Pathogenesis and pathophysiology of cataracts Samuel Masket, MD Canoga Park, California, USA Current Opinion in Ophthalmology 1990, ‘The lens remains a very unique organ, In its “normal” Slate, it is optically clear and all of its pathologic re- actions share the tendency for lens opacification. Al- though varied forms of cataract occur and the subcap- sular lens epithelium is multipotential, to date no neo- plasms of lens material have been reported. The final ‘common path of lens pathology is cataract formation, Interest in prevention of the formation of progres- sion of cataract has generated continued research into etiogenesis. Environmental factors, such as exposure to ultraviolet light, dietary intake, diabetes, systemic hypertension, and cigarette smoking, have been stud- ied as possibly cataractogenic. Potentially anticatarac- tous protective agents, such as aspirin, continue 10 stimulate research. Trauma remains a frequent cause of cataract, particularly among participants in contact, sports or games in which missiles are used Objective measures of cataract formation and progression of disease Devices designed to quantify lens opacification with age and cataract formation have been developed [1,21 These instruments appear to be more accurate in theit assessment of formation of nuclear cataracts than cor- tical cataracts. They may be useful to study the pro- gression or potential retrogression of nuclear cataract formation in response to time or treatment modalities Clinical observations of patients with nuclear cataract formation indicate an apparent loss of spectral sensi- tivity to the shorter wavelengths; typically, patients ex- hibit diminished awareness of blue colors. This phe- nomenon has been reported in a study that evaluated a new device, the ABBY lens absorption apparatus ‘which was designed to provide an estimate of light ab- sorption in the individual lens (3 While objective measuring devices of lens opacifi cation are under development and evaluation {1-3}, the Scheimpflug Cataract Video Camera (Zeiss, Ober hausen, FRG) has been established as an accurate means for photographing lens opacities at varied depths of the lens (Fig. D3; reproducible photographs as determined in an inter- and intraobserver study e3- tablished reliability of the device [4]. AS new means for cataract reversal and prevention are released for investigation, an objective lens opacification measur- ing system will be necessary; the devices just described should answer that need. Fig. 1. Artist's conception of the image seen in the binocular eyepiece. For centration, the first Purkinje image is aligned fon the anterior aspect of the lens. (From Edwards et al [4l; with permission.) Ocular trauma Interest in physical conditioning and fitness has re- sulted in a larger number of people participating in recreational sports. As would be expected, this has ‘been accompanied by an increasing number of ocu- lar injuries. Unfortunately, many of these injuries oc- ccur in young individuals; the number of ocular injuries from hazardous sports has increased by 58% since 1973 (Bell, JAMA 1981, 246:156). Traumatic cataract was present in 11% of eyes enucleated at the Massachusetts Bye and Ear Infirmary after sports-related injuries be- tween 1980 and 1986 [5], Racquet sports present sig- nificant ocular hazards to participants because the balls used in these games travel at great velocity and may fit through open-style eye guards. Standards have been established for appropriate protective eye wear in the United States and Canada (6]. In addition, suggestions for reducing ocular injuries associated with amateur and professional hockey have been proposed (71. Oc- ular protection from boxing-telated injuries may be af- forded by changing the gloves to the “thumbless" style, ©1990 Current Science ISSN 1040-8738Cataract surgery and lens implantation although cataract formation (Fig. 2) appears to be re- lated to the contrecoup damage of ocular compression and decompression after a direct blow [8] Fig. 2. Typical cataract seen in boxers. A recent recreational fad involves a series of “war games" in which contestants are equipped with re- ppeater guns that are powered by carbon dioxide and fire gelatin bullets that contain colored dyes. The gelatin bullet explodes on contact, and the player who has been struck by the bullet will be marked with dye and declared “dead.” Eye protectors are supplied as a rule; almost invariably, however, ocular injuries have been reported after contestants removed the protective ‘eye guards. Traumatic cataract was reported in 13 of 44 ocular injuries (9. Perforating ocular injuries associated with occupational accidents are most likely induced by metallic foreign bodies in both industrial and agricultural trades, Trau: matic cataracts were reported in 31% of injured eyes in a series of 77 perforated globes reported over a 5-year period (10). Similarly, lawnmower injuries to the eyes often cause ocular penetration and traumatic cataract a Drug therapy Previous studies have determined that highly reactive oxidative metabolites, particularly singlet oxygen (free radical, can be generated by photochemical reactions in the lens; the released oxygen species lead to oxi- dation of lipids and proteins and may play a role in cataractogenesis (12), The lens is well equipped with enzymatic protective systems (superoxidase dismuta catalase, glutathione peroxidase) and endogenous free radical scavengers (glutathione, ascorbic acid), both of which lose their efficiency with age and cataract for: mation, Perhaps future anticataractous medications will increase the ability of the lens to metabolize free oxy- gen radicals. It has been proposed that aspirin, as an example, may have anticataractous properties that are based on an antiperoxidative mechanism (Beacy et al, Photochem Photobiol 1987, 45:677-678) or inhibition of aldose reductase (Sharma et al, Exp Eye Res 1982, 35:21-27) Ascorbic acid, vitamin C, isan essential human nutrient ‘with unusually high concentration in the aqueous hu- mor, lens, comea, and vitreous; an active transport of ascorbate across the blood-aqueous barrier maintains high aqueous levels, which may be 20 times that of the plasma. It is believed that aqueous ascorbate acts as a reducing agent against oxygen and its free radicals ‘This theory tested positively in experiments in which mice were exposed to hyperbaric oxygen, a known ccataractogenic agent [13]. Similarly, butylated hydrox- ytoluene, a known antioxidant, was shown to prevent fr retard cataract formation in galactosemic rats [1]. Ieis possible that diabetic cataractogenesis is therefore related more to oxidative lens damage than to the ac- cumulation of the polyols sorbitol and galactitol in the lens as a result of increased aldose reductase activity {14}, (Aldose reductase reduces aldose sugars to their alcohols.) Moreover, an aldose reductase inhibitor, AL- 1576, was found to be ineffective as a protector against the cataractogenic effects of ultraviolet B and x-ray ir radiation on cultured mouse lenses [15] 1 appears that future development of human anti cataractous drugs is promising and will likely focus on protection of the lens from the negative effects of oxidative metabolism. Lens metabolism ‘Transparency of the lens is, in part, dependent on the orderly arrangement of lens fiber cell lamellae and the composition, distribution, and organization of highly concentrated constituent proteins, mostly the lens crys- tallins; itis presumed, although ‘difficult 10 establish, that organization of the macromolecular components is dependent on lens metabolism (16), Earlier laboratory investigations have determined that the perinuclear re- gion of the lens in rabbits susceptible to alterations in tonic concentration that can result in lens opacification, A study {16] was conducted to determine the effect on organ-cultured rabbit lenses incubated in a medium de- ficient in sodium chloride; somewhat reversible opaci- fication of the lens fibers in the perinuclear region was observed by scanning electronphotomicroscopy. ‘As mentioned previously, oxidative processes are linked with the development of human nuclear cataract formation; the nucleus is apparently more susceptible to oxidative damage than is the cortex. Maintenance of a reduced environment is necessary to guard against cataractogenesis; indeed, the lens is endowed with a high level of reduced glutathione, which exists in a diminishing gradient from lens epithelium to nucleus {17}, Similar to the human lens, rabbit lenses subjected to hyperbaric oxygen will demonstrate nuclear cataract formation, It appears that oxygen easily diffuses into the nuclear region and that the aucleus is incapable of maintaining a reduced environment, even at low levels of oxygen [17,18It is possible that factors other than oxidative meta- bolism may be responsible for cataract formation. Dis- ruption of ion transport may be cataractogenic, and if abnormal gating of ionic channels is involved in the cataract process, it may be possible, in the future, t0 identify drugs that can modify the process by block- ing the current flow through those channels respon- sible for lens opacification [19]. Lens glycation, or incorporation of glucose metabolic products, increases progressively with age and is greater in diabetics than nondiabetics; therefore, lens alycation is thought to be related to senile cataracto- Benesis by means of lens protein hyperaggregation in response to glycation (20) Case-control studies Case-control studies are utilized in a retrospective fash- ion to determine the presence of risk factors for a given disease. Because the studies are, by nature, not blinded, not randomized, and not prospectively con- trolled, their results have been open to question. How ever, case-control studies are easy and efficient to per- form. Simply stated, case-control studies compare number of people with a certain disorder to 2 num- ber of people without the disorder to discern possible etiogenic differences 21]. The chief question regarding the validity of case-contiol studies is whether the dif ferences are truly causal. Two case-control studies from England reported certain risk factors for cataract forma- tion; glaucoma, myopia, steroid including the diuretic spironolactone) ingestion, heavy smoking, nifedipine ingestion, and severe diarthea were found to be asso- ciated with a greater likelihood of adult cataract forma- tion [21,22]. Ingestion of aspirin, acetaminophen, and ibuprofen was found to be associated with a reduced incidence of cataract formation in their studies Note, however, that case-control studies do not isolate single factors. For example, glaucoma was found to be associated with an increased risk of cataract. An anal- ysis of their data [21], however, reveals that a. signif- icant proportion of the glaucoma patients had surgi- cal procedures for their glaucoma. Because glaucoma ‘surgery is known to be associated with significant risk for cataract formation, one cannot assign glaucoma per se asthe cataractogenic agent; furthermore, antighauco- ‘matous miotics also induce or advance cataract forma- tion, Is it fai, then, to indiet glaucoma as a risk factor for cataract? In another case-control study (23] of risk factors for cataract formation in a young (less than 60 years of age) urban population in a health maintenance orga- nization, it was learned that a positive family history, elevated white blood cell count, diabetes mellitus, ele- vated pulse rate, and syphilis were factors that were found to be of greater incidence in the group with cataracts than the age-matched noncataractous group, It seems clear that although case-control studies point toward areas for specific research, they should not be Pathogenesis and pathophysiology Masket considered as literal and linear evidence for any spe- cific cataractogenic agent or anticataractous medication or device, Light toxicity Recent interest in toxicity of the visible and invisible light spectrum has centered on the potential for ultra- Violet light to induce cataract formation. Although the chief concern regarding ultraviolet light toxicity is ret nal damage, itis reported that ultraviolet B exposut in the range of 300 fo 315 nm, can induce corneal and lenticular injury [24, 25] Ina case-control study (26) that compared 168 patients with surgically removed posterior subcapsular cataracts to 168 age- and sex-matched phakic controls in the same geographic area, it was determined that high exposure {0 ultraviolet B was associated with an in- creased risk for development of posterior subcapsular cataracts. That investigation also reconfirmed th ciation of posterior subcapsular cataracts with di and steroid use, and added blue eyes and low educa- tion level as associated factors. The data of the study [26] suggested a strong relationship between ultraviolet B exposure and posterior subcapsular cataracts; care- fully planned laboratory and clinical research should be conducted. Conversely, as suggested above, the in- formation garnered from case-control studies must be carefully scrutinized, Radiation X-ray irradiation has been clearly established. as cataractogenic. Ina report (271 of 507 patients who had. received radiotherapy to the region of the eyes at vary- ing time intervals prior to investigation, it was learned. that the age-matched risk for cataract formation was five times greater in the group that received ocular ia- diation. Because of the increased isk for cataract for- mation with ocular irradiation, it has been suggested (28) that digital subtraction angiography should be em- ployed for cerebral angiography because conventional Angiography subjects the lens to a far greater dose of irradiation Congenital and genetic factors Ectopia lentis et pupillae is a rare syndrome that is inherited as an autosomal recessive trait, One re- port [29] presents a relatively large series of 16 cases. Cataract appears to be present in about one third of affected individuals. Manifestations of the disorder i clude displacement of the lens and pupil (Fig. 3), se- vere axial myopia, poor vision, retinal detachment, en- larged corneal diameters, cataract, iris transillumina- tion defects, poor pupillary dilation, persistent pupil- lary membranes, iridohyaloid adhesions, and promi- nent itis gonioprocesses [29]8 Cataract surgery and lens implantation oe 3, Ectopia of both lens and pupil. Notice that visual axis isin the “aphakic" portion of the pupil. (From Goldberg (291; ‘with permission ‘An interesting recent finding regarding uniocular con- genital or juvenile traumatic cataract is the associa tion of amblyopia with progressive increase in ocu- lar length and decreasing vision after cataract removal. This finding was not associated with bilateral congen ital cataract removal, only uniocular cataract removal, suggesting that the observed elongation is due to poor vision rather than the aphakie condition [30] Annotated references and recommended reading OF srerest (OF outstanding interes 1. Dams Mf, PoOGOR M, EDWARDS P: Reproducibility of che + carly carace detector (Kown ECD 2000). Opbthaliie Sur 1988, 19-664-666, Describes the use ofan early cataract detector by laser ight scanning Good reproducibility of cataract formation was hoted forthe noceat region, An excellent editorial by Aquavella follows the paper and i highly recommended reading 2 DE-NATALE R, FLAME J, ZULAUF M, BEBIET: tnfuence of + age on the wansparency ofthe lent in aormals: + population Study with help of the Lene Opacity Meter 701. Cpbidalme logica 1988, 197-1416 This paper describes the use of a light-scattering lens opacification meter. It describes normal readings in noncaaratous ineividual a varying apes 3. SAMPLE PA, ESTERSON FD, WEIMREG RN, BOYNION RM: The + aging lens: in wit assessment of light absorption in 86 he san eyes. Dest Ophrbalmal Vis Set 1986, 2913051311 ‘This paper describes loss of contrasenstvity with age as 2 result of increased lens density. 4, Ebwa1Ds PA, Davruss MD, GREEW $B: Reproducibilicy study s+ on the Scheimpflug Cataract Video Camera. Curr Bye Ree 1988, 7.955-960, Impressive reproducibility of lens opacification was noted with this Video camera system. Any future studies tegurding prevention, re versal, or progression of cataract as 2 result of treatment require use of sensitive equipment as noted in this paper. 5. FOUNTAN RR, Aunexr DM: The histopathology of sport re- + tated ocular trauma, 1980-1986. Znt Opbrbaimol Clin 198, 28.206-210 Pan ofa symposium on spons-elated injury. tis paper reviews the histopathology ofa varity of ocular injures that result in enude- 6. EASTERBROOK M: Ocular injuries in sncquet sports. Int pb thal! Cin 1988, 28:232-237. ‘The need for protective eye wear in racquet sports is sessed in this paper, which also reviews the curently accepable protective devices 7. PASKOY TJ: Ocular injures in hockey. Int Opbtbaimol Cin #1988, 28228231 ‘This paper. from a Canadian author, reviews the Ukelhood of eye lj ands pretenton by prope Neaderr design approved fo use in hockey 4 Sumi DJ: Ocular injuries in boxing. Int Opbrhalmel Cin = tome, 28242265 As boxing continues 10 arouse concern for head injury, this imely paper reviews the mechanisms for retinal and lens int. 9. EASTERHEOOK M, PASMBY T]: Ocular injuries and war games. Int Ophibalmol Clim 1988, 28:222-225 ‘Alo part of the symposium on ocular injures, this paper stresses how feally eves become injured when trivial games ate played by participants improperly equipped. 10. Menica-Guenez E, GUTIERKEZ-Duaz FE, GUTERREZ-DIZ A, + Femo-OsUNa M: Pesforting ocular wotnds in occupational accidems. Opbrbalmologica 1988, 197:97-103. Industral acidents served asthe reates case For perforating ocu- Jar injuries in 5-year study of occupational eye ines, 11, Jowy.G, Wimaesseoos CD, Fest RM, MORRIS R: Ocala lawn + mower injuries. Opbthaimatogy 1988, 95:1367-1370 cular Tawamower inusies account for approximately 3b of the 70,000 injures reported annually from the use of lawnmowers. The ‘overwhelming majority of these injures are preventable with appro rate use ofthe equipment and ocular safey shielts, 12 Tse G, GuLLERMET V, LATOUR E, CoguRtET C, BONNE #)C Oxidative stress and lens opacity an overall approach fo screening antcuarsctour drugs, Opbtbalmic. Res 1968, 2027-30, The concept tha oxidative tess is cataractogenic t0 the lens was the basis for this study which presets an approach tothe screening of anticataractous drugs 13, Vata SD. RcHARDS RD: Ascorbic acid and the eye lent + Opbibalmic Res 1988, 2065-173, ‘This ance reviews the effect of ascorbic aid on lens metabolism and suggest that damage is due the tm situ generation of active radicals and other oxygen species. The paper suggests that ascortne is protective ofthe lens ater hyperbaric oxygen exposure 14, SRIVASTAVA. SK, ANSARI NH: Prevention of sugarinduced + cataracrogenesis in eats by busated hydronyoluene, Dia betes 1988, 37 1505-1506. {laboratory study involving the use of ras to evaluate the protective effec of buylated hydroxytoluene, an antionidart,on sugar induced 15. Scar C, SCHMIDT J, WEGENER A, HOCKWIN O; Effect of an +) aldose reductase inhibitor, AL-1576, on the development af UV-B and say carat. Gragfes Arch Clin Esp Opbtbalel 1988, 226.455-460, A laboratory study with Brown Norway rts determine the protec: Uwe effect of an antioxidant, AL-IS76, an aldose reduetor inhibin, ‘on ulraviolet Band x-ray cataract The resuls ofthe study were neg: 16. GROMEVASSHLI B, ROBINSON D, LAUY J, Sem T, +” Famxswornt P: Morphological studies of an ion-depeedent perinuclear cataract model. Exp Bye Res 1968, 47-415 428,A laboratory study involving the use of rabbit eye to determine the ‘eationship ofa sodium chloride-defcient cell medium and the for ‘mation of perinuclear cataract formation 17, GIRUN FJ, SCHRMSCHER L, CHAKRAPANI B, REDDY VN: Es: © porate of rabbit lens to hyperbaric oxygen in site: ce ional effect on GSH level. Invest Opbibalmal Vis Set 1988, 29:1312-1319. ‘The effect of hyperbaric oxygen on nuclear cataract formation in the rabbit eye was steadied with regard tothe level of reduced glu tathione in gradient from the lens epithelium 10 lens nucleus. The resuls of the stdy indicate that oxygen i capable of difusing into the nuclear region and thatthe nuciews i les capable of maintaining 4 reduced environment in the presence of hyperbanc oxygen IR, CosTAcUOLA C, IUUANO G, MENDONE M, NEST A, MOSEL +) F-RNALDI E: Systemic human diseases as oxidative risk fac- tors in catarsetogencsis. Opbihalmic Res 1968. 20:308-316 ‘This paper suggests that the increased incidence of cataract forma: ‘on inthe diabetic population is related more to oxidative lens dam lage than to abnormal ugar metabolism inthe lens 19, RAE JL: Pharmacologic blockade of ionic channels in lens membranes. Ophthalmic Res 1988, 20-132-138. Since cellular lonic transport is responsible for the movements of sodium, calcium, and potassium across cell membranes, this paper Inypothesizs that ithe sonic channel responsible for tanspon can be nentified, that will modify ton flow and affect the pathogenesis of cataract formation, 20, ios P, CAREZAS-CHRRATO J: The stable products of the non = entymatie gleation of pig etllins: new findings related fo the pathogenesis of diabeic cataracts. Diaberes Res 1988 63-187 Lens glycation increases with age and is greater in diabetic than in formal persons. This stdy explores the possi of the glycation erated poten hypeagseation her as cxtaractogen od 21, Hanoisc J: Cateconteal studies and ris factors for cataract 2 discussion paper. B Soc Med 1988, B1585-587, ‘Tis paper discusses the rationale, concept, and statistics For case- Control sudies as related to cataract formation. 22. HARDING JJ, V0 HEYSINGEN Ri Drugs, inching alcohol, 2 Ghat act a8 rik factor for cataract, and posible protection gains cataract by spitinike analgesics and cyclopenth ide, Br J Opbtbalmol 1988, 72:809-814 [Acase-contol stay from a specific English environment that eval ‘ied the ellect of systemic drugs and hfestyle habits onthe incidence of cataract formation 23. SCHWAB. TR, ARMSTRONG MA, FRiEDNAN GD, Wone IG. 2°” Canrennen AC, DAWSON CR: Cataract extraction: ik factor inva beth maintenance organization population under 60 years of age, arch Ophthalmol 1988, 106 1062-1055. Pathogenesis and pathophysiology Masket A retrospective study in case-contol fashion of those factors that ‘were found to be responsible or associated with cataract formation ins young population inthe San Francisco Bay area All patents ‘were under 60 years of age. Diabetes 30d 2 postive family history for cataract formation wete found to indicate a poskive coreation ‘with cataract formation in a young populous 24, SLINEY DH Ocular injury due to light voxicry. Jit Ophthal = pol Cli 1988, 28.246-250. Travile B imadiation s presented as causing comeal and letrcu Tar injury: Retinal injury by visible and svisibe ight also discussed 25. TAMOR HR: Proce eye from ulteaviolt light fo prevent +) cataract rather than eetinal damage letter. JANA 1989, 261: 53550, | leter tonne editor suggesting that retinal damage from ultraviolet Blight» unsubstantiated fut that cataract formation an established fection to excensultaviolet B iadiaton, 26, BoCHOW TW, WEST SK, AZAR A, MUNOZ B, SOMMER A. Ge TaVLOW HR: Unravote light exposure and risk of posterior subcapsular cataracts, A7Ch Ophthalmol 1989, 107 09-372 “This cane control study fom limited gengraphic region around Chesapeake Bay strongly suggests the assocation of eaarat with tranolet B radiation Specially, poster subcapsular cataract as oggested 35 being caused by ultawolet B yradiaton. The authors "upges fim dat reducing ocular exposure will reduce cataract fre 27, DEAN G, AUDERSON M, MAXIMILIEN R. Increased isk of 2 Cataract in patience receiving radiotherapy tothe ey: & pilot fod. Br] Radiol 1984. 61 300-311 A terospective study suggested that pavens receiving eadiotherapy To the region ofthe eye ate ata Fvefold greater risk for cataract for Imation as compared to age-matched conto. 28. CaweLnES P, Ocular ls dose in cerebral vascolar imaging. Br) Radiol 1988, 61302205 “The wal radiation dose wo the lens was considered for patients un ern dtl subacton and conventional angiography. Since the former signiieamly reduces the lens dose, ie use was suggested ‘whenever possile 29. GOLDNERG MF. Clinical manifestations of ectpia lenis et 2 papillae in 16 patients Optibalmolog 1988. 95 1080-1087, “This paper presents cae report in famaes with combined ectopic lens and ectopic pups Cataracts are present it 3 igh proportion of eases, BO, RASoORY R, BEN-EZNA D: Congenital and traumatic cataract the effect om ocular axial length. Arch Opbibalmol 1968, 106 1086-1068, “This paper presents 3 most interesting observation regarding the progressive elongation of ambyopic ees associated with uniocular Extract formation. I suggested thatthe eye elongates sn atlempt stemmewopizzion