically, the patients were young men with diabetes mellitus of greater than 15 years' duration. However,
5/19/F
10
6/34/M
11
5 was a particularly severe ex¬ ample in a young woman with diabe¬ tes of only nine years' duration. The patients were all insulin-dependent and in only one was the age of onset case
more
than 15 years.
Blood Pressure
While four patients (cases 1, 3, 6, 8) had moderate to severe hyper¬ tension, no elevation of blood pres¬ sure was noted in three cases and one patient (case 4) was normotensive while receiving antihypertensive medications. It would appear that al¬ though hypertension may have ag¬ gravated the arteriolar changes in several of the patients, it was not es¬ sential to the production of these
7/30/M
8/29/M
Renal Diseases
Two patients had a normal serum creatinine level (cases 5 and 8) while four showed a moderate elevation (cases 1, 2, 4, and 7) and two a more severe elevation (cases 3 and 6). There was no correlation between the cre¬ atinine levels and the degree of ret¬ inal ischemia. Neovascularization
All patients developed neovas¬ cularization of the optic discs of
23
51
23
50
16
17
OD OS OD
Final 16/200 7/200 12/200
OS
20/50
6/200
OD
20/25
CF2'
OS
20/30
20/200
OD OS OD OS OD OS OD OS OD
2/200 20/200 HM 1/200 20/20 20/25 20/25 20/30 20/40
HM NLP LP HM HM 1/200 HM 3/200 LP
OS
20/100
CF
Eye
18
Acuity*
*
CF, counting fingers; HM, hand movements; NLP, no light perception; LP, light perception. f NVD, new vessels on the optic disc or within one disc diameter of the disc. t NVE, new vessels "elsewhere" (greater than one disc diameter from the disc). § Highest values recorded during follow-up period.
the affected eyes, with a predilection for the temporal aspect of the disc. New vessels were also present else¬ where in many of the eyes. Vitreous hemorrhage occurred in ten of the 15 eyes.
and
changes.
13
Visual Initial 20/40 20/50 20/100
and
Rubeosis Iridis Secondary Glaucoma
A total of eight eyes developed se¬ rubeosis iridis with secondary glaucoma. This occurred unilaterally in six patients and in both eyes in one patient. Attempts to control the in¬ traocular pressure and to retain use¬ ful visual acuity were not very suc¬ cessful. Pressure was controlled below 30 mm Hg in two eyes using a combi¬ nation of orally administered aceta¬ zolamide, topically applied cortico¬ steroids, and epinephrine (OS, case 2; vere
OD,
case
5).
Three eyes also required cyclocryotherapy in order to achieve pres¬ sure control below 30 mm Hg (OD, case 3; OS, case 5; OD, case 6), and two eyes were not controlled below 30 mm Hg (OS, case 4; OS, case 7). One eye was lost to follow-up (OD, case 8). All of the eyes with glaucoma ended up with visual acuity of less than
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10/200 and in most visual acuity was reduced to hand movements or worse. Increased intraocular pressure is particularly detrimental in this group of patients with an already compro¬ mised retinal circulation. For ex¬ ample, one patient was seen with an acute rise in intraocular pressure to 46 mm Hg and a visual acuity of 20/200 (OS, case 7). Fundus examina¬ tion revealed slow granular blood flow in many of the retinal vessels. Fluorescein angiography showed poor macular perfusion as evidenced by slow and incomplete capillary filling. After the pressure was lowered to 20 mm Hg with the use of cyclocryotherapy and acetazolamide the visual acuity improved to 20/40. There was less evidence of granular blood flow, and repeat fluorescein angiography revealed better retinal perfusion with a more rapid and more complete fill¬ ing of the retinal vascular tree. A rise in intraocular pressure may further an already compromised circulation, but it should be
aggravate retinal
pointed out that extensive ischemie changes in the retinas of these pa¬ tients preceded the onset of glaucoma in all
cases.
Clinical Data
Macular Edema
Vitreous
NVDt
NVEif
Hemorrhage Rubeosis Glaucoma
Mild
+
Mild
+
photocoagulation
photocoagulation Argon laser photoco¬ agulation (2) Cyclocryotherapy (2) Argon laser photocoagu¬
—
+
+ + + +
Treatment
None Xenon None Xenon
+ +
lation Xenon photocoagulation None None
+ +
Cyclocryotherapy (2) Cyclocryotherapy
+
None None
Mild Mild
Cyclocryotherapy photocoagulation Argon laser photocoagulatlon
+
Mild
Photocoagulation Therapy The results of
photocoagulation therapy were disappointing. Five pa¬ tients received direct photocoagulation of retinal
vessels as well two with the xenon arc photocoagulator, one with the argon laser, and two with a com¬ bination of both (cases 1, 2, 3, 4, and 8). All cases had neovascularization of as
scatter
new
treatment,
the disc stance
(NVD), and in only
one
in¬
(case 2) did the NVD improve;
in the other four there was progres¬ sion in spite of treatment. Our experience suggests that scat¬
photocoagulation therapy may a detrimental effect on posterior pole perfusion in patients with pre¬ existing severe ischemie changes. In ter
have
two
cases
acuity
(cases
decreased
2 and
4) the visual
sharply immediately
after treatment and failed to recover substantially. As is well known, it is a common
Serum
Nitrogen,
Creatinine,
mg/100
mg/100
ml
202/128
26
1.5
144/86
32
1.7
186/126
60
5.4
168/86
30
2.4
116/88
15
0.6
198/100
67
6.5
136/78
32
1.7
156/100
19
1.1
ml
None
—
The high incidence of severe ru¬ beosis may be attributed to the wide¬ spread retinal ischemia, as rubeosis often occurs in a setting of ischemie posterior segment disease (eg, central retinal vein or artery obstruction). On the other hand, it may be postulated that the vaso-obliterative process oc¬ curs in the anterior segment as well as the retina. Rubeosis iridis as well as disc and retinal neovascularization is well known in patients with ex¬ traocular obstruction of the major ar¬ teries (eg, carotid artery occlusion and pulseless disease).*·9 In this re¬ gard, one of our patients (case 2) had normal ODM values, but functionally important large vessel obstruction in the other cases cannot be ruled out, as ODM was not performed.
Blood Urea
Xenon
+
+
Blood
Pressure,? mm Hg
experience
to
see a
tempo¬
rary decline in visual acuity following extensive photocoagulation therapy, but this is usually due to transient edema or serous detachment of the macula and is reversible within sev¬ eral weeks of treatment. In one case (case 1) there was angiographie evi¬ dence of progressive arteriolar ob¬ struction within three weeks of treat¬ ment. Although these three cases might have followed the same course without treatment, the results sug¬ gest that photocoagulation may ag¬ gravate the vaso-obliterative process. It may be advisable to avoid scatter photocoagulation in cases showing ar¬ teriolar obstruction at the posterior
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or, if it is employed, to use a smaller number of less intense burns. Aiello et al10 reported a dramatic regression of retinopathy follow¬ ing scatter treatment with a much smaller than usual number of ruby la¬ ser applications in five patients show¬ ing severe retinal arteriosclerosis pe¬ ripheral to neovascular patches.
pole
Visual
Acuity
The poor visual prognosis can be from the data in the Table. Of the 15 eyes under consideration, only one has retained visual acuity of 20/200 or better and 12 have visual acuity of less than 10/200. In ten eyes at some time during the period of the observation it was possible to verify decreased visual acuity that was out of proportion to the degree of macu¬ lar edema or vitreous hemorrhage. In all of these cases there was fluores¬ cein angiographie evidence of exten¬ sive arteriolar and capillary oblitera¬ tion at the posterior pole, and the decreased acuity was attributed to ischemie involvement of the macula and the papillomacular bundle. Fur¬ ther loss of visual acuity occurred later in a number of cases due to the seen
development of vitreous hem¬ orrhage from disc or retinal new ves¬ sels or due to the additional complica¬ tion of neovascular glaucoma. added
COMMENT
patients described in this re¬ all have a form of proliferative port diabetic retinopathy marked by a striking degree of retinal arteriolar obstruction. The resultant ischemie changes at the posterior pole lead to severe loss of central vision with large central and paracentral sco¬ tomas. Although macular edema may be present at times in these patients, the decrease in visual acuity is greater than one would predict from the degree of edema. A high incidence of rubeosis iridis and neovascular glaucoma is found, which may reflect the severity of the ischemie retinal process. Poor progno¬ sis for retaining useful visual acuity results from the combined factors of macular ischemia, vitreous hemor¬ rhage from retinal neovascularization, and neovascular glaucoma from se¬ vere rubeosis iridis. In addition there is suggestive evidence that extensive photocoagulation may increase the degree of macular ischemia and fur¬ ther compromise visual acuity. Ischemie involvement of the macula in diabetic retinopathy may range from a mild degree of capillary The
closure to the severe ischemie macu¬ described in this report. In many patients with diabetic ret¬ inopathy, fluorescein angiography re¬ veals a widening of the normal perifoveal capillary-free zone (PCFZ) due to capillary closure." When mild, this may cause little or no change in visual acuity. We have observed eyes in which the area of the PCFZ was four to five times greater than normal, yet in which the visual acuity was 20/20. Greater degrees of vaso-obliteration, including both capillaries and small arterioles, will produce a larger dec¬ rement in visual acuity,12 " but it is still surprising how much visual func¬ tion the macula retains with rather extensive retinal vascular occlusion." Even with involvement of the largerorder arterioles, the visual acuity may remain at the 20/70 to 20/100 levels, as was true in patients 1, 2, and 3 when they were initially examined. It appears, however, that the level of compensation may be precarious as evidenced by the sudden and pro¬ found decrease in visual acuity with a small further loss of arteriolar supply to the macula or with an increase in intraocular pressure.
lopathy
This work was supported in part by a grant from Research to Prevent Blindness, Inc., and by grant P15-EY00342 from the National Eye Insti¬ tute to Matthew D. Davis, MD.
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References 1. Ashton N: Arteriolar involvement in diabetic retinopathy. Br J Ophthalmol 37:282-292, 1953. 2. Cogan DG, Toussaint D, Kuwabara T: Retinal vascular patterns: IV. Diabetic retinopathy. Arch Ophthalmol 66:366-378, 1961. 3. Bloodworth JMB: Diabetic retinopathy. Diabetes 11:1-22, 1962. 4. Ashton N: Studies of the retinal capillaries in relation to diabetic and other retinopathies. Br J Ophthalmol 47:521-538, 1963. 5. Scott DJ, Dollery CT, Hill DW, et al: Fluorescein studies of diabetic retinopathy. Br Med J 1:811-814, 1964. 6. Kohner EM, Dollery CT, Paterson JW, et al: Arterial fluorescein studies in diabetic retinopathy. Diabetes 16:1-10, 1967. 7. Oosterhuis JA, Vink R: Fluorescein photography in diabetic retinopathy, in Henkes H (ed): Perspectives in Ophthalmology. Rotterdam, Excerpta Medica Foundation, 1968, pp 115-132. 8. Smith JL: Unilateral glaucoma in carotid occlusive disease. JAMA 182:683-684, 1962. 9. Ostler HB: Pulseless disease. Am J Ophthalmol 43:583-589, 1957. 10. Aiello LM, Beetham WP, Balodimos MC, et al: Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy, in Goldberg MF, Fine SL (eds): Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890, 1968, pp 437-463. 11. Bresnick GH, de Venecia G, Myers FL, et al: Perifoveal capillary closure in diabetic retinopathy, to be published. 12. Speakman JS, Mortimer CB, Briant TDR, et al: Pituitary ablation for diabetic retinopathy. Canad Med Ass J 94:627-635, 1966. 13. Balodimos MC, Aiello LM, Koncz L, et al: Fluorescein angiography in diabetic retinopathy, in Almaric P (ed): Proceedings of the International Symposium on Fluorescein Angiography, Albi, 1969. Basel, S Karger, 1971, p 391.
H.
Bresnick, MD; Guillermo
De
Venecia, MD;
\s=b\ Eight patients with proliferative diabetic retinopathy developed extensive retinal arteriolar and capillary obstruction. Ophthalmoscopy showed many white, thread-like retinal arterioles associated with capillary and venous dilatation. Widespread retinal arteriolar and capillary nonperfusion was demonstrated by fluorescein angiography. Ischemic maculopathy resulted in severe loss of visual acuity in some eyes. The severe degree of retinal ischemia was accompanied by optic disc pallor and neovascularization and a high incidence of rubeosis iridis with neovascular glaucoma. Patients with this variety of diabetic retinopathy have a poor prognosis of retaining useful vision.
(Arch Ophthalmol 93:1300-1310, 1975)
Submitted for publication June 4, 1974. From the Department of Ophthalmology, University of Wisconsin School of Medicine, Madison.
Reprint requests to Department of Ophthalmology, University Hospitals, 1300 University Ave, Madison, WI 53706 (Dr Bresnick).
Frank L.
Myers, MD;
James A.
Harris, MD; Matthew D. Davis,
retinal ischemia is a prom¬ inent feature of diabetic reti¬ nopathy. Atrophy of retinal capillaries, often associated with narrowing or obliteration of precapillary arterioles, has been found in various histological preparations,14 and focal capillary and arteriolar nonperfusion has been demonstrated by fluorescein angiog¬ raphy.5 7 In some cases of diabetic retinopathy arteriolar obliteration is very extensive, involves both small and large order arterioles, and be¬ comes the predominate feature of the retinopathy. This report describes a series of eight such diabetic patients in whom arteriolar obstruction was widespread, advanced rapidly, and caused profound loss of vision. The clinical features shared to some extent by all of these patients may be summarized as follows. Retinal ischemia: Extensive capil¬ lary and arteriolar obliteration is es¬ pecially severe at the posterior pole. Obstructed arterioles may appear as white, thread-like vessels. Capillary and venous dilation: These changes are most prominent bordering ischemie zones. Granular bhod flow: Some of the remaining patent blood vessels on the venous side of the vascular tree may show severe stasis characterized by granular flow. Loss of visual acuity: Macular edema may be present, but the loss of
Focal
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MD
visual acuity is out of proportion to the degree of macular edema. Visual loss may be of sudden onset. Visual field defects: Central and
paracentral
scotomas
correspond
to
of retinal ischemia. Severe con¬ striction of the peripheral visual field may occur with extensive vaso-obliteration. Optic disc pallor and neo¬ vascularization of the optic disc: New vessels occur predominantly on the temporal side of the disc. Rubeosis iridis: Severe rubeosis causes a high incidence of neovascular glaucoma. Bilateral symmetry: Both eyes tend to be similarly involved. Poor visual prognosis: The progres¬ sive capillary and arteriolar closure usually leads to pronounced visual areas
disability.
REPORT OF CASES Five of the eight cases will be reported in detail to illustrate the prominent clini¬ cal features of this variety of diabetic ret¬
inopathy.
Case 1.—A 30-year-old man who had had diabetes for 27 years was first seen in Sep¬ tember 1972 with a six-month history of blurred vision in both eyes. Both parents, a sister, and two maternal uncles were dia¬ betic. His mother had died at age 60 and his sister at age 33, both blind, apparently from diabetic retinopathy. The patient's corrected visual acuity was 20/40 in the right eye and 20/50 in the left
Fig 1.—Top left, Several small arteriolar branches to the (arrows) appear as white threads. Intraretinal hemor¬ rhages and cotton-wool exudates are scattered around posterior pole. Neovascular net seen at superior portion of optic disc (case 1, OD, Sept 18, 1972). Top right, Many sclerotic arterioles. Neo¬ vascularization is seen at temporal aspect of disc and along su¬ perior temporal vein. Note irregular caliber of macular branch of inferior temporal artery (arrow) (OS, Sept 18, 1972). Bottom left, Fluorescein angiogram of early arteriovenous phase. Poor capil¬ lary filling around macula. Note narrowed column of fluorescein macula
Fig 2.—Visual field OS; large central 1973).
scotoma
(case 1, Jan 2,
origin of macular branches of superior temporal artery. One nonperfused arteriole (arrow) shows only residual stump at its origin (OD, Nov 2, 1972). Bottom right, Fluorescein angiogram of arteriovenous phase. Poor perfusion of temporal portion of poste¬ rior pole. Macula appears supplied only by vessels in papillo¬ macular region and few tiny arteriolar twigs of macular branch of inferior temporal arteriole. Note narrowed fluorescein column in this arteriole at its origin (arrow). Fluorescein leaks from disc new vessels (OS, Sept 18, 1972). at
Fig 3.—Fluorescein angiogram of early arteriovenous phase. Small twigs of macular branch of inferior temporal artery fail to perfuse (arrow) (compare Fig 1, bottom right) (case 1, OS, Jan 2, 1973).
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(OD, -6.00 +3.25x180; OS, -5.50 + 2.25 175). There were many white, thread-like
arterioles in the posterior fundus of both eyes. The discs were moderately pale and there were surface new vessels on their temporal aspects (Fig 1, top left and top right). Moderate venous dilatation and tortuosity were present, and granular blood flow was seen in some of the retinal veins. Neovascularization was rebtricted to the disc in the right eye. In the left eye there were three patches of surface new vessels in the temporal quadrants in addi¬ tion to the disc new vessels. A small vitreous hemorrhage was noted inferiorly
in the right eye, but there was none in the left. On examination with the slit lamp and flat contact lens, neither posterior hyaloid detachment nor macular edema could be detected in either eye. Fluorescein angiography was carried out in the left eye on Sept 18, 1972, and in the right eye on Nov 2, 1972. The angiograms showed widespread areas of nonperfusion of the retinal vascular bed in the posterior pole of both eyes (Fig 1, bottom left and bottom right). Many of the medium-sized arteriolar branches that appeared white in color photographs failed to fill in the fluo¬ rescein angiogram, while some filled slowly
and showed a granular filling pattern. In instances there was a small residual stump of fluorescence marking the origin of an arteriole that was obstructed just af¬ ter it arose from the parent vessel. In each eye only a few residual arteriolar branches to the macula remained and there was very poor capillary filling in the distribution of these vessels. In the left eye, the major macular branch of the inferior temporal artery showed an attenuated fluorescein column at its origin and in its early course. In the absence of macular edema, the moderate decrease in visual acuity in each eye was attributed to ischemie involvesome
Fig 4.—Visual field OD; paracentral scotoma in field nasal to fixation (case 1, Jan 2, 1973).
Fig 5.—Left, Eye three weeks following photocoagulation. All major arterioles show narrowed blood column with increased sheathing. Note segmentation of blood column in macular branch of inferior temporal artery. New vessels along superior temporal
vein appear dried up (arrow) (case 1, OS, Jan 22, 1973). Right, Fluorescein angiogram of early arteriovenous phase. Nonperfu¬ sion of macular branch of inferior temporal artery. New vessels on disc still leak fluorescein (OS, Jan 22, 1973).
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Fig 6.—Top left, Multiple white, thread-like arterioles surround posterior pole. Note dilated intraretinal vessels bordering is¬ chemie zone in papillomacular area. Visual acuity is 20/100. (case 2, OD, Feb 28, 1973). Top right, Thread-like arterioles to macula with apparently incomplete blood column. Dilated intra¬ retinal vessels in zone bordering ischemie macula similar to right eye. Visual acuity 20/50 (before photocoagulation) (OS, Feb 2,
Considering the sparsity of patent vessels in the macular re¬ gion, it was surprising that the visual acuity was not even worse. On Jan 2, 1973, the patient returned stating that visual acuity had suddenly become worse in his left eye on the preceding day. Visual acu¬ ity was 20/200. Goldmann perimetry ment of the macula.
showed a dense central scotoma that extended into the nasal field (Fig 2). Fundus examination showed that the macular branch of the inferior temporal artery, in which previously a narrow blood column could be seen, had become com¬ pletely white. Repeat fluorescein angiogra-
1973). Bottom left, Arterioles in nasal quadrants also appear thread-like. Note sheathing of major arterioles around disc. Optic disc is pale (OS, Feb 2, 1973). Bottom right, Eye three weeks fol¬ lowing photocoagulation. Narrowing and increased sheathing of major retinal arterioles (compare Fig 6, bottom left). Visual acuity 3/200 (OS, Feb 28, 1973).
phy (Fig 3) demonstrated further oblitera¬ tion of the arteriolar supply to the macula, providing a plausible explanation for the progression of visual loss. The right eye appeared unchanged by ophthalmoscopy. There was a large paracentral scotoma in the nasal field that did not involve fixation and that was consistent with the better visual acuity in this eye (Fig 4). Photocoagulation was carried out in the left eye with a xenon arc photocoagulator on Jan 3, 1973. A total of 553 moderately intense retinal burns produced with set¬ tings of Green II-III and a three degree field was scattered from the borders of the
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posterior pole out to the equator. In the temporal quadrants, treatment began two disc diameters from the center of the mac¬ ula and in the nasal quadrants one disc diameter from the optic disc. Spacing of approximately the diameter of one burn was left between burns. Dilated intrareti¬ nal capillaries, capillary microaneurysms, and retinal hemorrhages were treated pref¬ erentially, but normal-appearing retina was also photocoagulated in the course of com¬ pleting the scatter treatment. The new vessels in the temporal quadrants were treated directly, but the disc new vessels were
not.
Fig 7.—Left, Fluorescein angiogram of late venous phase. Ab¬ sent perfusion corresponds to distribution of the thread-like arte¬ rioles Leakage of fluorescein from disc new vessels (case 2, OD, Feb 28, 1973). Right, Fluorescein angiogram of arteriovenous
phase. Absent perfusion in entire temporal portion of posterior pole including macula. Dilated intraretinal capillaries border is¬ chemie zone. Fluorescein leakage from persistent disc new ves¬ sels (OS, Feb 28, 1973).
Fig 8.—Visual field OS showing cecocentral and scotomas (case 2, Feb 28, 1973).
Nineteen days later, the visual acuity in the left eye remained 20/200 and disc neo¬ vascularization had increased (Fig 5, left). Repeat fluorescein angiography showed a further decrease in arteriolar filling at the posterior pole (Fig 5, right). The visual acuity in the right eye remained 20/40 and the retinopathy appeared essentially un¬
changed.
During the following year there was a gradually progressive increase in arterio¬ lar obliteration, constriction in visual fields, and decrease in visual acuity in both eyes. On April 14,1974, the corrected visual acuity was 16/200 in the right eye and 7/200 in the left eye.
Patient 1 showed severe retinal arterio¬ lar obliteration at the posterior poles of both eyes. Sudden loss of central visual acuity in the left eye was accompanied by fluorescein angiographie evidence of fur¬ ther obstruction of arteriolar supply to the macula, suggesting an ischemie basis for the visual decrement. In addition, there was angiographie evidence of further arte¬ riolar obliteration at the posterior pole fol¬ lowing the peripheral scatter photocoagu¬ lation therapy. Case 2.—A 32-year-old man whose diabe¬ tes was of 17 years' duration was first seen in February 1973, with a history of pro¬ gressive visual loss for one year in both
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paracentral
one aunt were dia¬ betic. Corrected visual acuity was 20/100 in the right eye and 20/50 in the left (OD, -4.00 +2.00X180; OS, -3.00 +1.00x183). Because of pain in the left eye one week previously, he had seen his local ophthal¬ mologist who found an elevated intraocu¬ lar pressure in the left eye and placed him on a regimen of acetazolamide, 250 mg four times daily, and topically applied dexamethasone, 0.1%. Ophthalmoscopic examination showed many white, thread-like retinal arterioles involving the posterior pole and the nasal quadrants in both eyes (Fig 6, top left, top right, and bottom left). Sheathing of all
eyes. Two sisters and
Fig 9.—Left, Several nonperfused zones along macular branch temporal artery. Stump of one small arteriolar branch supplying ischemie zone is marked by arrow. Most of capillaries around posterior pole appear dilated. Macula well perfused. Vi¬ sual acuity 20/30 (case 3, OS, Sept 14,1971). Right, Pronounced of inferior
of ischemie process. Several stumps along arteriole which correspond to sites of origin of previously patent arteriolar twigs. Retinal capillaries in distribution of these twigs fail to perfuse, including those to inferior macula. Visual acuity decreased to 20/70 (OS, Feb 1, 1972).
progression
are seen,
Fig 10.—Left, Perimacular arterioles re¬ duced to white threads (arrows). Scat¬ tered intraretinal hemorrhages and hard exudates are present in posterior pole (case 4, OD, Aug 8, 1972). Right, Central two-thirds of disc shows NVD. Major arte¬ rioles are focally narrowed (OD, Aug 8, 1972).
Fig
11.—Fluorescein
angiogram
of
phase. Capillary nonperfusion dif¬ fusely involves area temporal to macula and superior temporal quadrant. Dilated capillaries and microvascular abnormal¬ ities are present between macula and disc. Filling of superior retinal vein is markedly delayed (case 4, OD, Aug 8, 1972).
venous
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the major retinal arterioles was present within one disc diameter of the optic disc. The veins were dilated and tortuous and granular blood flow was seen in several of them in the posterior fundus. New vessels were present on the temporal aspect of each optic disc. The color of the disc was normal in the right eye but moderately pale in the left. Mild diffuse macular edema was present in both eyes. Posterior hyaloid detachment was not detected in ei¬ ther eye. There was a cuff of new vessels on the peripupillary iris in each eye, but the intraocular pressure was normal sev¬ eral hours following the most recent dose of acetazolamide (OD, 16 mm Hg; OS, 11 mm
Hg by applanation tonometry).
Because of the disc neovascularization, scatter photocoagulation with a xenon pho¬ tocoagulator was performed in the left eye on Feb 9, 1973, in the same fashion as de¬ scribed previously in case 1. No direct focal treatment was applied to the disc new ves¬ sels. On Feb 28, 1973, visual acuity in the left eye had decreased to 3/200. Venous dila¬ tion and disc new vessels were decreased. The caliber of the visible blood column in the major retinal arterioles had dimin¬ ished, and "sheathing" of the arterioles was more pronounced. There was more pal¬ lor of the optic disc (Fig 6, bottom right). The visual acuity in the right eye remained 20/100 and the fundus appeared un¬ changed. Fluorescein angiography showed widespread obliteration of the retinal vas¬ cular bed at the posterior pole in both eyes (Fig 7, left and right). New vessels were still present on the optic disc of both eyes and along the superior temporal vein in the left eye. Perimetry of the left eye showed severe constriction of the visual field; it was most pronounced in the nasal quad¬ rants (Fig 8). The visual field of the right eye was constricted to a lesser degree. Ophthalmodynamometry (ODM) showed normal, symmetrical values in both eyes (OD, 100/70; OS, 105/66; BP, 128/72 mm
Hg).
The left eye was given additional pho¬ tocoagulation to treat surface new vessels along the inferior temporal and superi¬ or temporal veins in December 1973 and March 1974. The visual acuity in the left
Fig 12.—Top, Markedly beaded retinal veins are present in all quadrants. Hard exu¬ dates are scattered in peripapillary region (case 5, OD, Oct 10, 1972). Center, Foci of in¬ traretinal hemorrhages and hard exudates are present in posterior pole. Inferior tempo¬ ral vein shows extensive beading (OD, Oct 10, 1972). Bottom, Fluorescein angiogram of late venous phase shows no filling of major veins and vessels around macula (OD, Oct 10, 1972).
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eye was 6/200 on March 6, 1974. The visual acuity and retinopathy in the right eye remained unchanged until March 6, 1974, when a vitreous hemorrhage re¬ duced the visual acuity to 12/200. Intraocu¬ lar pressures were OD 24 mm Hg and OS 20 mm Hg with the patient taking no ocu¬ lar medications. Diminished visual acuity in both eyes when the patient was first seen could be explained best on the basis of macular is-
chemia secondary to retinal arteriolar ob¬ struction at the posterior pole. Further se¬ vere loss of visual acuity occurred in the left eye during the three weeks following scatter photocoagulation therapy. Al¬ though pretreatment fluorescein angiogra¬ phy was not performed, the time course of the visual loss and the evidence of ad¬ vanced arteriolar obliteration in the posttreatment angiogram suggest that the scatter treatment exacerbated the vasoobliterative process. Case 3.—The rapidity with which arte¬ riolar obstruction may advance is illus¬ trated in this case of a 29-year-old man with diabetes of 17 years' duration. When first seen in September 1971, visual acuity with best correction was 20/25 in the right eye and 20/30 in the left. (OD, -3.00 -1.50x100; OS, -3.00 +1.25x45) Fluores¬ cein angiography of the left eye revealed focal areas of retinal ischemia and diffuse capillary dilatation around the posterior pole (Fig 9, left). When fluorescein angiog¬ raphy was repeated three and one-half months later, there were numerous nonperfused arteriolar branches along the in¬ ferior temporal artery, including the blood supply to the inferior portion of the macula (Fig 9, right). The patient's visual acuity had decreased to 20/70 in this eye, with no evidence of macular edema by contact lens examination. Direct photocoagulation of new vessels beyond the disc and a scatter treatment of the retina peripheral to the posterior pole were carried out in the left eye with the argon laser on May 30, 1972. Progressive disc neovascularization devel¬ oped with repeated vitreous hemorrhages and tractional detachment of a portion of the retina along the superior and inferior temporal vessel arcade. Visual acuity was 20/200 in the left eye on Aug 8, 1973, and has remained at that level through April 11, 1974. The right eye showed a similar degree of posterior pole ischemia and developed ru¬ beosis iridis with severe neovascular glau¬ coma in October 1972. Treatment with cyclocryotherapy (Oct 3, 1972, and May 18, 1973) together with topical administration of epinephrine and systemic adminis¬ tration of acetazolamide failed to ade¬ quately control the pressure, and the visual acuity in the right eye was reduced to hand motions. Case 4.—A 50-year-old man with diabe¬ tes mellitus of 13 years' duration was seen initially on Aug 8, 1972. Vascular hyper¬ tension had been present for several years, and the patient was taking antihypertensive drugs. Two years previously he had noted a gradual decrease in visual acuity in both eyes. One month previously he had been examined by another ophthalmologist
who recorded a corrected visual acuity of 20/60 in each eye. Ocular examination showed a corrected visual acuity of 2/200 in the right eye and 20/200 in the left. The anterior segments were normal and there was no evidence of rubeosis iridis. Ophthalmoscopic examina¬ tion revealed many white, thread-like arte¬ rioles involving the posterior pole and the nasal quadrants in both eyes (Fig 10, left). Characteristic granular flow was noted in most of the major retinal veins. The right macula was moderately edematous while the left macula showed moderate pigmen¬ tary disturbance. Occasional foci of hard exudates were present in the posterior pole of each eye. Neovascularization involved the central two-thirds of the right optic disc and the central one-third of the left (Fig 10, right). The right disc was of nor¬ mal color, and the left was moderately
pale.
Fluorescein angiography showed dilated retinal capillaries and extensive intrareti¬ nal microvascular abnormalities in a zone around the right disc extending one and a half to two disc diameters from it (Fig 11). Only the nasal half of the perifoveal capil¬ lary network was delineated by the fluo¬ rescein. The temporal half of the peri¬ foveal capillary network and the capillary bed elsewhere were not perfused with fluo¬
rescein, suggesting widespread capillary obliteration. The filling of major retinal
veins was markedly delayed and there was late staining of their walls. Leakage of dye was noted from the new vessels on the disc. Late fluorescein photographs of the left fundus suggested a similar vascular pattern with a much larger area of appar¬ ent
capillary nonperfusion.
When the patient was seen again on Aug 28, 1972, the visual acuity of the left eye had improved to 20/70. Because of neo¬ vascularization of the disc, scatter pho¬ tocoagulation treatment with a xenon photocoagulator was carried out in the right eye in two episodes 24 hours apart. Treat¬ ment was similar to that in case 1, with a total of 720 burns being given. No direct focal treatment was applied to the new vessels on the disc. On Sept 19, 1972, visual acuity was un¬ changed in both eyes. The new vessels on the disc in the right eye showed slight pro¬ gression. Granular flow was still present, involving most of the retinal veins. On Nov 29, 1972 the patient developed neovascular glaucoma in the left eye. He was unable to return for examination be¬ cause of deterioration of his general health. When he was seen on Dec 12, 1972, visual acuity was hand movements in the right eye, and no light perception in the left. In the right eye, examination of the
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anterior segment gave normal results. The severe decrease in visual acuity in the right eye was attributed to progression of retinal ischemia. In the left eye there was severe corneal epithelial edema and exten¬ sive neovascularization on the iris surface and in the anterior chamber angle. The in¬ traocular pressure was 14 mm Hg in the right eye and 60 mm Hg in the left. The patient was admitted to University Hospi¬ tals and topically applied corticosteroid drops every hour and acetazolamide 250 mg four times a day were started. Within 24 hours the intraocular pressure in the left eye fell to 25 mm Hg. The patient was discharged on a regimen of topically given dexamethasone, 0.1% and systemically ad¬ ministered acetazolamide. He died on Nov 4, 1973 of uremia and diabetic acidosis. The profound loss of visual acuity in both eyes during the one-month interval between the patient's examination by the referring ophthalmologist and his initial visit with us appeared to be related to pro¬ gressive retinal ischemia. Scatter pho¬ tocoagulation treatment may have aggra¬ vated the already compromised vascular tree. The total loss of visual acuity in the opposite untreated eye is believed to be in part the result of neovascular glaucoma. Case 5.-A 17-year-old girl had been dia¬ betic since the age of 10. Control of her di¬ abetes had been difficult, and she had been hospitalized on several occasions for ketoacidosis. At age 15 her visual acuity be¬ gan to deteriorate and became progres¬ sively worse until she could only count fingers at two feet. In May 1972, at the age of 17, cataract aspiration was carried out in the right eye. There was no improve¬ ment in visual acuity. On our initial examination of the patient on Oct 10, 1972, visual acuity was hand movements in the right eye and 1/200 in the left. A secondary membrane was pres¬ ent in the right eye and a moderately ex¬ tensive diabetic cataract was present in the left. Although examination of her fundi was difficult because of lens opac¬ ities, very striking beading of the retinal veins was evident in all quadrants in both eyes (Fig 12, top and center). No new ves¬ sels could be seen and the macula did not appear edematous in either eye. Visual field examination showed a 10° to 15° cen¬ tral scotoma with full peripheral field to a large test object. Fluorescein angiography showed essentially no filling of the retinal vessels in the posterior pole in either eye. Filling of the dilated retinal veins was
markedly delayed (Fig 12, bottom). On Dec 26, 1972, neovascular glaucoma
noted in both eyes, with intraocular pressure of 48 mm Hg in the right eye and 58 mm Hg in the left. Cyclocryotherapy was
carried out in the left eye on Feb 20, on March 19, 1973. Subse¬ quently, treatment with acetazolamide, 250 mg four times a day, and 1% epinephrine drops in each eye twice a day was contin¬ ued. Intraocular pressures in both eyes were controlled below 20 mm Hg. Because of increased opacity of the left lens, cata¬ ract aspiration was done on March 4, 1974. On her last visit of April 18, 1974, visual acuity was OD light perception and OS hand movements. The left fundus showed several elevated neovascular patches. was
1973, and again
Diabetes
Patient/Age, yr/Sex
Age at Onset, yr
Duration,
Followup,
yr
mo
1/30/M
27
19
2/32/M
15
17
13
3/29/M
12
17
34
RESULTS
4/50/M
37
13
The clinical data on all eight pa¬ tients are presented in the Table. Only 15 eyes will be considered. The right eye of patient 7 could not be evaluated for ischemie retinopathy because vitreous hemorrhages shortly after his first visit prevented visual¬ ization of the fundus. Character¬ istically, the patients were young men with diabetes mellitus of greater than 15 years' duration. However,
5/19/F
10
6/34/M
11
5 was a particularly severe ex¬ ample in a young woman with diabe¬ tes of only nine years' duration. The patients were all insulin-dependent and in only one was the age of onset case
more
than 15 years.
Blood Pressure
While four patients (cases 1, 3, 6, 8) had moderate to severe hyper¬ tension, no elevation of blood pres¬ sure was noted in three cases and one patient (case 4) was normotensive while receiving antihypertensive medications. It would appear that al¬ though hypertension may have ag¬ gravated the arteriolar changes in several of the patients, it was not es¬ sential to the production of these
7/30/M
8/29/M
Renal Diseases
Two patients had a normal serum creatinine level (cases 5 and 8) while four showed a moderate elevation (cases 1, 2, 4, and 7) and two a more severe elevation (cases 3 and 6). There was no correlation between the cre¬ atinine levels and the degree of ret¬ inal ischemia. Neovascularization
All patients developed neovas¬ cularization of the optic discs of
23
51
23
50
16
17
OD OS OD
Final 16/200 7/200 12/200
OS
20/50
6/200
OD
20/25
CF2'
OS
20/30
20/200
OD OS OD OS OD OS OD OS OD
2/200 20/200 HM 1/200 20/20 20/25 20/25 20/30 20/40
HM NLP LP HM HM 1/200 HM 3/200 LP
OS
20/100
CF
Eye
18
Acuity*
*
CF, counting fingers; HM, hand movements; NLP, no light perception; LP, light perception. f NVD, new vessels on the optic disc or within one disc diameter of the disc. t NVE, new vessels "elsewhere" (greater than one disc diameter from the disc). § Highest values recorded during follow-up period.
the affected eyes, with a predilection for the temporal aspect of the disc. New vessels were also present else¬ where in many of the eyes. Vitreous hemorrhage occurred in ten of the 15 eyes.
and
changes.
13
Visual Initial 20/40 20/50 20/100
and
Rubeosis Iridis Secondary Glaucoma
A total of eight eyes developed se¬ rubeosis iridis with secondary glaucoma. This occurred unilaterally in six patients and in both eyes in one patient. Attempts to control the in¬ traocular pressure and to retain use¬ ful visual acuity were not very suc¬ cessful. Pressure was controlled below 30 mm Hg in two eyes using a combi¬ nation of orally administered aceta¬ zolamide, topically applied cortico¬ steroids, and epinephrine (OS, case 2; vere
OD,
case
5).
Three eyes also required cyclocryotherapy in order to achieve pres¬ sure control below 30 mm Hg (OD, case 3; OS, case 5; OD, case 6), and two eyes were not controlled below 30 mm Hg (OS, case 4; OS, case 7). One eye was lost to follow-up (OD, case 8). All of the eyes with glaucoma ended up with visual acuity of less than
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10/200 and in most visual acuity was reduced to hand movements or worse. Increased intraocular pressure is particularly detrimental in this group of patients with an already compro¬ mised retinal circulation. For ex¬ ample, one patient was seen with an acute rise in intraocular pressure to 46 mm Hg and a visual acuity of 20/200 (OS, case 7). Fundus examina¬ tion revealed slow granular blood flow in many of the retinal vessels. Fluorescein angiography showed poor macular perfusion as evidenced by slow and incomplete capillary filling. After the pressure was lowered to 20 mm Hg with the use of cyclocryotherapy and acetazolamide the visual acuity improved to 20/40. There was less evidence of granular blood flow, and repeat fluorescein angiography revealed better retinal perfusion with a more rapid and more complete fill¬ ing of the retinal vascular tree. A rise in intraocular pressure may further an already compromised circulation, but it should be
aggravate retinal
pointed out that extensive ischemie changes in the retinas of these pa¬ tients preceded the onset of glaucoma in all
cases.
Clinical Data
Macular Edema
Vitreous
NVDt
NVEif
Hemorrhage Rubeosis Glaucoma
Mild
+
Mild
+
photocoagulation
photocoagulation Argon laser photoco¬ agulation (2) Cyclocryotherapy (2) Argon laser photocoagu¬
—
+
+ + + +
Treatment
None Xenon None Xenon
+ +
lation Xenon photocoagulation None None
+ +
Cyclocryotherapy (2) Cyclocryotherapy
+
None None
Mild Mild
Cyclocryotherapy photocoagulation Argon laser photocoagulatlon
+
Mild
Photocoagulation Therapy The results of
photocoagulation therapy were disappointing. Five pa¬ tients received direct photocoagulation of retinal
vessels as well two with the xenon arc photocoagulator, one with the argon laser, and two with a com¬ bination of both (cases 1, 2, 3, 4, and 8). All cases had neovascularization of as
scatter
new
treatment,
the disc stance
(NVD), and in only
one
in¬
(case 2) did the NVD improve;
in the other four there was progres¬ sion in spite of treatment. Our experience suggests that scat¬
photocoagulation therapy may a detrimental effect on posterior pole perfusion in patients with pre¬ existing severe ischemie changes. In ter
have
two
cases
acuity
(cases
decreased
2 and
4) the visual
sharply immediately
after treatment and failed to recover substantially. As is well known, it is a common
Serum
Nitrogen,
Creatinine,
mg/100
mg/100
ml
202/128
26
1.5
144/86
32
1.7
186/126
60
5.4
168/86
30
2.4
116/88
15
0.6
198/100
67
6.5
136/78
32
1.7
156/100
19
1.1
ml
None
—
The high incidence of severe ru¬ beosis may be attributed to the wide¬ spread retinal ischemia, as rubeosis often occurs in a setting of ischemie posterior segment disease (eg, central retinal vein or artery obstruction). On the other hand, it may be postulated that the vaso-obliterative process oc¬ curs in the anterior segment as well as the retina. Rubeosis iridis as well as disc and retinal neovascularization is well known in patients with ex¬ traocular obstruction of the major ar¬ teries (eg, carotid artery occlusion and pulseless disease).*·9 In this re¬ gard, one of our patients (case 2) had normal ODM values, but functionally important large vessel obstruction in the other cases cannot be ruled out, as ODM was not performed.
Blood Urea
Xenon
+
+
Blood
Pressure,? mm Hg
experience
to
see a
tempo¬
rary decline in visual acuity following extensive photocoagulation therapy, but this is usually due to transient edema or serous detachment of the macula and is reversible within sev¬ eral weeks of treatment. In one case (case 1) there was angiographie evi¬ dence of progressive arteriolar ob¬ struction within three weeks of treat¬ ment. Although these three cases might have followed the same course without treatment, the results sug¬ gest that photocoagulation may ag¬ gravate the vaso-obliterative process. It may be advisable to avoid scatter photocoagulation in cases showing ar¬ teriolar obstruction at the posterior
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or, if it is employed, to use a smaller number of less intense burns. Aiello et al10 reported a dramatic regression of retinopathy follow¬ ing scatter treatment with a much smaller than usual number of ruby la¬ ser applications in five patients show¬ ing severe retinal arteriosclerosis pe¬ ripheral to neovascular patches.
pole
Visual
Acuity
The poor visual prognosis can be from the data in the Table. Of the 15 eyes under consideration, only one has retained visual acuity of 20/200 or better and 12 have visual acuity of less than 10/200. In ten eyes at some time during the period of the observation it was possible to verify decreased visual acuity that was out of proportion to the degree of macu¬ lar edema or vitreous hemorrhage. In all of these cases there was fluores¬ cein angiographie evidence of exten¬ sive arteriolar and capillary oblitera¬ tion at the posterior pole, and the decreased acuity was attributed to ischemie involvement of the macula and the papillomacular bundle. Fur¬ ther loss of visual acuity occurred later in a number of cases due to the seen
development of vitreous hem¬ orrhage from disc or retinal new ves¬ sels or due to the additional complica¬ tion of neovascular glaucoma. added
COMMENT
patients described in this re¬ all have a form of proliferative port diabetic retinopathy marked by a striking degree of retinal arteriolar obstruction. The resultant ischemie changes at the posterior pole lead to severe loss of central vision with large central and paracentral sco¬ tomas. Although macular edema may be present at times in these patients, the decrease in visual acuity is greater than one would predict from the degree of edema. A high incidence of rubeosis iridis and neovascular glaucoma is found, which may reflect the severity of the ischemie retinal process. Poor progno¬ sis for retaining useful visual acuity results from the combined factors of macular ischemia, vitreous hemor¬ rhage from retinal neovascularization, and neovascular glaucoma from se¬ vere rubeosis iridis. In addition there is suggestive evidence that extensive photocoagulation may increase the degree of macular ischemia and fur¬ ther compromise visual acuity. Ischemie involvement of the macula in diabetic retinopathy may range from a mild degree of capillary The
closure to the severe ischemie macu¬ described in this report. In many patients with diabetic ret¬ inopathy, fluorescein angiography re¬ veals a widening of the normal perifoveal capillary-free zone (PCFZ) due to capillary closure." When mild, this may cause little or no change in visual acuity. We have observed eyes in which the area of the PCFZ was four to five times greater than normal, yet in which the visual acuity was 20/20. Greater degrees of vaso-obliteration, including both capillaries and small arterioles, will produce a larger dec¬ rement in visual acuity,12 " but it is still surprising how much visual func¬ tion the macula retains with rather extensive retinal vascular occlusion." Even with involvement of the largerorder arterioles, the visual acuity may remain at the 20/70 to 20/100 levels, as was true in patients 1, 2, and 3 when they were initially examined. It appears, however, that the level of compensation may be precarious as evidenced by the sudden and pro¬ found decrease in visual acuity with a small further loss of arteriolar supply to the macula or with an increase in intraocular pressure.
lopathy
This work was supported in part by a grant from Research to Prevent Blindness, Inc., and by grant P15-EY00342 from the National Eye Insti¬ tute to Matthew D. Davis, MD.
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References 1. Ashton N: Arteriolar involvement in diabetic retinopathy. Br J Ophthalmol 37:282-292, 1953. 2. Cogan DG, Toussaint D, Kuwabara T: Retinal vascular patterns: IV. Diabetic retinopathy. Arch Ophthalmol 66:366-378, 1961. 3. Bloodworth JMB: Diabetic retinopathy. Diabetes 11:1-22, 1962. 4. Ashton N: Studies of the retinal capillaries in relation to diabetic and other retinopathies. Br J Ophthalmol 47:521-538, 1963. 5. Scott DJ, Dollery CT, Hill DW, et al: Fluorescein studies of diabetic retinopathy. Br Med J 1:811-814, 1964. 6. Kohner EM, Dollery CT, Paterson JW, et al: Arterial fluorescein studies in diabetic retinopathy. Diabetes 16:1-10, 1967. 7. Oosterhuis JA, Vink R: Fluorescein photography in diabetic retinopathy, in Henkes H (ed): Perspectives in Ophthalmology. Rotterdam, Excerpta Medica Foundation, 1968, pp 115-132. 8. Smith JL: Unilateral glaucoma in carotid occlusive disease. JAMA 182:683-684, 1962. 9. Ostler HB: Pulseless disease. Am J Ophthalmol 43:583-589, 1957. 10. Aiello LM, Beetham WP, Balodimos MC, et al: Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy, in Goldberg MF, Fine SL (eds): Symposium on the Treatment of Diabetic Retinopathy. Public Health Service Publication No. 1890, 1968, pp 437-463. 11. Bresnick GH, de Venecia G, Myers FL, et al: Perifoveal capillary closure in diabetic retinopathy, to be published. 12. Speakman JS, Mortimer CB, Briant TDR, et al: Pituitary ablation for diabetic retinopathy. Canad Med Ass J 94:627-635, 1966. 13. Balodimos MC, Aiello LM, Koncz L, et al: Fluorescein angiography in diabetic retinopathy, in Almaric P (ed): Proceedings of the International Symposium on Fluorescein Angiography, Albi, 1969. Basel, S Karger, 1971, p 391.
