Human age-related cataract and lens epithelial cell death

PURPOSE: To evaluate the importance of lens epithelial cell death in age-related cataract. To determine whether the large percentage of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive lens epithelial cells previously reported in human capsulotomy specimens results from apoptosis or necrosis. METHODS: Capsulotomy specimens from patients who had undergone cataract surgery and epithelia from cataractous lenses of eye bank eyes were compared with epithelia from noncataractous lenses of eye bank eyes. DNA fragmentation was assayed using the TUNEL method. Cell membrane integrity was tested using a fluorescent stain for DNA, BOBO-3, that is excluded from living cells. Cell proliferation was assayed by labeling with 5-bromo-2'-deoxyuridine (BrdU). The number of cells in different regions of the lens epithelium was measured by digital imaging and computerized counting of nuclei after staining with methyl green. RESULTS: TUNEL-positive cells were sometimes detected adjacent to denuded regions of capsulotomy specimens, especially when epithelia were not fixed immediately after surgery. TUNEL-stained cells usually stained with BOBO-3, indicating loss of plasma membrane integrity. No BrdU-labeled cells were detected in capsulotomy specimens. Cell density in cataractous lens epithelia was similar to that in normal lens epithelia. In cataractous lenses from eye bank eyes, cell density in the region of the epithelium overlying the cataract was higher than cell density in the region of the epithelium overlying the transparent part of the lens. No correlation was found between cell density and cataract severity or between cell density and age. CONCLUSIONS: TUNEL staining of lens epithelial cells in capsulotomy specimens most likely results from necrotic cell death caused by damage during or soon after cataract surgery. Loss of cells from the lens epithelium, by apoptosis or other mechanisms of cell death, does not seem to play a major role in age-related cataract formation.     

Malonaldehyde, superoxide dismutase and human cataract

UV-spectrophotometry and fluorometry were used to study Malonaldehyde (MDA) and Superoxide Dismutase (SOD) in normal, cataractous human lenses and red blood cells of the patients with cataract. MDA content of senile and complicated cataractous lenses was significantly higher than that of normal human lenses, while that of complicated cataract was significantly higher than that of senile cataract. SOD activity of senile and complicated cataractous lenses was significantly lower than that of normal human lenses, while there was no marked difference between senile and complicated cataractous lenses. Significant correlation between cataractous lenses and red blood cells was not found in MDA content and SOD activity. There was a negative correlation between SOD and MDA in normal human lenses, but no correlation between SOD and MDA in cataractous lenses. The study shows that lipid peroxidation may be one of the possible mechanisms of cataractogenesis in human, and emphasizes the role of SOD in prevention of photoperoxidative damages to the tissues.     

The oxidative stress in the cataract formation

The lens of the eye is an avascular tissue surrounded by fluids such as the aqueous humor and vitreous body, with one side facing toward the outside of the body. We investigated peroxidative reactions occurring in cataractous lenses, examining changes within the lens tissues as well as in the surrounding environment. 1. Peroxidative reactions in lenses. 1) Aging and peroxidative reactions. The activity of superoxide dismutase (SOD) began to decrease in the lenses of rats at six months of age. Moreover, the level of lipid peroxide increased significantly in the lenses of rats at 24 months of age. Lipoproteins became increasingly oxidized with age. The levels of Na+, K+, and Ca++, ions that are important to the maintenance of membrane function, also varied significantly with age. In the lenses of six-month-old Senescence Accelerated Mice (SAM), there was a marked decrease in the ability of scavenge active oxygen and a marked increase in the amount of lipid peroxide. In human lenses, the level of autofluorescence increased as the lens fiber structure changed with age. 2) Generation of free radicals inside the lens. We verified that HO. and ascorbic acid radicals were being generated inside cataractous lenses using electron spin resonance (ESR). 3) Changes in oxidation-related substances in cataractous lenses. Senile cataractous lenses and diabetic cataractous lenses were classified as four types, cortical, nuclear, posterior subcapsular, and mature. In cataractous lenses from all types of diabetic patients, the levels of glucose, glycated protein, and lipid peroxide were higher than in senile cataractous lenses. Among the four types of cataracts, the accumulation of peroxides was the greatest in the nuclear type both diabetic and senile cataractous lenses. 4) Transitional metals. Iron ions and copper ions existed in lens tissue. In particular, the subepithelial region of the lens stained strongly for copper ions. The increased level of copper ions in cataractous lenses is likely to be related to the increased peroxidation in this tissue. 5) Changes in membrane. Lowered levels of phospholipids and a higher degree of saturation of fatty acids were observed in senile cataractous lenses as compared with normal lenses. The increased saturation of fatty acids indicated that there was a damage to the membrane structure due to peroxidative reactions. The receptors for low density lipoprotein (LDL) were shown to exist on the epithelium of normal lenses. Acetyl-LDL, a denatured lipoprotein was incorporated into senile cataractous lenses but not into normal lenses, suggesting that the barrier function of the membrane deteriorates in cataractous lenses. Moreover, in diabetic cataractous lenses, the levels of very low density lipoprotein (VLDL) and LDL significantly increased. 2. Change in the environment surrounding the lens and peroxidative reactions. 1) Changes in the levels of oxidation-related substances in blood, aqueous humor, and vitreous body from diabetic patients: all had decreased levels of reduced glutathione and superoxide scavenging activity, and increased levels of lipid peroxide and glycated protein. This may have been due to a reduction in the anti-oxidative potential in the environment surrounding the lens due to the enhanced glycation. Changes in the level of oxidation related substances in the vitreous body in particular, will likely have a significant impact on the lens. 2) Changes in lenses as the surrounding environment deteriorates. Human lenses were cultured for three weeks under conditions similar to those found in vivo utilizing the culture system that we had originally designed and constructed. When protective activity against peroxidation was reduced, the amount of lipid peroxide increased significantly. In the presence of high levels of glucose, the levels of lipid peroxide increased and the amount and activity of SOD decreased. 3. Effects of changes in the external environment on peroxidative reactions.     

Results of oral glucose tolerance tests in 123 cases of senile cataract with associated glucose metabolism disorders

Systematic oral glucose tolerance tests in patients due for operation for senile cataract revealed the presence of latent diabetes, undiagnosed by standard investigations, in 20% of cases. The proportion of diabetics in patients with cataract is abnormally high when compared to a population free from cataract (43% as against 16%), which is in favor of a diabetic condition being the cause of lens opacification. An H.G.P.O. is therefore justified in all patients over 50 years of age with cataracts, especially those that are bilateral and mainly cortical.     

Histological comparison of morphea and lichen sclerosus et atrophicus

To clarify the role of the lens capsule in cataract formation, changes in the protein conformational structure of immature cataractous lens capsules from patients with systemic hypertension or glaucoma have been investigated, as compared to normal lens capsules. The protein secondary structure and composition of these capsular samples were determined using Fourier transform infrared microspectroscopy with second-derivative, deconvolution and curve-fitting methods. We found that the composition of both random coil and beta-type (beta-sheet and beta-turn) structures in the immature cataractous human lens capsules was increasingly induced by systemic hypertension or glaucoma, but alpha-helix content clearly decreased, leading to the alteration of protein conformational structures in lens capsules. A possible pathway of cataract formation exacerbated by systemic hypertension or glaucoma is discussed. According to the results, we propose that systemic hypertension or glaucoma induce changes in the protein conformational structures of the lens capsule, then cause alteration of membrane transport and permeability for ions, and finally increase intraocular pressure, resulting in the exacerbation of cataract formation. The effect on the conformational structure of cataractous human lens capsules is more pronounced for systemic hypertension than for glaucoma. The present study implies that systemic hypertension or glaucoma can exacerbate cataract formation in senile patients by modifying the protein secondary structures in the lens capsule.     

Corneal endothelium in patients with diabetes after extracapsular cataract extraction with intraocular lens implantation in the posterior chamber

We have examined endothelial cell density before and 3, 6, 12 months after extracapsular cataract extraction with intraocular lens implantation (posterior chamber) in diabetic patients and in non-diabetics. We have not found statistically significant differences between the mean loss of endothelial cells due to surgery in diabetic and non-diabetic patients.     

Effects of semotiadil, a novel Ca2+ channel antagonist, on the electrical activity of Langendorff-perfused guinea pig hearts in comparison with diltiazem, amlodipine and nifedipine

In view of renewed interest in the lens epithelium as the initiation site for cataract development, it seemed timely to review recent studies which appear to establish UV damage in the lens epithelium as the cause of UV cataract. While UV photons can and do interact with lens proteins in the cortex and nucleus, experimental results from cultured lenses and tissue cultured epithelial cells also demonstrate both mutagenic and cytotoxic effects in the epithelium. This minireview examines UV-induced changes in lens physiology that appear to follow epithelial cell damage, including inactivation of critical enzymes of transport and metabolic processes. Changes in membrane function include altered cation transport, increased permeability, and altered biosynthesis. One potential scenario for the propagation of damage from the epithelium to the underlying fiber cells includes calcium elevation, an early event in cataract development and critical to many physiological processes.     

Pseudoexfoliation syndrome and secondary cataract

AIM/BACKGROUND: The pseudoexfoliation (PEX) syndrome is frequently associated with impairment of the blood-aqueous barrier. This study analysed if this might stimulate secondary cataract following cataract extraction. METHODS: This historical cohort study included 197 eyes of 197 patients (99 with and 98 without PEX) that underwent extracapsular cataract extraction with posterior chamber lens implantation (PMMA optic) between 1985 and 1991. Secondary cataract was defined as opacification of the axial posterior capsule and decrease of visual acuity by two or more lines. Mean follow up was 23.8 months. For statistical analysis, the Kaplan-Meier method and multivariate Cox regression analysis were used. RESULTS: Secondary cataract was observed within 24 months in 35% (SD 7%) of all eyes, and was significantly more frequent in eyes with PEX (45 (11)%) than in eyes without PEX (24 (9)%, p < 0.03). Eyes with diabetes mellitus (n = 32) showed a significantly lower frequency of secondary cataract (11 (11)%) than eyes without diabetes mellitus (39 (8)%, p < 0.01). The influences of sex, open angle glaucoma, type of cataract, surgeon, positioning of IOL, and phacoemulsification versus nuclear expression on secondary cataract did not reach statistical significance. CONCLUSION: The higher frequency of secondary cataract could be considered as another potential complication of cataract surgery in eyes with PEX.     

Serum factors precipitating with bovine lens extract in cataract patients and noncataract patients

The present study tested the assertion that there exists exclusively in persons with senile cataracts a serum factor capable of precipitating with gamma crystallin extract from bovine lens. The results of this work do not support this assertion without the imposition of rigid specifications regarding test solution concentrations and observation time. Among the 84 subjects tested, 2 individuals had posterior subcapsular cataracts. The precipitates resulting from incubation with serum from these individuals were similar to those resulting from incubations with serum from senile cataract patients. The present study did not confirm the existence of exclusive serum factors capable of precipitating with gamma crystallin extract in patients with senile cataracts.     

Secondary intraocular lens implantation after cataract surgery in children

PURPOSE: To report results of secondary intraocular lens implantation after cataract surgery in children. METHODS: We reviewed clinical records for a 5-year period of patients who had cataract surgery in childhood and received a secondary intraocular lens implant. We studied indications for secondary intraocular lens placement; surgical procedures for intraocular lens implantation; preoperative and postoperative visual acuity, refractive error, and binocular status; and complications of the procedure. RESULTS: A secondary intraocular lens was placed in 28 eyes of 25 patients who had cataract surgery in childhood. In 20 eyes, the lenses were placed in the ciliary sulcus. The other eight eyes had insufficient capsular support for an intraocular lens; in two, the intraocular lens was placed in the anterior chamber and, in six, in the posterior chamber with suture fixation to the sclera. Twenty of 28 eyes (71%) had measurable improvement in visual acuity; only one eye had a decrease in visual acuity of 2 lines. Fifteen patients (54%) had a final refraction within 1.50 diopters of the fellow eye; 21 (75%) were within 3.00 diopters. During follow-up, two eyes developed glaucoma. One had transient pressure elevation; one required two filtration procedures. Three patients required Nd:YAG capsulotomy. Six patients demonstrated Worth fusion at distance and near; three demonstrated 200 seconds of arc or better stereo visual acuity. CONCLUSION: Secondary placement of an intraocular lens in the posterior chamber appears to be a safe, effective alternative for correction of aphakia in the contact lens- or spectacles-intolerant child or young adult.     

Influence of systemic diseases and environmental factors on age at appearance, location and type of acquired cataract

We studied 257 patients scheduled for cataract surgery for possible correlation with systemic diseases, blood chemistry, and environmental exposure. We found that posterior subcapsular cataract appeared in patients 10 years younger on average than those with other types of cataract. Nuclear cataract patients had higher blood levels of uric acid and creatinine and lower blood levels of calcium. We suggest capsular insult as a possible pathophysiological explanation for cataract formation in young age groups (as well as diabetes) and a toxic effect of blood metabolites in patients with renal failure, resulting in earlier and more prevalent sclerosis of lens fibers. No effect of smoking or of exposure to sunlight on the distribution of various types of cataracts was noted.     

Lens epithelium: a primary target of UVB irradiation

Cultured rabbit lenses and cultured rabbit lens epithelial cells were irradiated with UV to correlate morphological changes in the epithelium with physiological changes in the whole lens during the development of UV-induced cataract. Two UV spectral ranges were utilized; one spanned 290 to 340 nm and was designated near-UV, the other was a narrower, pure UVB region: 303 to 313 nm, designated UVB. Irradiation with either spectrum of the anterior surface of whole lenses caused opacification and a dose-dependent loss of ion homeostasis as measured by Na+ and Ca2+ concentrations in whole lenses. It was determined that cation pump activity, assessed by 86Rb uptake, continued to decline steadily during culture after UV irradiation. Whole mount preparations of the epithelial cell layer of UVB-irradiated lenses revealed morphological changes within 2 hr of irradiation and cell death after 20 hr. Following posterior irradiation of whole lenses, the epithelial cells remained viable and lenses remained transparent during 3 days of culture, presumably because UV photons did not reach the epithelium. Absorption of UV photons by posterior fiber cell membranes and proteins did not cause opacification. To learn more about the epithelial damage, cultured rabbit lens epithelial cells were irradiated, UVB treatment retarded growth over a 7-day period in cultured cells. The surviving cells at day 7 were abnormal in appearance and the potassium concentration was approximately 50% less than controls, a finding which may explain the previously reported reduction in protein synthesis by UVB irradiation. Collectively, the data suggest that UV cataract is initiated by damage to the epithelium, including a change in membrane permeability leading to loss of ion homeostasis in the lens.     

Prospective evaluation of corneal endothelial cell loss after pediatric cataract surgery

PURPOSE: To study the alterations in endothelial cell count and morphology after pediatric cataract surgery using currently practiced techniques. SETTING: L.V. Prasad Eye Institute, Hyderabad, India. METHODS: In a prospective nonrandomized series comprising 20 eyes of 14 children with congenital or developmental cataract, endothelial cell loss from cataract surgery was evaluated. Mean patient age was 9.3 years (range 5 to 15 years). Extracapsular cataract extraction (ECCE) with intraocular lens (IOL) implantation was performed in 11 eyes (Group 1). Primary posterior capsulotomy and anterior vitrectomy were performed with ECCE and IOL implantation in 9 eyes (Group 2). Noncontact specular microscopy was done preoperatively and 6 to 8 and 24 to 36 weeks postoperatively. Endothelial cell loss, alteration in the coefficient of variation, and the change in the number of hexagonal cells were determined by semiautomated analysis of endothelial pictures. RESULTS: Mean endothelial cell loss was 198.39 cells/mm2 (5.28%) in Group 1 and 295.17 cells/mm2 (7.50%) in Group 2 at 24 to 36 weeks. There was no statistically significant difference in alteration in endothelial cell count and morphology between the 2 groups. CONCLUSIONS: The results suggest that endothelial cell loss with currently practiced techniques of pediatric cataract surgery is within acceptable limits.     

A clinical study of inhibition of secondary cataract with heparin

Extracapsular cataract extraction with posterior chamber lens implantation was performed on 47 eyes with senile cataract of which 25 eyes were in the control group and 22 eyes were irrigated with heparin solution (25U/ml) in the operation, the drug group. Postoperatively, 2 eyes with hyphema were found in the drug group, but the deposition of fibrin and cells on the anterior lenticular surface and the posterior capsular opacification were significantly less than those in the control group. 3 months after the operation, the mean visual acuity in the drug group was 0.70 +/- 0.26 markedly higher than that in the control group, 0.54 +/- 0.28 (P < 0.05).     

Research in neurosurgery

We have measured the levels of glucose and sugar alcohols in the lens epithelium of 24 non-diabetic and 21 diabetic patients undergoing extracapsular cataract extraction for age-related cataract. Lens status was assessed preoperatively according to the Lens Opacities Classification System II. In comparison to non-diabetics, the lens epithelia of diabetic patients have increased levels of glucose and sorbitol, and lower content of myo-inositol. Both myo-inositol decrease and sorbitol accumulation are strictly related to the fasting blood sugar level. No correlation or trend was detected in diabetic subjects between myo-inositol or sorbitol level and cataract type. In non-diabetic patients nuclear opacification was associated with a significant increase of myo-inositol level in lens epithelium.     

Pediatric cataract management with variations in surgical technique and aphakic optical correction

PURPOSE: The purpose of the study was to compare the results of three techniques of cataract surgery in children. Two methods included intraocular lens (IOL) implantation and one used contact lens correction of aphakia. DESIGN: Nonrandomized clinical trial. PARTICIPANTS: Seventy-seven eyes of 50 children between the ages of 2 1/2 and 16 years who had cataract surgery for the treatment of uncomplicated cataract. INTERVENTION: Thirty-one eyes underwent a "conventional" style of implantation, and a "phaco-style" of surgery was used in 24 eyes. A contact lens was used as the primary means of aphakic correction in 22 eyes. MAIN OUTCOME MEASURES: The visual results and complications of each type of surgery were compared. RESULTS: Corrected visual acuities did not differ significantly between the three groups 6 months after surgery. The incidence and type of complications were significantly different. Better lens centration, less long-term iris changes, or wound-related problems were observed with "phaco-style" modification of the technique of IOL insertion. CONCLUSIONS: Pediatric IOL insertion eliminated the need for contact lens wear and did not lead to a significantly different corrected visual acuity 6 months after surgery compared with lensectomy with contact lens correction. Adoption of some of the techniques of modern small-incision cataract surgery for pediatric IOL procedures produces a significant reduction in postoperative anterior segment complications compared with a standard limbal approach. Such modifications allow pediatric IOL insertion to be a safe alternative for the correction of pediatric aphakia.     

Use of of the high frequency capsulotomy instrument in cataract surgery--effect of coagulation on corneal endothelium

Intumescent or hypermature cataracts make a safe capsulorhexis impossible. High frequency capsulotomy represents a satisfying solution for this problem. Primary goal of the present study was to investigate a possible damage to the corneal endothelium by this method. MATERIALS AND METHODS: 55 patients with an uncomplicated senile cataract were enclosed into a prospective randomized study undergoing cataract surgery with capsulorhexis or with high frequency capsulotomy. Corneal endothelium was examined preoperatively as well as postoperatively at several intervals. RESULTS: Concerning loss of endothelial cells and parameters of polymegatism and pleomorphism there were no statistically significant differences between both groups. CONCLUSION: The diathermy during high frequency capsulotomy does not show any clinically relevant negative effects on the corneal endothelium within cataract surgery.     

Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens

SPARC (secreted protein acidic and rich in cysteine, also known as osteonectin/BM40) is a secreted Ca2+-binding glycoprotein that interacts with a range of extracellular matrix molecules, including collagen IV. It is widely expressed during embryogenesis, and in vitro studies have suggested roles in the regulation of cell adhesion and proliferation, and in the modulation of cytokine activity. In order to analyse the function of this protein in vivo, the endogenous Sparc locus was disrupted by homologous recombination in murine embryonic stem cells. SPARC-deficient mice (Sparctm1Cam) appear normal and fertile until around 6 months of age, when they develop severe eye pathology characterized by cataract formation and rupture of the lens capsule. The first sign of lens pathology occurs in the equatorial bow region where vacuoles gradually form within differentiating epithelial cells and fibre cells. The lens capsule, however, shows no qualitative changes in the major basal lamina proteins laminin, collagen IV, perlecan or entactin. These mice are an excellent resource for further studies on how SPARC affects cell behaviour in vivo.     

The future of intervention research at NIOSH

PURPOSE: Analysis of cataract surgery with intraocular lens implantation in children and youth performed between 1990 and 1995 in Bialystok University Eye Clinic. MATERIALS AND METHODS: Twenty patients between 5 and 19 years of age were operated. The subjects comprised 15 cases of traumatic and 5 of congenital cataract. Intraocular lens implantation was performed as a primary procedure in 18 patients and as a secondary procedure in 2 cases. RESULTS: Visual acuity of 5/50 to 5/12 was achieved in 14 patients and 5/10 to 5/5 in 6 patients. Posterior capsule opacification requiring YAG-laser capsulotomy was found in 12 patients (60%). CONCLUSIONS: Intraocular lens implantation may be a safe and effective technique for optical correction in children with traumatic and congenital cataracts.     

Intraocular pressure regulation after combined glaucoma and cataract operation

BACKGROUND: The success rate of combined glaucoma and small incision cataract surgery is not yet established. PATIENTS AND METHODS: Therefore, 56 eyes of 52 patients (mean age 79.0 years) having trabeculectomy combined with phacoemul-sification and implantation of a silicone posterior chamber lens were retrospectively investigated. RESULTS: The mean follow-up was 21.6 weeks. Due to the combined surgery the mean intraocular pressure decreased significantly (p < 0.001) from 21.8 to 14.8 mmHg. Seventy-five percent of the patients did not need any antiglaucomatous medication, while 25% still had to use a local medication, but less frequently. The overall visual acuity increased significantly (p < 0.001) from a preoperative value of 0.24 to 0.52 postoperatively. CONCLUSIONS: The results of combined glaucoma and cataract surgery seem as good as those reported for two separate glaucoma and cataract procedures.