Aclinicopathological case report of retinopathy of ... · pancreatitis MARILYN C. KINCAID, W....

British Journal of Ophthalmology, 1982, 66, 219-226

A clinicopathological case report of retinopathy ofpancreatitisMARILYN C. KINCAID, W. RICHARD GREEN, DAVID L. KNOX, AND

CHARLES MOHLER

From the Eye Pathology Laboratory, the Wilmer Ophthalmological Institute, andDepartment of Pathology, the Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

SUMMARY A 32-year-old black woman with pancreatitis developed visual loss in both eyes. Onophthalmoscopic examination she had extensive ischaemic infarcts at the posterior poles of botheyes, a clinical picture which has been reported previously in patients with pancreatitis and noted tobe similar to Purtscher's retinopathy. On histopathological examination of the eyes after deaththere were arteriolar occlusions in both the choroid and retina and inner ischaemic infarctions withinner retinal oedema. Owing to the 23-day interval from arteriolar occlusion until death the exactnature of the original occlusion could not be determined. However, either fat emboli or activatedcomplement C5-induced granulocyte embolus formation are possible causes.

Purtscher' first described in 1910 the retinopathy thatnow bears his name. It occurs after trauma to thehead' or the body2 and is characterised by visual losswithin hours and the appearance of cotton-wool spotsand haemorrhages at the posterior pole. Morerecently a similar fundus picture has been recognisedin pancreatitis.34 The pathogenesis remains obscure.Some have theorised that fat emboli play a causativerole in some cases of Purtscher's retinopathy5 and inthe retinopathy of pancreatitis,3 but others6 disputethis view. Kelley7 believed, on the basis of capillaryleakage seen on fluorescein angiography performedwithin hours of injury, that primary endothelialdamage was a more likely cause. However, he couldnot rule out microemboli.More recently the role of granulocyte emboli

formed by complement activation, specificallyC5-induced granulocytic clumping, has beenproposed as the aetiology in both Purtscher'sretinopathy and in the retinopathy of pancreatitis.4

Case report

The patient was a 32-year-old chronic alcoholicwoman. She was admitted to the medical service on21 May 1972 with epigastric pain and a 3-day history

Correspondence to W. Richard Green, MD, Eye PathologyLaboratory, Johns Hopkins Hospital, 600 N. Wolfe Street,Baltimore, MD 21205, USA.

of anorexia. At the time of admission the liver wastender and palpable 3 cm below the right costalmargin. There were skin ecchymoses, and anasogastric tube drained guaiac-positive coffee-ground material. Her blood pressure was 160/90mmHg. Platelet count, white cell count, and clottingtimes were normal. Haematocrit was 30%. Amylasewas 208 CRW units (normal=20-160). Haemoglobinelectrophoresis was normal.On the evening of 22 May she had a tonic-clonic

seizure and became comatose for 3 days. A neuro-logical examination was normal except for the alteredmental status. Arteriogram and echoencephalogramwere normal, but the cerebrospinal fluid containedan elevated protein level of 118 mg/dl (1'18 g/l)(normal= 15-45 (0'15-0-45 g/l)), with a nonnalglucose level. The neurologist noted 'occasional' dothaemorrhages, with retinal oedema in both eyes. Theamylase rose to 372 CRW units, and she developed afever, for which she was given kanamycin andchloramphenicol.On 24 May 1972 she was seen by one of us (D.L.K.)

and found to have diffuse intra- and subretinaloedema, with narrowed retinal arterioles in botheyes. There were a few retinal haemorrhages. Thiswas thought to be consistent with hypertensiveretinopathy. Because of her obtunded state her visioncould not be tested.Her amylase continued to rise, up to 720 units.

Calcium was low at 5 mg/dl (1 -25 mmol/l) (normal=219

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Marilyn C. Kincaid, W. Richard Green, David L. Knox, and Charles Mohler

Fig. I Composite photograph ofleft eye taken at the bedside. Themacula appears as a cherry-redspot, andfluffy-white exudates areseen throughout the posterior pole.The arterioles (arrow) arenarrowed.

9-11 (2 25-2 75 mmol/l)), and albumin was low at1P7 g/dl (17 g/l) (normal=3-5-5-5 (35-55 g/l)).However, as the amylase level fell, her mental statusimproved.

Because of a low haematocrit she was transfused,but developed pulmonary oedema, responsive onlyto repeated phlebotomies. On 26 May 1972Pseudomonas aeruginosa was grown from her lungs.She continued to have intermittent gastric bleeding,with a drop in the haematocrit. Gastroscopy disclosedmassive gastritis.On 1 June 1972 funduscopic examination by one of

us (D.L.K.) revealed pallor and oedema, narrowedarterioles, and subretinal dense white exudate,thought possibly to be lipid. The pupils were reactivebut sluggish.The following day another ophthalmologist saw the

patient. He described the deposition of a 'whiteopalescent coagulum' within the sensory retina in theposterior pole. Arteriolar narrowing was stillapparent, and because of the retinal oedema themacula appeared as a cherry-red spot (Fig. 1). Hebelieved that this was a form of lipaemia retinalisconsistent with hyperlipidaemia secondary to herpancreatitis, along with hypertensive small-vesseldisease. However, although the cholesterol level was467 mg/dl (12 mmol/l) on the day of admission, twodays later it had dropped to 187 mg/dl (4-8 mmol/l),

within the normal range, and it remained normal.The triglyceride level was 140 mg/dl (1-6 mmol/l),also normal.As the pancreatitis resolved and the amylase and

calcium levels fell towards normal her major problemcontinued to be bleeding from the gastrointestinaltract. Both prothrombin time and partial thrombo-plastin time remained prolonged, and she requiredrepeated transfusions. Gastroscopy showed apossible specific lesion on the lesser curvature; so on11 June she underwent a total gastrectomy,vagotomy, and oesophagojejunostomy. Postopera-tively she became oliguric, with rising blood ureanitrogen and creatinine. Since the haematocrit hadagain fallen, she was re-explored surgically thefollowing day, but no bleeding lesion was found. Shewas given kanamycin and penicillin for possiblesepsis, and was dialysed peritoneally. On 14 June shedeveloped pulmonary oedema, which improved withphlebotomy. However, she became unresponsivewith multiple organ failures and died on 15 June 1972.

Necropsy disclosed pancreatitis with fat necrosis ofthe body and tail of the pancreas, massive gastro-intestinal haemorrhage, and necrotising haem-orrhagic bronchopneumonia consistent with theclinically observed pseudomonas infection. Thekidneys showed hyaline scarring and interstitialfibrosis consistent with hypertension. The brain

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contained small haemorrhages in the cortex and alsothe right hippocampus, with bacteria in the necroticvessel walls. The brain lesions were thought to besimilar to those of the lung and could have arisen in asingle embolic episode. However, they were believedto be too recent to explain the original neurologicalsymptoms. There was no definite evidence ofpseudomonas lesions elsewhere.

221

Fig. 2A Low-power view oftheleft eye showing diffuse oedemaextending throughout inner retina.There is partial loss ofthe nervefibre, ganglion cell, and innerplexiform layers and inner portionofthe inner nuclear layer. The area

oftransition from normal retina isfairly abrupt (asterisk). Anoccluded vessel (arrow) is present.(Haematoxylin and eosin, x57).

Material and methods

Both eyes were obtained at necropsy and wereroutinely fixed in a buffered solution of 4%formaldehyde for several days. They were thenwashed in water and dissected in 60% alcohol. Theexternal gross appearance was unremarkable and theeyes were of normal size. They were opened

Fig. 2B Higherpower view ofthesame area showing the abrupttransition (asterisk) from normal tooedematous retina. An occludedarteriole (arrow head) is present. Afocal area ofphotoreceptordisruption (arrow) overlyingapparently normnal RPE is present.(Haematoxylin and eosin, x 109).

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Fig. 3A Full thickness of retinaofthe right eye with inner-retinaloedema and also disruption andloss ofphotoreceptors. There isouter segment (asterisk) and innersegment (arrowheads) loss. Theunderlying RPE and choroidappear normal. An occluded retinalarteriole (arrow) is present.(Haematoxvlin and eosin, x 120).

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horizontally, and whitish material, thought to beexudate, was present in the posterior poles of botheyes. The pupil-optic nerve portions were thenroutinely dehydrated and embedded in paraffin, and0-1 mm stepped sections taken for light microscopy.

In each eye, within the caps, areas of retinalvascular occlusion could be identified grossly.Therefore, portions of retina which included the

vascular occlusions were dissected from the caps andrefixed in a buffered 2-5% glutaraldehyde-formaldehyde solution, rinsed in phosphate buffer,postfixed in 2% osmium tetroxide, dehydrated withgraded acetone solutions, and embedded in Epon/Araldite for transmission electron microscopy. Theremainder of the retina from the caps was trypsin-digested to study the vasculature.

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Fig. 3B Occluded retinal arteriole(arrow) within an area ofoedematous inner retina. There isalso disruption and loss ofphotoreceptors (asterisk).(Haematoxylin and eosin, x356).

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Results

Both eyes showed similar changes. The anteriorsegments were normal except for some red blood cellsin the anterior chamber of the right eye. Theperipheral retina of both eyes showed typicalperipheral cystoid degeneration. Posteriorly therewere focal areas of oedema within the inner layers ofthe retina, with cystoid spaces and disruption of thenormal architecture (Fig. 2). Transition from normalto oedematous retina was abrupt. In some areas therewas also disruption of the photoreceptors, with loss ofphotoreceptor segments (Fig. 3). In these areas outersegments, and to a less extent, inner segments weremissing, with the remaining photoreceptors displayinga curious bunching together at the outer nuclearlayer. However, the underlying retinal pigmentepithelium (RPE) and choroid remained normal.In both eyes occluded retinal arterioles werepresent (Fig. 3B). The occluding material wasperiodic-acid-Schiff positive. A special stain for fibrinwas positive (Fig. 3C). Small haemorrhages werepresent in the outer plexiform layer (Fig. 4). Noocclusions were seen in the material prepared bytrypsin digestion. At other levels occluded choroidalvessels were evident which also contained fibrin (Fig.5).

Electron micrographs revealed small arterioleswith narrowed lumina containing proteinaceousmaterial centrally, consistent with recanalisedthrombi.

Fig. 3C Another area of retinashowing an arteriole completelvoccluded byfibrin.(Phosphotungsticacid-haematoxvlin, x471).

Discussion

This patient presented with a fundus picture classicfor Purtscher's retinopathy, with cotton-wool spotsand inner retinal oedema centred round the opticnerve and extending to the macular area.' 2 Thisfundus appearance has been described in acutepancreatitis also,34 but no histopathologic correlationhas been available in cases of pancreatitis.The histopathological findings in our patient

support the clinical picture. The inner retinal oedemawas widespread, with abrupt transition from normalto oedematous retina. In much of the involved areathere were striking changes in the photoreceptorcells. We suggest that the effect of inner retinaldistension is to cause the outer retinal layers tobecome bunched and squeezed together. Suchdistension might therefore account in part for thechanges seen in the photoreceptors. Impairment ofchoroidal circulation alone was probably notresponsible, as the retinal pigment epithelial cellsremained normal.

Unfortunately, because of the severity of her illnessand altered mental state, the patient's vision was nottested nor could a fluorescein angiogram be done. Itseems evident, however, that the retinopathy andpossibly the neurological findings were caused by herpancreatitis and not, for instance, due to emboli fromthe pseudomonas infection of the lung, whichoccurred much later in the disease course.

It is possible to separate Purtscher's retinopathv

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Fig. 4 A haemorrhage (asterisk)in the outer plexiform layer oftheretina ofthe left eye. (Haematoxylinand eosin, x284).

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into 2 types in accordance with aetiology: retinopathycaused by fat emboli, and retinopathy caused bysudden elevation in the intravascular pressure.The first histological evidence for fat emboli

causing Purtscher's retinopathy was provided byUrbaneks in 1934. Seven of his patients had long-bone fractures and developed retinopathy. Heobtained the eyes from 3 of them and demonstrated

Fig. 5 Occluded choroidalarterv /a SE(arrow) in the right eve. The X ALoccluding material isfibrin. Theoverlying retinal pigment -epithelium appears normal. A(Phosphotungstic Iacid-haematoxvlin, x 400). -

emboli in the retina and choroid which histologicallywere positive for fat.

Since then, there have been other case reports8'-0 inpatients with multiple injuries. These 3 reports alldescribe patients with extensive injuries and multiplefractures. Examination of the eyes and other bodytissues with special stains post mortem disclosednumerous fat emboli throughout. Fat embolism can

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also occur after surgery to fatty areas, such as thebreast. "

In Purtscher's' original report all the patients hadsustained head trauma. He suggested that trauma tothe head was transmitted by the cerebrospinal fluidaround the optic nerves with resultant stasis andpassage of perivascular lymph into the retina.Marr and Marr2 in their review noted that sudden

elevation of intrathoracic pressure caused by directtrauma or deceleration forces could produce thepicture of Purtscher's retinopathy. They postulatedthat this was due to increased venous back pressurecausing haemorrhage, small vessel occlusion, andretinal oedema.

Several antecedent injuries producing suddenelevation in intravascular pressure have beendescribed. Fundus changes were followed as theyevolved in a pilot who ejected from his jet travelling atsupersonic speed.'2 One hour after injury there was

arteriospasm with minimal haemorrhage but withvisual acuity of counting fingers. The following daythere were definite haemorrhages, both flame shapedand round, along with cotton-wool patches. By thefollowing day all findings were more pronounced,with subhyaloid haemorrhages. On the fourth dayoedema was more generalised, giving the macula a

cherry-red appearace. However, his vision didimprove. Slowly the haemorrhages and oedemaresolved, with the patient regaining normal visualacuity and fundus appearance after 3 months.

Gass6 considered that Purtscher's retinopathy fromchest compression is probably caused by capillarydamage. Fluorescein angiography in the patient hedescribed showed collapse and late leakage of thecapillary bed in the area of the optic nerve, where thehaemorrhages and exudates were. His patient laterdeveloped optic atrophy.

Kelley7 was able to examine a patient within an

hour of chest compression by a lap and shoulder seatbelt in a car accident. Fundus abnormalities,including superficial exudates, perimacular oedema,and haemorrhages, were evident in the right eye

within an hour of the accident. But fluoresceinangiography done within 2 hours of injury showedleakage from small vessels in both eyes. Unlike thepatient reported by Gass,6 this patient had no areas ofnonperfusion. Kelley' favoured the possibility ofdirect damage to the capillary endothelium as mostlikely, although he believed microemboli could notbe ruled out as a cause. His patient's vision returnedto normal within 2 weeks, but the fundus appearance

did not resolve until 10 weeks after the injury.Some patients with a typical Purtscher's

retinopathy sustained minor trauma, such as a fallfrom a bicycle or gymnastic equipment, without theloss of consciousness.2 The authors suggested that

such injuries might result in a transient rise of thevenous pressure within the head. The retinopathy inPurtscher's patients may be explained on the samebasis.Marr and Marr2 pointed out that it can be difficult

to separate the retinopathy of fat embolism from thatof increased hydrostatic pressure, but thought thatthis can be done in part by the presence or absence ofa fat-generating injury, such as a fracture, andassociated systemic findings, such as pulmonary andcerebral involvement. In their opinion fat emboliproduce retinopathy at least a day or two after theevent, while in retinopathy from increased hydro-static pressure the fundus findings appear withinhours. They believed diffuse oedema, with a cherry-red appearance of the macula, is more probably dueto fat emboli.

Duane'3 reported several patients with history oftrauma and varying fundus pictures. He believed thatthe retinopathy classically called Purtscher's wascaused by combined rapid rises of arterial and venouspressures. A combination of hard exudates, innerretinal haemorrhages, and arterial spasms werecaused by arterial pressure rise, and retinal oedema,transudation, and preretinal haemorrhage werecaused by venous pressure rise. He believed thefundus findings were too variable, with injuriessometimes too complex, to be ascribed simply toangiospasm or fat emboli.Other hypotheses, by no means mutually exclusive,

include air emboli 4 and granulocyte aggregatessecondary to complement activation.4Burton'4 thought air embolism to be an alternative

possibility in chest compression injuries. He citedexperimental work in which animals that died of chestcompressive injuries had air emboli in the lungs;however, the eyes were not examined. Burton'4 alsopointed out in his follow-up of 4 patients that finepigmentary changes occurred in the posterior poles of2 of them, suggesting that choroidal as well as retinalembolism had taken place.

It has been observed that acute pancreatitis can beassociated with a similar retinopathy.3 The authorspresented 3 patients with pancreatitis who hadblurred vision during the disease course. Twopatients had fluorescein angiograms which showedareas of arteriolar and capillary nonperfusion and lateleakage, consistent with numerous small emboli. Theauthors stated that fat emboli from omental adiposetissue, digested by enzymes released from theinflamed and damaged pancreas, were responsible forthe eye findings, as fat emboli to other organs inpancreatitis had been demonstrated.3

In a more recent report of a fourth patient withpancreatitis and Purtscher's retinopathy4 the authorsspeculated that, rather than emboli of fat, the emboli

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were aggregates of granulocytes caused by activatedC5, a component of complement. The authors couldnot directly prove that the patient's retinopathy wasdue to aggregates of granulocytes or that in theirpatient complement C5 levels were elevated.However, they obtained acute and convalescentserum from 12 other patients admitted to hospitalwith pancreatitis, and showed that their serum wouldaggregate granulocytes in the acute stage of thedisease but not after convalescence. They were ableto demonstrate that either trypsin or activated C5added to normal serum would also cause aggregation.

Experimental work in vitro has shown that com-plement factor CS, when activated, was theresponsible factor in granulocyte aggregation, sinceanti-C5 antibody abolished all aggregation activity.'Furthermore the size of the aggregates' wouldapproximate that of the 15-40 ,um glass spheres usedby Ashton and Henkind'6 to produce a fundusappearance similar to Purtscher's retinopathy.The authors4 proposed that digestive enzymes are

released from the pancreas when it is acutely inflamedand activate complement factor CS, which in turnaggregates granulocytes. This theory is also con-sistent with Purtscher's retinopathy from trauma,because acute trauma has been shown to activateseveral complement factors. 7 This would be anotherpossible cause for the fundus appearance. It is quitelikely that a combination of several factors, includinghydrostatic pressure changes, fat emboli, air emboli,and granulocyte emboli, could be responsible.

Histopathologically we were able to demonstratevascular occlusion at the posterior pole both in thechoroid and in the retina of our patient. Because shedied 23 days after admission, and 21 days from thetime the retinopathy was first observed, it was notpossible to characterise the emboli. Either lipidemboli or granulocytic aggregates are possiblealternatives.

This study was supported in part by Research Grant 1 ROI EY4)1684from the National Eye Institute (Dr Green) and a grant from theHeed Foundation (Dr Kincaid).

References

I Purtscher 0. Noch unbekannte Befunde nach Schadeltrauma.Ber Dtsch Ophthalmol Ges 1910; 36: 294-307.

2 Marr WG, Marr EG. Some observations on Purtscher's disease:traumatic retinal angiopathy. Am J Ophthalmol 1962; 54:693-705.

3 Inkeles DM, Walsh, JB. Retinal fat emboli as a sequela to acutepancreatitis. Am J Ophthalmol 1975; 80: 935-8.

4 Jacob HS, Goldstein TM, Shapiro 1. Craddock. PR.Hammerschmidt DE, Weissmann G. Sudden blindness in acutepancreatitis. Possible role of complement-induced retinalleukoembolization. Arch Intern Med 1981; 141:134-6.

5 Urbanek J. Uber Fettembolie des Auges. Albrecht von GraefesArch Klin Ophthalmol 1934; 131: 147-73.

6 Gass JDM. Atlas of Macular Disease. Diagnosis and Treatment.2nd ed. St Louis: Mosby, 1977: 316-7.

7 Kelley JS. Purtscher's retinopathy related to chest compressionby safety belts. Fluorescein angiographic findings. Am JOphthalmol 1972; 74: 278-83.

8 Fritz MHM Hogan MJ. Fat embolization involving the human eve.Am J Ophthalmol 1948; 31: 527-34.

9 DeVoe AG. Ocular fat embolism. A clinical and pathologicreport. Arch Ophthalmol 1950; 43:857-63.

10 Kearns TP. Fat embolism of the retina demonstrated bv a flatretinal preparation. Am J Ophthalmol 1956; 41: 1-2.

11 Morgan OG. Some cases of fat embolism of the retina. TransOphthalmol Soc UK 1949; 69: 441-5.

12 Lyle DJ. Stapp JP, Button RR. Ophthalmologic hvdrostaticpressure svndrome. Am J Ophthalmol 1957; 44: 652-7.

13 Duane TD. Valsalva hemorrhagic retinopathv. Am J Ophthalmol1973; 75: 637-42.

14 Burton TC. Unilateral Purtscher's retinopathv. Ophthalmology1980; 87: 1096-105.

15 Craddock PR. Hammerschmidt D. White JG. Dalmasso AP,Jacob HS. Complement CSa-induced granulocvte aggregation invitro. A possible mechanism of complement-mediated leukostasisand leukopenia. J Clin Invest 1977; 60: 260-4.

16 Ashton N. Henkind P. Experimental occlusion of retinalarterioles using graded glass ballotini. BrJ Ophthalmol 1965: 49:225-34.

17 Ruddv S. Gigli 1. Austen KF. The complement svstem of man. NEngliJ Med 1972: 287: 489-95.

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