Eye (1991) 5, 214-221

The Intraocular Changes of Anterior Segment Necrosis

ROSWELL R. PFISTER Birmingham, Alabama

Summary Anterior segment necrosis is an acute or chronic process occasioned by embar­ rassment of the supply of the anterior segment of the . In the acute form this vascular obstruction leads to severe corneal oedema, necrosis of anterior , hypo­ tony and formation. Depression of formation accounts for severe reduction of glucose levels in corneal stroma and aqueous humour lasting for two days after cautery of the long posterior ciliary (LPCA) in rabbits. Lac­ tate levels are initially significantly elevated but return to normal after one week. Stromal hydration was elevated for one week but then returned to normal. Corneal epithelial glycogen was diminished at one and two days after surgery but then returned to normal. Although unproven, oxygen deprivation probably plays a major role in endothelial ischaemia and therefore corneal oedema. It is concluded that the abnormalities seen in anterior segment necrosis stem from changes in aqueous meta­ bolic components resulting from severely reduced aqueous turnover. Hyperbaric oxygen and intracameral metabolite substitution are unproven treatments but merit further experimental study.

Anterior segment necrosis (ASN) occurs as a buckling surgery is performed in patients chronic or acute process wherein the vascular manifesting haemoglobin Sc. 4,5 Strabismol­ supply of the anterior portion of the eye is ogists responding to a questionnaire reported compromised. Ischaemic ocular syndromes a total of 30 cases of ASN for a calculated inci­ such as pulseless disease and the aortic arch dence of one in 1,333 operations.6 syndrome represent a chronic ischaemia ASN is more common after the Hummel­ which is characterised by neovascularisa­ scheim transplantation operation in older tion and atrophy, pupillary dilation and cor­ individuals. 7,8,9,10 neal oedema with .1,2 The acute form Histopathological evidence of ASN has occasionally occurs after surgical procedures been verified in two studies. Iris and ciliary in which there is extensive disinsertion of the body necrosis were demonstrated in 21 of 150 rectus muscles and/or obstruction of the long enucleated following trans scleral diath­ posterior ciliary arteries. 3 ermy, scleral resection, or polyethylene tubes In surgery, when three for retinal detachment.11 A more recent study muscles are disinserted, especially the medial showed ASN present in 8.2% of 49 eyes rectus, ASN is more likely to develop. These obtained from 43 patients who previously chances increase when the long posterior cili­ underwent retinal detachment surgery. 12 ary arteries are cauterised or when scleral The clinical presentation of ASN is domi-

From: Eye Research Laboratories, Brookwood Medical Center, Birmingham, Alabama. Correspondence to: Roswell R, Pfister M.D., Suite 211,2008 Brookwood Medical Center Drive, Birmingham, AL35209, THE INTRAOCULAR CHANGES OF ANTERIOR SEGMENT NECROSIS 215

nated by changes evident in the and the suprachoroidal space to the . anterior uvea. Wrinkling of Descemets mem­ The contribution each system makes to the brane and anterior uveitis with keratic pre­ anterior segment of the eye is 40% cipitates herald the early picture of ASN. anterior ciliary and 60% LPCA. In the rabbit Later, massive corneal stromal oedema may the anterior ciliary system makes a very minor be evident, followed by peripheral stromal contribution to this system.13 infiltratesand hypotony. Figure lea) shows the internal blood column in the normal rabbit eye and its inter­ Anterior Segment Circulatory ruption after LPCA cautery. (Fig l(b» In the Considerations rabbit eye transection of the four rectus Anterior segment necrosis (ASN) is predi­ muscles and perilimbal cautery has no effect cated on a failure of vascular perfusion of the on the corneal clarity. 14 There is a slight fall in anterior segment of the eye. Loss of the vas­ corneal epithelial glycogen but no effect on cular supply to the ciliary body and iris results aqueous humour glucose, corneal hydration, in partial necrosis of these tissues to a degree or corneal aerobic glycolysis. depending on the severity of the vascular deprivation. A decrease in the blood supply Experimental Anterior Segment Necrosis interferes with the active and passive trans­ Anterior segment necrosis has been induced port of ions and nutritional substances into in a number of animal models. Multiple disin­ the aqueous humour by the non-pigmented sertions of the rectus muscles in monkeyss or of the ciliary body. This depri­ injury to the ciliary arteries around the optic vation robs the cornea and crystalline of of rabbits has led to ASN.15 Simple cut­ substances vital to their health. ting of the long posterior ciliary arteries in In the human, the vascular supply of the rabbits caused no change in aqueous glucose, anterior segment of the eye is dependent on corneal transparency, or calcium uptake by two sources. The anterior ciliary arteries issue the cornea. 14,16 The most effective technique from the terminal arteries of the rectus in rabbits was diathermy to both long pos­ muscles, perforating the to join the terior ciliary arteries resulting in extensive iris greater arterial circle in the ciliary body at the and ciliary body changes. 17 root of the iris. The long posterior ciliary In the experiments described here, a per­ arteries branch (LPCA) from the ophthalmic itomy is performed in the anaesthetised rabbit deep in the and progress and the medial and lateral rectus muscles are anteriorly on the medial and lateral portions tenotomised. A radiodiathermy unit (MIRA) of the , intrasclerally. Additional is used to place a continuous row of three or branches given off by the LPCA in its intra­ four transscleral cautery points along the scleral course penetrate sclera and travel in course of the arteries from behind the equator

Fig la. Fig lb.

Fig. 1. Interior view of long posterior ciliary artery (a) in the normal and (b) after immediately after LPCA cautery. Note loss of blood column in b. 216 ROSWELL R. PFISTER to a position ahead of the rectus insertions. blush at the junction of normal and atrophic is then pulled back to the limbus. iris, expanding extensively over the ensuing one to two weeks. [4 General Anterior Segment Abnormalities The intraocular changes in experimentally Lens produced ASN in rabbit eyes has been pre­ Anterior subcapsular vacuoles appeared one viously documented in our laboratory.18 The day after diathermy. Water clefts between results noted here represent some citations cortical lamellar fibres developed by seven from that study, subsequent new and unpub­ days. Lens opacities progressed to a mature lished data, and additional studies gleaned cataract at six weeks. from the literature. After LPCA cautery in the rabbit, ocular Clinical Findings hypotony of less than five mm Hg persisted for Anterior chamber six weeks, though the intraocular pressure Cells and flare appeared in the aqueous was higher after six weeks than in the first humour immediately after cautery, reaching week. These results were confirmed by the maximum at seven days and disappearing Guerry who showed that after LPCA cautery after three weeks. The anterior chamber rabbit eyes show hyptony for weeks,21 some became shallow two to seven days later from giving rise to .22 The squirrel posterior corneal swelling. At three to six monkey. with a ciliary circulation similar to weeks the cornea had returned to near normal , showed a depression of the lOP to thickness but cataract formation had swelled about 50% after five days and for the sub­ the lens sufficiently to maintain a narrow sequent 24 days.23 (Fig. 2) Although the sur­ anterior chamber. gery diminishes the volume of blood delivered Ciliary body and Iris to the ciliary body, additional hypotensive Immediately after diathermy the effect might be gained by damage to the long became dilated and vertically oval with col­ posterior ciliary coursing in the same lapse of the iris vasculature. After one day, sheath. Proof for this is secured from chemical the iris appeared pale, ultimately reducing to sympathectomy experiments in which a 35% a velamentous frill with minimal circulation reduction in the lOP was noted.24 It is likely after three weeks. Mild hyphaema was that both mechanisms are operative to reduce occasionally present. Anderson has demon­ lOP in the experimental model. strated beginning as a pink Chemical Findings Aqueous glucose-Aqueous glucose was 15 I. 7 " n"'22 " ""'10 0 6 .of ,;: h �"E 10 E � - , :. 514 ,i .! 'r�ll I.. : . 3 I] " iI 5 I ; I 8 • 2 c n-l0 "-10 � , I ;!; 1 n=lO � I In'lO -�.- -1 ·"-- , ,'i ]flrfl 1,1! --�- • o+-��+-������������ Normal 0 1 �2 .. T 5 6 7 21 42 -I -4 -2 0 2 • • • 10 12 '4 ,I la 20 22 24 DAYS TIME (DAYS)

Fig. 2. Effect of cautery of both LPCA on the Fig. 3. Severe aqueous glucose depression after intraocular pressure in the squirrel monkey. (with induced anterior segment necrosis lasted for two days permission from Levy et ai, Invest Ophthalmol Vis Sci but level was normal at 4, 7 and 42 days (averages ± 1974, 13: 468-71.) SE). THE INTRAOCULAR CHANGES OF ANTERIOR SEGMENT NECROSIS 217

Stromal lactate-Figure 6 shows the large 6 increase in lactate concentration after three "-10 hours (P

24 2 2 24 nolO 20 22 n-lO I 18 "10 20 �:J: n i 16 �18 14 i1 � 6 ""'10 � 12 lilTnt ":=1 " 14 ill � 10 III 0 -. < �12 t; 8 SlO It II I :5 6 n,]" Ii: ... 8 ! 4 I �6 2 4 I IJ "[ 2 111�JI Normal JJtil - ri�� I 2 l 4 5 • 7 �u21 42 ·"00 1 -,-- -� -.--il 'III 0 -. I , 21 .t2 DAYS DAYS Fig. 5. Changes in aqueous humor lactate concentrations following long posterior ciliary cautery. Fig. 6. Stromal lactate changes after operation. Note Note decreasing levels of lactate falling to normal at rapid elevation in three hours and normal values four daysand to its minimum at seven days. Returnto through four days. Lactate then dropped below normal normal was noted a 42 days (average ± SE). (averages ± SE). 218 ROSWELL R. PFISTER

leukocytes (PMN) appeared in predesce­ 12 ments stroma during this period. At three and ..,. six weeks, monocytes had replaced the PMN. .1" 10 The normal is characterised t' r· "�"I. ...,. _17 by a fiat, polygonal array with numerous (; 7 intracytoplasmic organelles. Within three z" 6 If,. I � If> I hours after LPCA cautery there is hydropic ... 22 ! ! !4 ... ., 1 : . degeneration characterised by vacuoles i within the cytoplasm and organelles, an I: irregular cellular profile, and retraction 1 Ii of - I some margins and tight junctions from . , I2 3 • • • 7 21 42 Do\'IS adjacent cells (Fig. 9).

M Intraocular Effects on ASN Fig. 7. Stromal hydration changes after operation. Hydration peaked at four days and was high normal at Anterior chamber-Small numbers of PMN 21 days and 42 days (averages ± SE). and red blood cells were noted up to seven days after LPCA cautery. Experimental hydration studies showed a Ciliary body and Iris-Hydropic changes of very significantincrease at 24 hours, reaching the ciliary epithelium and iris at three hours a maximum at four days (Fig. 7). Stromal were followed by the appearance of large hydration was still high at seven days but had patchy areas of ciliary body denuded of epi­ subsided to high normal at 21 and 42 days. thelium at 15 hours. Partial epithelial Corneal histology-Mild hydropic changes regrowth began between three to six weeks. were noted in the but the The ciliary body stroma was oedematous up haematoxyln and eosin stains were otherwise to three weeks, variously showing necrosis, normal. Periodic acid Schiff stains showed cystoid spaces, and numerous widely dilated, moderate depletion of glycogen after 24 empty blood vessels. At six weeks, iris and hours, and severe depletion, especially cen­ ciliary body were moderately atrophic and the trally, at two days. (Fig. 8) It was normal vessels contained blood. thereafter. Marked stromal oedema was pres­ Lens-Six weeks after LPCA cautery all ent after four days, but this had disappeared eyes showed mature, cataractous , by three weeks. Invasion of polymorphonu­ usually containing subcapsular calcium clear neutrophils (PMN) from the perilimbal deposits. These results have been amplified arcades invaded the peripheral cornea at 15 by Fagerholm et al. who demonstrated lens hours, reaching a maximum between four to fibre retraction, morgagnian spheres and seven days. A sheet of polymorphonuclear membrane remnants in the subcapsular

Fig 8a. FigSb.

Fig. S. Normal epithelial glycogen was present (a) three hours after cautery but reduced significantly (b) two da1s after LPCA cautery (PAS stain, x200). THE INTRAOCULAR CHANGES OF ANTERIOR SEGMENT NECROSIS 219

frill. The ciliary body desquamates large patches of non-pigmented and pigmented epi­ thelium while the substance of the muscle undergoes cystic degeneration. Ultimately, the ciliary body atrophies with subsequent variable degrees of repair and regeneration. Hydration of the crystalline lens rapidly leads to a mature cataract. The cornea becomes oedematous, later developing peripheral infil­ trates. The cornea will recover clarity in mild or moderate cases but remain oedematous, vascularise, and scar in the more severe forms. The cornea becomes nutritionally Fig. 9. Corneal endothelial cells are irregular, vacuolated and partially separated three hours after deprived, showing substantial swelling as a LPCA cautery. result. This swelling derives from impairment of endothelial cell function as a consequence zone.20 Six months after injury a new capsule of metabolite deprivation. The normal rabbit formed which was continuous with, but pos­ cornea relies on aqueous glucose for 90% of terior to, the original capsule. Elongated epi­ its substrate supply. Of the total substrate util­ theloid cells, dispersed in a fibrous matrix, ised 85% is converted to lactate and 15% is were found enclosed between the old and the oxidised.25 In the absence of another sub­ new capsules. Amorphous electron-dense strate, Riley theorises that the cornea could material or needle like crystals located in the convert lactate to pyruvate, oxidising it to car­ cortex were identifiedby elemental analysis as bon dioxide by the Krebs cycle. Furthermore, calcium and phosphorus. The mechanism of lactate and alpha ketoglutarate perfusion of deposition was thought to be mineral pre­ the endothelium maintains normal corneal cipitation of hydroxyapatites on organic thickness. The presence of abundant mito­ molecules. chondria, enzymes of the Krebs cycle and cor­ neal temperature reversal phenemena in the Discussion presence of lactate, all suggest at least a The body of data presented clearly indicate potential pathway for lactate metabolism. In that interference with the circulation of the spite of this, the large amount of lactate pres­ anterior segment of the eye predisposes to ent in the aqueous humour might temporarily ASN. Animal models simulate the acute form poison the endothelial cells. of the disease; the model being most Oxygen availability in the anterior segment similar to the circulatory system in the after experimental ASN has not been for­ anterior segment of the . The mally studied. The classic concept of the oxy­ immediate effect of this loss of blood supply is gen profile across the normal cornea ocular hypotony. There is a breakdown in the calculates that oxygen, at the level of the blood-aqueous barrier occasioned by oxygen endothelium, is maintained at 50-55 mm and metabolite deprivation. The outpouring Hg.26 More recent data derived from an in of serum proteins and inflammatory cell vivo electrode slowly advancing through the ingress into all tissues adjacent to the anterior cornea shows stromal oxygen levels falling chamber testify to the enhanced vascular from the anterior stroma to about 30 mm Hg endothelial permeability. Curtailment of the in the deep stroma.2 7 A sudden rise in the oxy­ blood supply of the anterior segment of the gen tension to 70 mm Hg in the aqueous eye damages four vital intraocular structures: humour occurs once the endothelium is the iris, ciliary body, crystalline lens and cor­ pierced and the anterior chamber entered. nea. The pupil dilates, probably from inad­ (Fig. 10) These data show that the endothe­ vertant injury to the long posterior ciliary lium is normally bathed by aqueous rich in nerves. The iris becomes atrophic and in the oxygen and suggests that endothelium might worse cases degenerates to a velamentous require more oxygen for normal metabolism 220 ROSWELL R. PFISTER

TOUCHING £PI THELIUM ginating on the endothelium from the circula­ (MARKED RESPIRATORY FLUCTUATION) tion of the aqueous humour. The adverse 150 effect of PMN on endothelium is well appre­ ciated, often noted to cause corneal oedema

lO,.MI ADVANCES 1 z in uveitis. The oedema, however, is nowhere ELECTRODE 100 OF as marked as seen in ASN.

pOz AQUEOUS The formation of lactate in the eye after (mmHg) HUMOR ASN is of considerable importance. The normal gradient of lactate from cornea to 50 MIO·STROMAL TENSIONS aqueous humour is reversed three hours after LPCA cautery. In 15 hours, stromal lactate is again normal, but aqueous lactate is still high o ) ) I for three days. Excess lactate must not be o 2 3 4 5 6 coming from the cornea, but originating pos­ TIME (MINUTES) teriorly, most likely from the ischaemic ciliary Fig. 10. Typical recording as the oxygen needle body. It is likely that a high level of anaerobic electrode traverses the cornea and enters the aqueous glycolysis proceeded in the locally hypoxia humour. (with permission from Kwan M, Niinikoski J ciliary .body processes and contained inflam­ and Hunt TK: Invest Ophthalmol Vis Sci 1972, ll: 108- 14. ) matory exudate. A similar excess of lactate obtains anterior to intrastromal membranes. than can be provided by the of atmo­ The presence of this metabolite did not pro­ spheric oxygen. If this is true then aqueous tect the epithelium from delayed loss or sub­ humour oxygen (and therefore endothelial sequent ulceration. In ASN, glycogen stores oxygen level) is likely to be substantially in the epithelium were probably sufficient to reduced in ASN to that in the stroma (30 mm tide the cornea over this interval of metabolite Hg). The high level of aerobic activity in the depletion. endothelium would be curtailed, leading to The lens is entirely dependent on the aque­ severe corneal oedema. Takahashi supports ous humour for all of its nutritional supply. this point of view with respect to the endo­ For this reason it is uniquely vulnerable to vis­ thelium, by showing that an anoxic perfusate cissitudes in the composition of the aqueous rapidly causes severe corneal oedema.2H humour induced by reduction of the blood On the supposition that oxygen deprivation supply. The lens lacks tricarboxylic acid cycle was taking place in ASN, some workers have enzymes, hence is unable to metabolise lac­ suggested that increasing the partial pressure tate. Significant reduction of the glucose of oxygen in the aqueous humour by hyper­ supply and possible oxygen deprivation are baric oxygen might also be useful in ther­ therefore devastating to the lens epithelium apeusis. Hyperbaric oxygen has been shown and to the energetics necessary to maintain to increase the partial pressure of oxygen in transparency. This explains the microscopic the aqueous humour and preretinal vitreous findings of swelling lens fibres and the ulti­ in normal eyes.29 This treatment has already mate deposition of calcium in dystrophic tis­ been used successfully in sickle cell haemoglo­ sues.20 An insult to the lens of this magnitude binopathy where sickling of red blood cells in can rarely reverse, resulting in the develop­ the aqueous humour has been prevented by ment of a mature cataract. doubling transcorneal and intravascular oxy­ Preliminary unpublished data by Pfisterhas gen. At this time it is unknown whether shown that after operation to induce ASN, hyperbaric oxygen will be useful in the treat­ continuous perfusion of the anterior chamber ment of ASN. with BSS containing glucose, without sup, Corneal oedema might also be caused, in plementary oxygen, fails to keep the cornea; part, by the presence of cells or substances from swelling severely. This infusion, via a: inimical to the health of the endothelium. Evi­ fine, indwelling, intracameral silicone tube' dence for this is the presence of PMN in a during the firstfour days after LPCA cautery;: layer directly on the endothelium and mar- does keep the crystalline lens clear. It would THE INTRAOCULAR CHANGES OF ANTERIOR SEGMENT NECROSIS 221 appear that artificial maintenance of normal sclera and following operations for retinal aqueous glucose levels protects the crystalline detachment. Arch Ophthalmoll961, 66: 318-26. 12 Wilson OJ and Green WR: Histopathologic study of lens by supplying its major oxidisable sub­ the effect of retinal detachment surgery on49 eyes strate. The fact that the cornea is not affected obtained post mortem. Am J Ophthalmol1987, by this supplemental treatment suggests that 103: 167-79. the cornea is more dependent on oxygen and 13 Prince JH: The Rabbit in Eye Research. Springfield Ill, Charles C Thomas, 1964, pp 522-3. other metabolites. 14 Votockova J: The importance of the anterior ciliary Experiments showing glucose deprivation arteries in the nutrition of the cornea. Cs Oftal in the aqueous humour after ASN are not 1962,18: 1-7. 15 proof that a cause and effect relationship Radnot M and Jobbagyi P: Vascularisation of the cornea in ischemia of the anterior segment. Klin exists. However, severe deprivation of glu­ Mbl Augenheilk 1968,153: 840-4. cose, epithelial glycogen loss and apparent 16 Votockova J, Praus R, Sulcova H, Brettschneider I: inability to metabolite lactate augure strongly The effect of blockade of the arteriaecililsres pos­ for a primary role of glucose, other metab­ teriores longae on the transparence and on the olites, and oxygen in the pathophysiology of transport of Ca into the rabbit's cornea. 17 Freeman MH, Hawkins WR, Schepens CL: ASN. Anterior Segment Necrosis. Arch Ophthalnol 1966,75: 644-50. Key words: anterior segment, aqueous humor, ciliary 18 Pfister RR, Friend J, Dohlman CH: Anterior seg­ Arch Ophthalmol1971, body, cornea, glucose, hydration, lactate, necrosis. mcnt necrosis in rabbits. 86: 301-7. 19 Anderson OM and Morin JD: Experimental anterior segment necrosis ans rubeosis iridis. Canad J OphthalmoI1971, 6: 196-201. References 21l 1 Hedges TR: The Aortic arch syndromes. Arch Oph­ Fagerholm P, Lundevall, Trocme S, Wroblewski R: thalmol1964,71: 28-33. Human Experimental lens repair and calcifica­ tion. Exp Eye Res 1986,43: 965-72. 2 Knox OL: Ischemic ocular inflammation. Am J Oph­ 21 thalmoll965, 60: 995-1002. Guerry 0: Angiodiathermy of the long posterior cili­ ary arteries and its use in the treatment of glau­ 3 Boniuk M and Zimmerman LE: Necrosis of the iris, . 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I. following muscle surgery: the AAPO&S experi­ Effect on intraocular pressure and facility of out­ ence. J Pediatr Ophthalmol Strabismus 1986, 23: flow. Invest OphthalmoI1971,10: 120-?? 25 87-91. Riley M: Glucose and oxygen utilisation by the rab­ 7 Stucchi C and Bianchi G: O'epigmentation en sec­ bit cornea. Exp Eye Res 1969,8: 193-200. 26 teur de I'iris consecutive a des transplantation Fatt I: The steady-state distribution of oxygen and musculaires. Ophthalmol1957, 133: 231-6. carbon dioxide in the in vivo cornea. Expl Eye Res 8 Girard LJ and Beltranena F: Early and late compli­ 1968,7: 103-12. cations of extensive muscle surgery. Arch Oph­ 27 Kwan M, Niinikoski, Hunt T: In vivo measurements thalmoll960, 64: 576-84. of oxygen tension in the cornea, aqueous humor 9 Berens C and Girard LJ: Transplantation of the and anterior lens of the open eye. Invest Ophthal­ superior and inferior rectus muscles for paralysis mol 1972, 11: 108-14. of the lateral rectus. Am J Ophthalmoll950, 33: 28 Takahashi GH: The relation of corneal anoxia to 1041-9. corneal hydration. Invest Ophthalmol 1967, 6: 0 1 Duguid 1M: Anterior segment necrosis following 562-?? . retinal detachment surgery. Trans Ophthalmol 29 Jampol LM: Oxygen therapy and intraocular oxy­ Soc UK1967, 87: 171-8. genation. Trans Am Ophthalmol Soc 1987, 85: 11 Boniuk M and Zimmerman LE: Necrosis of uvea, 407-37.