|Year : 1981 | Volume
| Issue : 4 | Page : 393-399
Pathogenesis and control of corneal neovascularisation
Madan Mohan, J Vaid, SK Angra
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, A.I.I.M.S., Ansari Nagar, New Delhi, India
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, A.I.I.M.S., Ansari Nagar, New Delhi-110029
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mohan M, Vaid J, Angra S K. Pathogenesis and control of corneal neovascularisation. Indian J Ophthalmol 1981;29:393-9
|How to cite this URL:|
Mohan M, Vaid J, Angra S K. Pathogenesis and control of corneal neovascularisation. Indian J Ophthalmol [serial online] 1981 [cited 2020 Nov 27];29:393-9. Available from: https://www.ijo.in/text.asp?1981/29/4/393/30939
To gain the insight into various factors,,,,,,,,,, that might be responsible for pathomechanism of neovascularisation and its control, we studied the effect of histamine, acetylcholine, bacterial toxins, and collagenase for evaluating their vasculogenic effect. Dexamethasone and thiotepa were used to test their vasoinhibitory effect.
| Materials and methods|| |
Rabbits (1-2 kg) were divided into two groups. Group 1: 24 rabbits (48 eyes) were taken for production of vascularisation by the various substances, i.e. Histamine (1.5%), Acetyl choline (2.0%), Bacterial toxin (Preheated staphylococcus, 9X 10 8sub ml) and Collagenase (0.05%; 0.01%).
Group II:12 rabbits (24 eyes) were employed for testing vasoinhibitory effect of (1) Dexamethasone (Decardron) (0.8 and 1.3 mg/ml) and Thio-tepa (0.009 and 0.017 mg/ ml).
The experimental model was evolved modified using intra-corneal implantation nylon tubes [Figure - 1] containing the substances to be tested. Two tubes instead of one were implanted intracorneally from upper limbus upto 3 mnm from lower limbus [Figure - 1] the critical distance being found out in pilot experiments. In group I, one of the tubes contained the test substance and the other was filled with saline to act as the control [Figure - 2]. In group II, one tube contained the vasculogenic substance (Histamine, Acetylcholine) and the other was filled with the vaso-inhibitory substance
The clinical observations were made daily for six weeks. The oedema infiltration and vascularisation were noted at the lower limbus and around the open intra-corneal ends of the tubes. Tne oedema present at the upper limbus was ignored. The eyes were subjected to histopathology at varying intervals.
| Observations|| |
Group I- Production of vascularisation. There occurred oedema, engorgement of the capillaries and invasion of the cornea by multiple vascular loops-after a lag period of 48-72 hours. This response failed to develop where the distance of the tip was more than 5 mm from the opposite limbus as seen in our pilot experiments. In some of the control tubes minimal oedema with a vascular invasion of 1-2 mm. inside the limbus was seen which disappeared after a few days. In none of the controls vascular invasion is seen till the tip of the tubes. By the 10th day the smaller vessels developed opposite the tubes containing the `test' substance [Figure - 3]. They progressed till 25th day and merged to form larger trunks which continued to, grow along the sides of the tubes. The stage of regression or consolidation was evident by the 30th day. There was disappearance of perilimbal congestion, and decrease in the quantum of the neo vessels.
A possible neovascular response inside, the tube was almost the rule in both histamine and acetylcholine group. In some cases a haemorrhage was noted in addition to fine vessels [Figure - 4]. In none of the control tube was this observed. Histamine and acetylcholine initiated early attempt at vascularisation as compared to bacterial toxins. The coallgenase 0.01% resulted in marked oedema and neovascularisation around the `test' nylon tube, while higher concentrations (0.05%) caused softening and perforations of the cornea.
Histopathologically, sub-epithelial infiltration with chronic inflammatory cells and capillaries infiltrating into the cornea at the region of the limbus facing tube ends were seen in histamine, acetylcholine, or bacterial toxin groups [Figure - 5]. The area surrounding the tube containing `test' substances showed infiltration by chronic inflammatory cells, and blood vessels were seen inside these tubes except in bacterial toxin group [Figure - 6][Figure - 7]. The cornea around control tubes showed no reaction. The reaction in bacterial toxin group was on the whole milder as compared to acetylcholine or histamine group.
In collagenase group there was gross oedema of the limbus near the tube end with infiltrations and vascularisation. The severity of the reaction ran parallel to the concentration of collagenase.
Group II:- Evaluation of vaso-inhibition; one tube containing histamine solution and the other containing vasco-inhibitory substance was implanted intracorneally.
(i) Dexamethasone (Decadron). The vasoinhibitory effects could only be judged by the corneal release of Decadron, with concentration of 0.8 mg /ml and 1.3 mg/ml. There was no vascularisation seen in either group, but 50% of rabbits receiving 1.3 mg/ml of Decadron resulted in focal necrosis and perforation of test tube.
(ii) Thio-tepa: There was a marked oedema and congestion along the implanted tubes containing thio-tepa in both sub-groups (0.009 mg and 0.07 mg/ml). The oedema was followed by profuse vascularisation from all sides [Figure - 8] and resulted in necrosis in 48 hours.
Histopathology : Moderate oedema around the `test' nylon tube was observed at the lower limbus in Decadron 1.3 mg/ml group. With 0.8 mg/ml. Decadron the reaction was relatively mild. No vascularisation was seen with either concentration in the cornea or at the limbus.
In-thio-tepa group, the corneas showed gross thickening and patches of necrosis with intense vascularisation and leucocytic infiltration. No organisms could be isolated from the corneas, ruling out any chances of secondary infection.
| Discussion|| |
The loss of avascularity of the cornea leads to loss of its transparency with consequent reduction in vision. In order to gain insight into the pathogenesis of corneal neovascularisation, we used intra-corneal double tube implantation modified after Maurice et al. This system has the advantage over those of latter that the vasoinhibitory effect can also be tested simultaneously avoiding many variables.
The clinical profile of neovascularisation observed in this study was similar to that of earlier workers, In our experiments, when neovascularization was observed the open ends of the tube containing `test' substance were placed 3 mm from limbus, but when these were placed more than 5 mm from the limbus no change in the limbal vessels was seen. This is in agreement with the critical distance observed. This is also supported by observations of Mohan, Rateria & Angra in their experiments with alkali and thermal burns. The critical distance of the lesion from the limbus plays an important role in stimulating or preventing vascularisation suggests that some factor is liberated in the cornea which acts on the limbal vessels. The response is dependant on the distance of the agent from limbus and its optimum concentration.
Vascularisation of the cornea is an expression of the inflammatory response. This hypothesis is supported by our clinical and histopathological findings. We corroborate the views of Zaubermann, Bergman & Michaelson and Fromer & Klintworth.
We are of the opinion that the inflammatory response lends to exudation from the dilated capillaries and increased fluidity of the ground substance thereby resulting in oedema. Oedema as an important cause of vascularisation was propounded by Cogan but several workers disagree with the importance subscribed to its role as a prime factors,. In our experiments oedema was observed opposite the tube containing `test' substance, but the degree of vascularisation did not run parallel with the severity of oedema.
Some substance is released in injured corneas which when present in sufficient concentration triggers an inflammatory response in the limbal vessels. This substance might be of different nature depending upon the type of injury giving different types of morphological patterns of corneal vascularisations [Figure - 9].
The inflammation produced at the limbus by the offending agents i.e. biogenic amines, proteolytic enzymes or bacterial toxins incites vasodilation, oedema, and polymorphonuclear response. Later on the disintegration of polymorphonuclear cells and tissue damage stimulate the vaso-proliferation by further damaging the most cells and liberating biogenic amines or reducing the vaso-inhibitory substances. Thus we feel that the vascularisation of the cornea is not a single stage phenomenon but consists of four phases; (i) prevascular stage consisting of exudation/oedema followed by, (ii) vaso-stimulatory stage having vascular outpouching and buddings from blood vessels dilatations and haemorrhages, (iii) vasoproliferative stage when formed new vessels grow in the presence or absence of exudation and oedema, and (iv) vase-established stage with consolidation of vascular structures in which no inflammatory signs or exudation is present.
Checking of neovascularisation depends on the stage in which vaso-inhibitory drugs are used. In our study we have found that 0.8% mg of Dexamethasone leads to stoppage of neo-vascularisation, in stages I and 11. We could observe the checking of further proliferation in the vasoproliferative stage when intracorneal depot of Dexamethasone was introduced in another study. The result of our study suggest that various inhibitory substances act by aborting vascularisation in stages I and II, and help contain further proliferation in stage III and have no effect in stage IV.
| Summary|| |
In an experimental study on rabbits, using double nylon tube intra corneal implantation, various chemicals like acetylcholine, histamine, collagenase and bacterial toxins were tested for their vasculogenic effects on this model, the inhibitory effects of Decadron & Thiotepa has been evaluated.
| References|| |
Bachsich, P. and Wyburn G.M., 1947, Proc. Roy Soc. Edinb. Bol. 62:321.
Campbell, F.W. and Michaelson, I.C., 1949, Brit. J. Ophthalmol 33:248.
Cogan, D.G., 1949, Arch. Ophthalmol 41:406.
Fromer, C.H. and Klintworth, G.K., 1976, Amer. J. Path. 82:137.
Greymore, C., Ashton N., and Mc Cormick. A., 1969, Brit. J. Ophthalmol 52:677.
Klintworth, G K.. 1973, Amer. J. Path. 73:691.
Klintworth, G.K , 1977, Invest. Ophthalmol 16: 281.
Levene, R., Shapiro A. and Baum J., 1963, Arch. Ophthalmol 70:242.
Langham, M. 1953 Brit. J. Ophthalmol 37:210.
Maurice, D.M. and Zauberman H and Michvlson I.C., 1966, Exp. Eye Res. 5:168.
Meyer, K. and Chaffe, E., 1940, Amer J. Ophthalmol 23:1320.
Mohan, M., Rateria, N., Angra, S.K., 1974, East. Arch. Ophthalmo 12:141.
Zauberman, H., Michaelson I.C. and Bergmann F., 1969, Exp. Eye Res. 8:77.
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9]