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Retinopathy Associated with Acute Pancreatitis
Retinopathy Associated With Acute Pancreatitis Lory Snady-McCoy, M.D., and Peter H. Morse, M.D.
Two patients (a 28-year-old woman and a 23-year-old man) with acute pancreatitis developed severe visual loss. The acute stage of retinopathy consisted of retinal edema, cottonwool patches, and retinal hemorrhages, predominantly in the posterior pole of both eyes. During the five-year follow-up period, visual acuity improved and sequential fluorescein angiography of both patients demonstrated reperfusion of previously occluded retinal vessels. After resolution of the cotton-wool patches, the previously edematous areas were replaced by foci of retinal thinning. w.h~ch created irregularities in the internal Iimifing membrane light reflex. Visual fields demonstrated scotomas corresponding to the areas of the previous cotton-wool patches. INKELES AND W ALSH I provided the first description of an associated retinopathy in patients with acute pancreatitis in 1975. Ophthalmoscopically, the retinal manifestations are essentially the same as those in Purtscher's retinopathy." The retina has multiple, often confluent, cotton-wool patches located primarily within the temporal retinal vascular a.rcades and macula, retinal edema, and occasionally striate and blot hemorrhages. Visual loss and visual field deficits are the patient's primary subjective complaints. Because of the similar fundus appearance, fat emboli were believed to be responsible for both diseases. Two patients with this disease have been monitored at the University of Chicago for a five-year period.
Accepted for publication May 7, 1985. From the Department of Ophthalmo.logy an~ Eye Research Laboratories, University of Chicago, Pntzker School of Medicine, Chicago, Illinois. Reprint requests to Peter H. Morse, .M.D., Eye Research Laboratories, 939 E. 57th St., Chicago, IL 60637.
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Case Reports Case 1 A 28-year-old woman with a four-year history of alcohol abuse was admitte~ to the niver sity of Chicago General Surgical Service .on June 27, 1979, with right upper quadrant pam, nausea, emesis, and diarrhea. She also complained of decreased vision in bot~ eyes. H~r medical history included hypertension, chronic anemia, cholecystitis, and recurrent pancreatitis. Plasma amylase level was 12,000 UI100 ml (normal, 25 to 250 U/100 ml). Ultrasonography of the abdomen demonstrated an enlarged pancreas consistent with pancreatitis. Visual acuity without correction .was counting fingers at 2 feet in both eyes. Intraocular pressure by applanation tonometry was R.E.:14 mm Hg and L.E.: 12 mm Hg. Both pupils showed an afferent pupillary defect: O h thalmoscopic examination disclos~d optic ~Isk edema, arteriolar attenuation, diffuse retinal edema, an irregular foveolar reflex, and confluent cotton-wool patches involving the macular area (Fig. 1, left). Superficial striate hemorrhages were also seen superior to the optic nerve head in the right eye. Fluorescein angiography showed obscuration of the choroidal background pattern in the areas of the cotton-wool patches and hemorrhages, occluded retinal arteri~le~, cap~llary nonperfusion, and venous staining (FIg. 1, right). ,.. One month later, the patient s visual acuity was R.E.: 20/80, 8 point and L.B.: 201100, 8 point. Ophthalmoscopy demonstrated optic nerve head pallor, lessening of retinal edema and cotton-wool patches, and attenuation and early sheathing of the arterio~es. Fluorescein angiography showed reperfus~on of s~me of the previously occluded artenoles WhIC~ .remained reduced in caliber. Perivenous stammg and optic disk edema were considerably less marked.
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Fig. 1 (Snady-McCoy and Morse). Case 1, right eye. Left, During the acute phase of the retinopathy associated with pancreatitis. Note the attenuation and increased light reflex of the retinal arterioles, confluent cotton-wool patches involving the papillornacular bundle, and an irregularity of the macular reflex created by the surrounding retirial edema. Visual acuity was counting fingers at 2 feet. Right, A fluorescein angiogram obtained during the acute phase demonstrates arteriolar and capillary nonperfusion, especially inferotemporal to the foveola. There is diffuse hypofluorescence in the area of the cotton-wool patches. One month later, visual acuity had improved to R.E.: 20/25, 4 point and L.E.: 20/30, 4 point. The ophthalmoscopic examination showed optic disk atrophy, attenuated and sheathed arterioles, and continued resolution of the cotton-wool patches. Goldmann visual fields showed central and paracentral scotomas and generalized constriction. Seven months after the initial ophthalmologic examination, the cotton-wool patches had completely resolved. In areas where the cottonwool patches had been there was a mottling of the retinal pigment epithelium and multiple irregularities of the internal limiting membrane light reflex caused by a thinning of the inner one half of the retina. The alteration of the light reflex was particularly apparent in the areas previously occupied by large confluent COttonwool patches. Five years after the acute episode, the patient's best corrected visual acuity was R.E.: 20/25,4 point and L.E.: 20150 +2, 4 point. The ophthalmologic findings were unchanged (Fig. 2). Case 2 A 23-year-old alcoholic man was hospitalized because of acute pancreatitis and hemorrhagic gastritis on Oct. 8, 1979. His symptoms included nausea, vomiting, and hematernesis, which
had worsened during the previous 12 hours. The plasma amylase level was 710 UllOO ml (normal, 25 to 250 Ul100 ml), Ultrasonography of the abdomen was consistent with acute pancreatitis. Four days after admission, his visual acuity was R.E.: 201100, 14 point and L.E.: 20/200, 12 point. The intraocular pressure was R.E.: 10 mm Hg and L.E.: 11 mm Hg. Ophthalmoscopic examination disclosed isolated cottonwool patches proximal to the optic disk and near the macula, affecting the left eye more than the right (Fig. 3, left). Fluorescein angiography showed a relative hypofluorescence of the background choroidal vascular pattern in the areas of the cotton-wool patches and a mild hyperfluorescence in the macula (Fig. 3, right). Two months later, the patient's visual acuity was R.E.: 20/80, 6 point and L.E.: 20/200, 12 point. The cotton-wool patches had resolved and there were depressions in the retina accentuated by the internal limiting membrane light reflex with a mild mottling of the retinal pigment epithelium. Five years after the acute episode, the patient's best corrected visual acuity was R. E.: 20/60, 4 point and L.E.: 20170, 4 point. In addition to the irregular reflexes in the macular area, there were also small yellow deposits at the level of the retinal pigment epithelium and
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Fig. 2 (Snady-McCoy and Morse). Case 1, right eye. Five years after the acute episode the eye shows optic atrophy, generalized attentuation of the retinal vessels, mild sheathing of the arterioles, fine mottled hypopigmentation and hyperpigmentation of the fundus, and an irregularity of the retinal light reflex caused by retinal depression or thinning (arrows). Right, A fluorescein angiogram demonstrates attenuation of the retinal vessels and a relative hypoperfusion of the retinal capillaries inferotemporal and superotemporal to the foveola consistent with the areas of previous vascular nonperfusion. Fine mottled hypopigmentation and hyperpigmentation remain. The larger vessels, although attenuated, are patent, and the patient's visual acuity has returned to 20/25, 4 point.
scattered clumps of hyperpigmentation, especially in the left eye (Fig. 4, left). Fluorescein angiography demonstrated an enlargement in the caliber of a previously attenuated venule in an area where a cotton-wool patch had been.
There was complete vascular perfusion with evidence of mild hypopigmentation and hyperpigmentation (Fig. 4, right). Goldmann visual fields showed a large nasal step in the right eye and multiple isolated scotomas in the left eye,
Fig. 3 (Snady-McCoy and Morse). Case 2, left eye. Left, During the acute phase of pancreatitis retinopathy, cotton-wool patches are prominent along the superotemporal and inferotemporal vascular arcades. A less intense retinal edema surrounds the foveola. Note the irregular foveolar reflex and increased arteriolar light reflex. Visual acuity was 20/200, 12 point. Right, A fluorescein angiogram during the arteriolar phase shows the foci of cotton-wool patches as areas of hypofluorescence. There is some hyperfluorescence in the macula. A small venous branch lying beneath a cotton-wool patch is attenuated (arrow).
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Fig. 4 (Snady-McCoy and Morse). Case 2, left eye. Left, One year after the acute phase of pancreatitis retinopathy. Note the irregular internal limiting membrane reflex as the result of multiple retinal depressions caused by retinal thinning in the areas of previous cotton-wool patches. There is a fine speckled hyperpigmentation in the macula. Right, A fluorescein angiogram shows reperfusion of the small venous branch (arrow) and diffuse fine hyperpigmented mottling of the posterior pole. Visual acuity was 20170, 4 point. which corresponded in location to the previous sites of the cotton-wool patches and persistent retinal depressions.
Discussion In patients with retinopathy associated with acute pancreatitis, it was easy to apply the etiologic theory of fat embolism within the retinal and choroidal vessels because of the similarity of the ophthalmoscopically observed lesions. log Fat emboli have been demonstrated in histopathologic studies of organs inpatients with pancreatitis;' However, other origins of this syndrome have been hypothesized. The retinal tissue responses have also been ascribed to increased intraocular venous pressure and retinal venous stasis caused by increased cerebrospinal fluid pressure.! and increased intrathoracic pressure or retinal arteriolar spasm.r" Rapid increases or decreases in blood pressure affecting the retinal vessels may also occur in acute pancreatitis. Other concomitant conditions, such as anemia, may also influence the manifestations of pancreatitis retinopathy. Another theory implicates the complement system because activated proteases such as trypsin are released during injury or inflammation of the pancreas. 12,13 Inhibitors of proteases may be diminished or overwhelmed and these
uninhibited proteases will activate complemerit.":" Trypsin activates C3 and C5, and C5a aggregates have been found in the sera of patients with acute pancreatitis." C5a stimulates mast cells to release a substance that increases the permeability of blood vessels and induces surface changes in the granulocyte cell membranes, making them more adherent to endothelial cells and other grariulocytes.P-" Granulocytic aggregates may occlude retinal vessels as much as 60 urn in diameter. Additionally, activated granulocytes release oxygen radicals toxic to the vascular endothelium and cause increased vascular permeability." Pancreatitis may sometimes be associated with disseminated intravascular coagulation." Possibly all of these interrelated factors contribute to the vase-occlusive process. Arteriolar spasm, intravascular sludging of erythrocytes, fat emboli, complement-granulocyte or platelet-fibrin aggregates, and coagulative necrosis of the retinal vessels produce the tissue response seen in the retinopathy associated with pancreatitis and other retinal vaso-occlusive diseases. In the only clinicopathologic study of the retinopathy of pancreatitis, Kincaid and associates'" reported occluded retinal arterioles and choroidal vessels, focal areas of edema within the inner layers of the retina, cystoid spaces, small hemorrhages in the outer plexiform layer, and disruption of the photoreceptors
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with loss of photoreceptor segments. Electron micrographs showed that the lumina of the _occluded vessels contained proteinaceous material consistent with recanalized thrombi. It was not possible to identify the emboli as lipid, granulocyte, or platelet aggregates.F Although Kincaid and associates" described histopathologically occluded choroidal vessels, they believed they did not play an important part in the pathogenesis of the clinical manifestations in their patients because the retinal pigment epithelial cells remained normal. However, it is possible that impairment of the choroidal circulation causing retinal pigment epithelial damage occurs in patients with pancreatitis and may have contributed to the ophthalmoscopically visible pigment mottling observed." Both of our patients had an irregularity of the internal limiting membrane light reflex after resolution of the retinal edema and cotton-wool patches. This finding has been called the "retinal depression sign" in patients with sickle cell retinopathy, systemic hypertension, retinal arteriolitis, and juvenile-onset diabetes mellitus.P This sign is visible in patients with any disease producing arteriolar occlusion in the retina, including talc retinopathy, radiation retinopathy, vasculitis secondary to connective tissue disorders, and chronic granulocytic leukemia." To this list may now be added the retinopathy associated with pancreatitis. Treatment of retinopathy associated with pancreatitis is limited to observation and supportive care. Possible therapy, depending on the etiologic theory favored, includes administration of systemic corticosteroids that nullify vascular leukostasis and production of oxygen radicals." Systemic corticosteroids would theoretically be most effective before the development of overt retinopathy. The routine use of corticosteroids, however, is impractical especially in view of the increased susceptibility to infection of patients with acute pancreatitis. Protease inhibitors, which inactivate circulating pancreatic enzymes released during an acute attack of pancreatitis, thus inhibiting complement activation and the release of CSa, may be another treatment. However, clinical trials using aprotinin (Trasylol), a potent trypsin and kallikrein inhibitor, did not show any improvement in the clinical course of acute pancreatitis." These clinical trials have shown, moreover, that aprotinin may actually prolong the half-life of C5a and thus be detrimental. Therapeutic trials with other specific protease inhibitors may yield different results.
Aspirin, indomethacin, and ibuprofen do not inhibit granulocyte aggregation. Aspirin, however, does inhibit platelet aggregation. Antioxidants such as vitamin E may help to decrease vascular permeability but this has no proven clinical efficacy. . The findings of the retinopathy of pancreatitis are similar to those in other vascular occlusive retinopathies clinically, histopathologically, and with respect to long-term sequelae. The retinopathy is often not observed by the general physician or noted by the patient unless the location of the visual field deficits or loss of vision produces signs more severe than the overwhelming systemic symptoms. Often the patient is so severely ill that visual symptoms may not be noted for several days. The ophthalmoscopic manifestations of the retinopathy of pancreatitis are likely to be a spectrum ranging from mild asymptomatic vascular compromise to severe retinal edema and cotton-wool patches. The visual outcome depends on the preexisting state of the retinal vasculature and retinal tissue, the location of the cotton-wool patches, the duration and severity of the vascular compromise, the cause of the vase-occlusion, its potential reversibility, and the reversibility of the injury to the retinal ganglion cells. Even with a complete occlusion of a macular arteriole on fluorescein angiography, as occurred in our Patient 1, there may be an unexpected return of good central vision. Thus, the prognosis is guarded but not hopeless.
References 1. Inkeles, D. M., and Walsh, ]. B.: Retinal fat emboli as a sequela to acute pancreatitis. Am. [, Ophthalmol. 80:935, 1975. 2. Purtscher, 0.: Noch unbekannte Befunde nach Schiideltrauma. Ber. Versamm. Dtsch. Ophthalmol. Ges. 36:294, 1910. 3. Ubanek, j.. fIber fettembolie des auges. Albrecht yon Graefe's Arch. Klin. Ophthalmol. 131:147, 1933. 4. Lynch, M. ].: Nephrosis and fat embolism in acute hemorrhagic pancreatitis. Arch. Intern, Med. 94;709, 1954. 5. Fischbein, F., and Safir, A.: Monocular Purtscher's retinopathy. Arch. Ophthalmo1.85:480, 1971. 6. Burton, T. c.: Unilateral Purtscher's retinopathy. Ophthalmology 87:1096, 1980. 7. Duane, T. D.: Valsalva hemorrhagic retinopathy. Am. [. Ophthalmol. 75:637, 1973. 8. Lyle, D. j.. Stapp, ]. P., and Button, R. R.:
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Ophthalmologic hydrostatic pressure syndrome. Am. J. Ophthalmol. 44:652, 1957. 9. Kelley, J. 5.: Purtscher's retinopathy related to chest compression by safety belts. Fluorescein angiographic findings. Am. J. Ophthalmol. 74:278, 1973. 10. Baarsrna, G. 5., and Van Balen, A. T. M.: Purtscher's disease. Doc. Ophthalmol. 44:95, 1977. 11. Beckingsale, A. B., and Rosenthal, A. R.: Early fundus fluorescein angiographic findings and sequelae in traumatic retinopathy. Case report. Br. J. Ophthalmol. 67:119, 1983. 12. Jacob, H. 5., Craddock, P. B., Hammerschmidt, D. E., and Maldow, e. F.: Complementinduced granulocyte aggregation. N. Engl. J. Med. 302:789, 1980. 13. Jacob, H. 5.: Granulocyte-complement interaction. Arch. Intern. Med. 138:461, 1978. 14. Craddock, P. R., Hammerschmidt, D., White, J. G., Dalmasso, A. P., and Jacob, H. 5.: Complement (C5a)-induced granulocyte aggregation in vitro. J. Clin. Invest. 60:260, 1977. 15. Craddock, P. R., White, J. G., and Jacob, H. 5.: Potentiation of complement (C5a)-induced granulocyte aggregation by cytochalasin .B. J. Lab. Clin. Med. 91:490, 1978. 16. Craddock, P. R., Fehr, J., Dalmasso, A. P., Brigham, K. L., and Jacob, H. 5.: Hemodialysis leukopenia. J. Clin. Invest. 59:879, 1977. 17. Goldstein, I. M., Cala, D., Radin, A., Kaplan,
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H. B., Horn, J., and Ranson, J.: Evidence of complement catabolism in acute pancreatitis. Am. J. Med. Sci. 275:257, 1978. 18. Ruddy,S., Gigli, I., and Austen, K. F.: The complement system of man. Part 1. N. Engl. J. Med. 287:489, 1972. 19. Kwaan, H. C.; Anderson, M. C.; and Gramatica, L.: A study of pancreatic enzymes as a factor in the pathogenesis of disseminated intravascular coagulation during acute pancreatitis. Surgery 69:663, 1971. 20. Kincaid, M.e., Green, W. R., Knox, D. L., and Mohler, e.: A clinicopathological case report of retinopathy of pancreatitis. Br. J. Ophthalmol. 66:219, 1982. 21. Gaudric, A., Coscas. G., and Bird, A. c.: Choroidal ischemia. Am. J. Ophthalmol. 94:489, 1982. 22. Goldbaum, M. H.: Retinal depression sign indicating a small retinal infarct. Am. J. Ophthalmol. 86:45, 1978. 23. [ampol, L. M.: Arteriolar occlusive diseases of the macula. Ophthalmology 90:534, 1983. 24. Hammerschmidt, D. E., White, J. G., Craddock, P. R., and Jacob, H. 5.: Corticosteroids inhibit complement-induced granuloctye aggregation. J. Clin. Invest. 63:798, 1979. 25. Skyring, A., Singer, A., and Tornya, P.: Treat- . ment of acute pancreatitis with Trasylol. Report of a controlled therapeutic trial. Br., Med. J. 2:627, 1965.
Two patients (a 28-year-old woman and a 23-year-old man) with acute pancreatitis developed severe visual loss. The acute stage of retinopathy consisted of retinal edema, cottonwool patches, and retinal hemorrhages, predominantly in the posterior pole of both eyes. During the five-year follow-up period, visual acuity improved and sequential fluorescein angiography of both patients demonstrated reperfusion of previously occluded retinal vessels. After resolution of the cotton-wool patches, the previously edematous areas were replaced by foci of retinal thinning. w.h~ch created irregularities in the internal Iimifing membrane light reflex. Visual fields demonstrated scotomas corresponding to the areas of the previous cotton-wool patches. INKELES AND W ALSH I provided the first description of an associated retinopathy in patients with acute pancreatitis in 1975. Ophthalmoscopically, the retinal manifestations are essentially the same as those in Purtscher's retinopathy." The retina has multiple, often confluent, cotton-wool patches located primarily within the temporal retinal vascular a.rcades and macula, retinal edema, and occasionally striate and blot hemorrhages. Visual loss and visual field deficits are the patient's primary subjective complaints. Because of the similar fundus appearance, fat emboli were believed to be responsible for both diseases. Two patients with this disease have been monitored at the University of Chicago for a five-year period.
Accepted for publication May 7, 1985. From the Department of Ophthalmo.logy an~ Eye Research Laboratories, University of Chicago, Pntzker School of Medicine, Chicago, Illinois. Reprint requests to Peter H. Morse, .M.D., Eye Research Laboratories, 939 E. 57th St., Chicago, IL 60637.
246
Case Reports Case 1 A 28-year-old woman with a four-year history of alcohol abuse was admitte~ to the niver sity of Chicago General Surgical Service .on June 27, 1979, with right upper quadrant pam, nausea, emesis, and diarrhea. She also complained of decreased vision in bot~ eyes. H~r medical history included hypertension, chronic anemia, cholecystitis, and recurrent pancreatitis. Plasma amylase level was 12,000 UI100 ml (normal, 25 to 250 U/100 ml). Ultrasonography of the abdomen demonstrated an enlarged pancreas consistent with pancreatitis. Visual acuity without correction .was counting fingers at 2 feet in both eyes. Intraocular pressure by applanation tonometry was R.E.:14 mm Hg and L.E.: 12 mm Hg. Both pupils showed an afferent pupillary defect: O h thalmoscopic examination disclos~d optic ~Isk edema, arteriolar attenuation, diffuse retinal edema, an irregular foveolar reflex, and confluent cotton-wool patches involving the macular area (Fig. 1, left). Superficial striate hemorrhages were also seen superior to the optic nerve head in the right eye. Fluorescein angiography showed obscuration of the choroidal background pattern in the areas of the cotton-wool patches and hemorrhages, occluded retinal arteri~le~, cap~llary nonperfusion, and venous staining (FIg. 1, right). ,.. One month later, the patient s visual acuity was R.E.: 20/80, 8 point and L.B.: 201100, 8 point. Ophthalmoscopy demonstrated optic nerve head pallor, lessening of retinal edema and cotton-wool patches, and attenuation and early sheathing of the arterio~es. Fluorescein angiography showed reperfus~on of s~me of the previously occluded artenoles WhIC~ .remained reduced in caliber. Perivenous stammg and optic disk edema were considerably less marked.
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Fig. 1 (Snady-McCoy and Morse). Case 1, right eye. Left, During the acute phase of the retinopathy associated with pancreatitis. Note the attenuation and increased light reflex of the retinal arterioles, confluent cotton-wool patches involving the papillornacular bundle, and an irregularity of the macular reflex created by the surrounding retirial edema. Visual acuity was counting fingers at 2 feet. Right, A fluorescein angiogram obtained during the acute phase demonstrates arteriolar and capillary nonperfusion, especially inferotemporal to the foveola. There is diffuse hypofluorescence in the area of the cotton-wool patches. One month later, visual acuity had improved to R.E.: 20/25, 4 point and L.E.: 20/30, 4 point. The ophthalmoscopic examination showed optic disk atrophy, attenuated and sheathed arterioles, and continued resolution of the cotton-wool patches. Goldmann visual fields showed central and paracentral scotomas and generalized constriction. Seven months after the initial ophthalmologic examination, the cotton-wool patches had completely resolved. In areas where the cottonwool patches had been there was a mottling of the retinal pigment epithelium and multiple irregularities of the internal limiting membrane light reflex caused by a thinning of the inner one half of the retina. The alteration of the light reflex was particularly apparent in the areas previously occupied by large confluent COttonwool patches. Five years after the acute episode, the patient's best corrected visual acuity was R.E.: 20/25,4 point and L.E.: 20150 +2, 4 point. The ophthalmologic findings were unchanged (Fig. 2). Case 2 A 23-year-old alcoholic man was hospitalized because of acute pancreatitis and hemorrhagic gastritis on Oct. 8, 1979. His symptoms included nausea, vomiting, and hematernesis, which
had worsened during the previous 12 hours. The plasma amylase level was 710 UllOO ml (normal, 25 to 250 Ul100 ml), Ultrasonography of the abdomen was consistent with acute pancreatitis. Four days after admission, his visual acuity was R.E.: 201100, 14 point and L.E.: 20/200, 12 point. The intraocular pressure was R.E.: 10 mm Hg and L.E.: 11 mm Hg. Ophthalmoscopic examination disclosed isolated cottonwool patches proximal to the optic disk and near the macula, affecting the left eye more than the right (Fig. 3, left). Fluorescein angiography showed a relative hypofluorescence of the background choroidal vascular pattern in the areas of the cotton-wool patches and a mild hyperfluorescence in the macula (Fig. 3, right). Two months later, the patient's visual acuity was R.E.: 20/80, 6 point and L.E.: 20/200, 12 point. The cotton-wool patches had resolved and there were depressions in the retina accentuated by the internal limiting membrane light reflex with a mild mottling of the retinal pigment epithelium. Five years after the acute episode, the patient's best corrected visual acuity was R. E.: 20/60, 4 point and L.E.: 20170, 4 point. In addition to the irregular reflexes in the macular area, there were also small yellow deposits at the level of the retinal pigment epithelium and
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Fig. 2 (Snady-McCoy and Morse). Case 1, right eye. Five years after the acute episode the eye shows optic atrophy, generalized attentuation of the retinal vessels, mild sheathing of the arterioles, fine mottled hypopigmentation and hyperpigmentation of the fundus, and an irregularity of the retinal light reflex caused by retinal depression or thinning (arrows). Right, A fluorescein angiogram demonstrates attenuation of the retinal vessels and a relative hypoperfusion of the retinal capillaries inferotemporal and superotemporal to the foveola consistent with the areas of previous vascular nonperfusion. Fine mottled hypopigmentation and hyperpigmentation remain. The larger vessels, although attenuated, are patent, and the patient's visual acuity has returned to 20/25, 4 point.
scattered clumps of hyperpigmentation, especially in the left eye (Fig. 4, left). Fluorescein angiography demonstrated an enlargement in the caliber of a previously attenuated venule in an area where a cotton-wool patch had been.
There was complete vascular perfusion with evidence of mild hypopigmentation and hyperpigmentation (Fig. 4, right). Goldmann visual fields showed a large nasal step in the right eye and multiple isolated scotomas in the left eye,
Fig. 3 (Snady-McCoy and Morse). Case 2, left eye. Left, During the acute phase of pancreatitis retinopathy, cotton-wool patches are prominent along the superotemporal and inferotemporal vascular arcades. A less intense retinal edema surrounds the foveola. Note the irregular foveolar reflex and increased arteriolar light reflex. Visual acuity was 20/200, 12 point. Right, A fluorescein angiogram during the arteriolar phase shows the foci of cotton-wool patches as areas of hypofluorescence. There is some hyperfluorescence in the macula. A small venous branch lying beneath a cotton-wool patch is attenuated (arrow).
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Fig. 4 (Snady-McCoy and Morse). Case 2, left eye. Left, One year after the acute phase of pancreatitis retinopathy. Note the irregular internal limiting membrane reflex as the result of multiple retinal depressions caused by retinal thinning in the areas of previous cotton-wool patches. There is a fine speckled hyperpigmentation in the macula. Right, A fluorescein angiogram shows reperfusion of the small venous branch (arrow) and diffuse fine hyperpigmented mottling of the posterior pole. Visual acuity was 20170, 4 point. which corresponded in location to the previous sites of the cotton-wool patches and persistent retinal depressions.
Discussion In patients with retinopathy associated with acute pancreatitis, it was easy to apply the etiologic theory of fat embolism within the retinal and choroidal vessels because of the similarity of the ophthalmoscopically observed lesions. log Fat emboli have been demonstrated in histopathologic studies of organs inpatients with pancreatitis;' However, other origins of this syndrome have been hypothesized. The retinal tissue responses have also been ascribed to increased intraocular venous pressure and retinal venous stasis caused by increased cerebrospinal fluid pressure.! and increased intrathoracic pressure or retinal arteriolar spasm.r" Rapid increases or decreases in blood pressure affecting the retinal vessels may also occur in acute pancreatitis. Other concomitant conditions, such as anemia, may also influence the manifestations of pancreatitis retinopathy. Another theory implicates the complement system because activated proteases such as trypsin are released during injury or inflammation of the pancreas. 12,13 Inhibitors of proteases may be diminished or overwhelmed and these
uninhibited proteases will activate complemerit.":" Trypsin activates C3 and C5, and C5a aggregates have been found in the sera of patients with acute pancreatitis." C5a stimulates mast cells to release a substance that increases the permeability of blood vessels and induces surface changes in the granulocyte cell membranes, making them more adherent to endothelial cells and other grariulocytes.P-" Granulocytic aggregates may occlude retinal vessels as much as 60 urn in diameter. Additionally, activated granulocytes release oxygen radicals toxic to the vascular endothelium and cause increased vascular permeability." Pancreatitis may sometimes be associated with disseminated intravascular coagulation." Possibly all of these interrelated factors contribute to the vase-occlusive process. Arteriolar spasm, intravascular sludging of erythrocytes, fat emboli, complement-granulocyte or platelet-fibrin aggregates, and coagulative necrosis of the retinal vessels produce the tissue response seen in the retinopathy associated with pancreatitis and other retinal vaso-occlusive diseases. In the only clinicopathologic study of the retinopathy of pancreatitis, Kincaid and associates'" reported occluded retinal arterioles and choroidal vessels, focal areas of edema within the inner layers of the retina, cystoid spaces, small hemorrhages in the outer plexiform layer, and disruption of the photoreceptors
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with loss of photoreceptor segments. Electron micrographs showed that the lumina of the _occluded vessels contained proteinaceous material consistent with recanalized thrombi. It was not possible to identify the emboli as lipid, granulocyte, or platelet aggregates.F Although Kincaid and associates" described histopathologically occluded choroidal vessels, they believed they did not play an important part in the pathogenesis of the clinical manifestations in their patients because the retinal pigment epithelial cells remained normal. However, it is possible that impairment of the choroidal circulation causing retinal pigment epithelial damage occurs in patients with pancreatitis and may have contributed to the ophthalmoscopically visible pigment mottling observed." Both of our patients had an irregularity of the internal limiting membrane light reflex after resolution of the retinal edema and cotton-wool patches. This finding has been called the "retinal depression sign" in patients with sickle cell retinopathy, systemic hypertension, retinal arteriolitis, and juvenile-onset diabetes mellitus.P This sign is visible in patients with any disease producing arteriolar occlusion in the retina, including talc retinopathy, radiation retinopathy, vasculitis secondary to connective tissue disorders, and chronic granulocytic leukemia." To this list may now be added the retinopathy associated with pancreatitis. Treatment of retinopathy associated with pancreatitis is limited to observation and supportive care. Possible therapy, depending on the etiologic theory favored, includes administration of systemic corticosteroids that nullify vascular leukostasis and production of oxygen radicals." Systemic corticosteroids would theoretically be most effective before the development of overt retinopathy. The routine use of corticosteroids, however, is impractical especially in view of the increased susceptibility to infection of patients with acute pancreatitis. Protease inhibitors, which inactivate circulating pancreatic enzymes released during an acute attack of pancreatitis, thus inhibiting complement activation and the release of CSa, may be another treatment. However, clinical trials using aprotinin (Trasylol), a potent trypsin and kallikrein inhibitor, did not show any improvement in the clinical course of acute pancreatitis." These clinical trials have shown, moreover, that aprotinin may actually prolong the half-life of C5a and thus be detrimental. Therapeutic trials with other specific protease inhibitors may yield different results.
Aspirin, indomethacin, and ibuprofen do not inhibit granulocyte aggregation. Aspirin, however, does inhibit platelet aggregation. Antioxidants such as vitamin E may help to decrease vascular permeability but this has no proven clinical efficacy. . The findings of the retinopathy of pancreatitis are similar to those in other vascular occlusive retinopathies clinically, histopathologically, and with respect to long-term sequelae. The retinopathy is often not observed by the general physician or noted by the patient unless the location of the visual field deficits or loss of vision produces signs more severe than the overwhelming systemic symptoms. Often the patient is so severely ill that visual symptoms may not be noted for several days. The ophthalmoscopic manifestations of the retinopathy of pancreatitis are likely to be a spectrum ranging from mild asymptomatic vascular compromise to severe retinal edema and cotton-wool patches. The visual outcome depends on the preexisting state of the retinal vasculature and retinal tissue, the location of the cotton-wool patches, the duration and severity of the vascular compromise, the cause of the vase-occlusion, its potential reversibility, and the reversibility of the injury to the retinal ganglion cells. Even with a complete occlusion of a macular arteriole on fluorescein angiography, as occurred in our Patient 1, there may be an unexpected return of good central vision. Thus, the prognosis is guarded but not hopeless.
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