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Nicholas Phelps Brown MD, FRCS, FRCOphth

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Mechanisms of cataract formation

A cataract is the name given to any light scattering reduction in transparency in the lens, but not necessarily having any demonstrable effect on vision. This definition may be reasonably extended to include opacity of the lens capsule and the deposition of opaque material (such as copper) of non lenticular origin. Lens transparency
Lens transparency depends on the regular arrangement of the lens fibres and of the cytoplasm within the fibre. Disorganisation of the lens fibre, or disorganisation of the cytoplasm within the fibre, causes scattering and accounts for the development of cataract. In any particular morphological type of cataract, one or other mechanism may predominate. The healthy lens is transparent because of the regular arrangement of the lens fibres with a minimal extracellular space. Within the lens fibres, transparency is explained on the basis of small spatial fluctuations in the number of protein molecules over the dimensions, comparable to the wavelength of light. Due to the high concentration of these molecules in the lens; none scatter light independently of one another. Turbidity is proportional to the molecular weight of these proteins. Scattering within the cytoplasm is explained either by the grouping of protein molecules to form large aggregates, or by the separation of the molecules due to water entry. Probably both of these mechanisms occur simultaneously in cortical cataract. At a cellular level, scattering is explained by abnormalities of the fibre cell membranes and by separation between fibres. This is confirmed by the electron microscopy of cataract which shows whirls formed by fibre membranes, granularity and vesiculation of the cytoplasm with electron dense inclusions, and enlargement of the extracellular space. Aggregate molecules develop along with age changes in the crystallin protein of the fibre cytoplasm, leading to unfolding of the protein molecule. This is followed by crosslinking between adjacent molecules to form aggregates, which scatter light. Loss of transparency is thus explained on the basis of disorganisation of the fibre membranes at a microscopical level, or of the lens proteins at a molecular level. These processes may occur separately, or together in the various morphological types of cataract. Age-related nuclear cataracts lose transparency by the formation of white scatter (Figure 1) or of brunescence (Figure 2). White scatter is accounted for by protein aggregates. Brunescence is accounted

ABDO has awarded this article 2 CET credits (LV).

The College of Optometrists has awarded this article 2 CET credits. There are 12 MCQs with a pass mark of 60%.

Figure 1 Age-related white nuclear cataract

Figure 2 Age-related brunescent nuclear cataract

Anterior Y suture Posterior Y suture Figure 3 The arrangement of the lens fibres and sutures in the human lens

Figure 4 Age-related cortical spoke cataract

for by the accumulation of a yellow brown insoluble protein pigment, which causes loss of transparency by light absorption and is also responsible for scatter. In age-related cortical cataract, and in subcapsular cataract, there is loss of transparency due to both molecular and to membrane changes, whereas in nuclear cataract the changes are limited to the molecular.

The form of cataract

The form of a cataract is determined by the architecture of the lens and cataracts are separated by their form into two groups. These are: fibre-based cataracts and nonfibre-based cataracts. In the fibre-based cataract the form of the cataract is determined by the anatomical arrangement of the lens fibres (Figure 3); a typical example being the

Figure 5 Age-related posterior subcapsular cataract

common age-related cortical spoke cataract in which a wedge shaped group of fibres in a cortical layer are affected (Figure 4). Nuclear cataracts (Figures 1 and 2) are also examples of fibre-based cataract, the cataract being confined to those fibre layers comprising the nucleus. In non-fibre-based cataract (Figure 5), the form of the cataract

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Figure 7 Concussion cataract with a typical flower shape Figure 6 Lammellar cataract in a patient with a previous episode of hypocalcaemia

concussional cataract (Figure 7). In either case, the suture line represents a frame to the opacity. In the spoke cataract, the opacity progresses along the fibres until the suture is reached and the progress is thereby restrained. In the traumatic cataract, the suture lines represent the base from which the petal shape forms. In this case, the growth does not pass along the full extent of the fibre, which demonstrates that there must be an annealing process present within the lens, which shuts off the healthy remnant of the fibre from the diseased part. Thus the lens is not without its repair mechanisms and this gives encouragement for possible medical treatment.

Formation of new opaque fibres

Newly formed fibres that are opaque at the time of their formation, or soon after, are seen only in congenital (Figure 8) and in developmental cataract. All the fibres in a lamella, or only small groups of fibres, may be opaque and the lens growth is otherwise normal.

Figure 9 The posterior subcapsular cataract after X-ray irradiation of the eye

Basic mechanisims of cataract formation

Figure 8 Congenital hereditary nuclear cataract with a few overlying riders

Formation of material in place of lens fibres

Granular material and aberrant epithelial cells are produced by a lens germinal epithelium which has lost the ability to produce normal lens fibres. There is clear evidence for this mechanism in radiation cataract. This mechanism may also account for the formation of other posterior subcapsular cataracts including age-related cataract. The granular material is first seen in the posterior subcapsular region in the lens periphery. The granules then move axially, in the direction normally taken by the growing lens fibres, to form a subcapsular cataract around the posterior pole (Figure 9).

There are a limited number of ways in which opacification may occur.

Opacification of previously clear fibres

The youngest, most superficially situated fibres, which occupy the anterior subcapsular clear zone (C1a) are the most sensitive to mechanical or to biochemical disturbance, such as concussion, hypocalcaemia, or hyperglycaemia. Thus many acquired cataracts are initially subcapsular and then come to lie at a greater depth with time, if the process causing the cataract ceases and healthy fibre growth is resumed. In age-related cataract, it is the older fibres deeper within the cortex and the nuclear fibres, which lose transparency and the cataract remains with time in the layer within the lens at which it originated. When a cataract begins because of light scattering developing in previously clear mature lens fibres (fibre-based cataract) there are a limited number of forms that the opacity can take and these forms are determined by the anatomy of the lens fibres and their arrangement within the lens. Thus when all the fibres in a particular fibre shell are affected, a lamellar cataract is formed (Figure 6). When groups of fibres are affected, the appearance is that of a spoke (Figure 4), when the origin is in the periphery, or a flower shape, when the origin is sutural as in the typical

Fibrous metaplasia
Fibroblastic cells are the cause of subcapsular cataract in the complicated cataract associated with retinal detachment. It is presumed that these cells arise by fibrous metaplasia of the lens epithelium. Such fibroblastic cells are also seen following capsular trauma. Although the lens is an epithelial structure with active mitosis throughout life, malignant change with the formation of a lens cancer does not occur.

Figure 10 Glaucoma flecks (10x magnification)

is unrelated to the fibre anatomy; a typical example being subcapsular cataract in which the cataract is an amorphous collection of granular material and vacuoles. The form that a cataract will take in any particular eye is determined by the nature of adverse influences to which the lens fibre is subjected and to a hereditary component. The latter is significant both in cataract developing at a young age and in agerelated cataract.

Opacification of the lens epithelium

Opacification of the lens epithelium is seen typically in glaucoma flecks (Figure 10), which can follow an acute glaucoma attack. Glaucoma flecks are due to lens epithelial necrosis. This is probably also responsible for the punctate form of traumatic cataract;

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for the lens epithelial changes seen after chemical injury to the eye and sometimes also in acute iritis. Changes in the lens epithelium are seen in anterior subcapsular cataract, which add to the light scattering due to the cataractous changes in anterior subcapsular lens fibres.

and these are associated with fibre folds, which are seen as fine undulations at the slit lamp microscope and were previously named lamellar separation. Eventually the fibre breaks down to form round Morganian globules. Protein aggregates also cause an increase in scatter.

Accumulation of pigment
The lens contains a fluorescent chromophore which is responsible for the faint yellow colour of the young lens. This colouration increases gradually with ageing and more so in the diabetic in which this is increased by glycation. Chromophores accumulate in the nucleus in the development of senile brunescent cataract (Figure 2).

Age-related nuclear cataract

Nuclear cataract (Figures 1 and 2) is the result of light scattering due to the accumulation of high molecular weight protein, without histological changes. Aggregation of the lens crystallin molecules is responsible for the white scatter; the accumulation of the yellow/brown chromophore protein aggregates are responsible for brunescence as well as for scatter.

Figure 11 Cortical water clefts

Deposition of extraneous material in the lens

Products of abnormal metabolism accumulate in the lens in some storage disorders, such as in Fabry's disease (a lipid storage disorder) and in mannosidosis. The deposits of substances such as chlorpromazine typically follow the lens sutures. Various drugs, such as chlorpromazine, (or their metabolites) and metals may precipitate as fine granules, typically in the superficial cortex and in the capsule anteriorly.

Age-related posterior subcapsular cataract

The process of swelling and breakdown of lens fibres, as in cortical cataract, has been identified and there is also the abnormality in the germinal epithelial behaviour with abnormal epithelial cells moving from the equator towards the posterior pole and extracellular granular and fibrillary material is produced. In other cases, the cataract forms in situ at the posterior pole. In corticosteroid cataract, this appears to be due to an adjunct between the corticosteroid and the lens protein.

Histology of cataract Anterior epithelium

Degenerative changes occur, which include vacuolation. Electron microscopy shows variations in cytoplasmic density and electron-dense bodies. At a later stage proliferation of the epithelial cells may occur, giving rise to bladder cells (overinflated cells) or there may be fibrous metaplasia.

Biochemical changes in cataract protein and water content

Protein synthesis is continuous in the normal lens and the protein content increases with age. In cortical cataract there is a decrease in total protein content and initially the lens is low in weight. This is followed by an increase in the percentage water content. There is a decrease in soluble proteins and a relative increase in insoluble protein (albuminoid). In nuclear cataract, the water balance remains normal and there is no decrease in protein content, but there is an increase in the insoluble protein at the expense of the soluble. Protein molecular aggregates form causing light scatter. Denaturation of lens proteins leads to unfolding of protein molecules and aggregation of the proteins to form the large molecules, which scatter light. Several agents lead to protein denaturation. These include free radicals causing oxidation, sugars causing glycation and cyanate causing carbamylation. Cyanate is derived from urea in renal failure and is also derived from cigarette smoke. It may be the increase in blood urea in dehydration caused by chronic diarrhoea which accounts for the association of chronic diarrhoea with cataract. Ascorbate may also produce a form

of protein glycation. The actinic effect of light, especially ultraviolet light, is a factor in the production of free radicals and also in causing direct damage to lens protein. It is likely that the various factors act in combination (Figure 12). The unfolded proteins are susceptible to aggregation in conditions of oxidative stress by the formation of disulphide bonded covalent, cross linking to form the molecular aggregates, which scatter light. Alcohols accumulate and with them water, leading to molecular separation and scatter in disordered sugar metabolism. Sorbitol accumulates in diabetes and galactilol in galactosaemia. There is an increase in sodium and calcium in the lens developing cataract and this is probably secondary to reduced enzyme activity in the lens. The potassium level falls, but only in cortical cataract. Increased cadmium and lead have also been found in lenses with cataract. The former is probably from cigarette smoke and the latter probably from car exhaust. These may therefore be factors in the causation of cataract.

Enzymes
The lens contains the natural free radical scavenger glutathione which declines in concentration with age. Other lens enzyme activity also declines in age and especially in cataract and is a factor in allowing water entry.

Age-related cortical cataract

Cataractous lens fibres become swollen and the nuclei of the superficial fibres degenerate and disappear. Electron microscopy shows a convoluted appearance of the fibre membranes with granularity of the cytoplasm, or reduction in cytoplasmic density and vesiculation. Amorphous bodies may form, which in non-progressive cataract, such as the coronary opacity, are seen to be separated from the normal lens fibres. These fibres that had previously run through the area of the cataract are shut off by membranes that have developed across them. These membranes lack gap junctions and ball and socket features. Water clefts form between the fibres (Figure 11). Electron microscopy shows that the fibres adjacent to the water clefts have an unusual membrane surface, with many sponge-like projections into the clefts. Near equatorial breaks may appear in the fibres

Vitamins
Ascorbic acid (vitamin C) is found in high concentration in the normal lens and declines with age and in cataract. The fall in ascorbic acid and in glutathione levels may be the result of oxidative stress and would itself render the lens suceptible to further oxidative damage. Degradation of ascorbic acid may lead to oxalate formation and account for retro-dot cataract formation. Oxalate bodies are also found in hypermature cataract. One of the causes of the denaturation of lens proteins is oxidation due to free radicals in the lens. The free radicals may

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the lens and are genetically determined. Heredity also plays a role in the tendency to develop age-related cataract, and studies in twins show that the form of the cataract tends to be the same in each twin.

Metabolic cataract
The errors of metabolism are inborn or acquired. The underlying biochemical abnormality is likely to be an endocrine abnormality, or an enzyme defect. Examples are: Lowe's syndrome (oculo-cerebral-renal syndrome) - male infants are affected Diabetes Galactosaemia Hypocalcaemia (Figure 6) The controlled diabetic is prone to develop cataract of the age-related type at a younger age than average, but without particular morphology. The true diabetic cataract occurs in uncontrolled young diabetics. This cataract forms as a subcapsular snowstorm. If treatment for diabetes is given in time, the cataract will remain as a lamellar and come to lie deeper within the lens as new clear fibres are formed superficial to the affected lamella.
Figure 12 The many possible mechanisms of lens protein degradation in cataract formation (after J. Harding)

Other metabolic abnormalities

The lens is sensitive to many metabolic disturbances. These include: Fabry's disease Glucose-6-phosphate dehydrogenase deficiency Chronic renal failure Mannosidosis Dystrophia myotonica The opacity typically follows the lens suture pattern as in dystrophia myotonica (Figure 13).

be neutralised by the anti-oxidant vitamins. Thus the presence of anti-oxidant vitamins, C, E and carotene (pro-vitamin A) may be important in preventing cataract.

Clinical factors associated with cataract

So far we have studied the basic mechanism of cataract formation. Now, from the clinical point of view, there are many internal and external factors that are identified in the cause of cataract. More than one factor may act in conjunction with another in what is termed co-cataractogenesis.
Figure 13 The cataract of dystrophia myotonica follows the posterior lens sutures

Hereditary Metabolic - Inborn errors - Acquired defects Toxic - Drugs - Chemicals Nutritional Physical - Dehydration - Traumatic - Radiation - Ionising - Non-ionising Complicated Systemic A particular cause may predispose to a specific morphological type of cataract or there may be a disposition to cataract without particular morphology, as in diabetes. It is possible here to provide only the basic outline.

Toxic cataract
Drugs and other toxic substances may cause cataract. The cataract may be specific to the cause. Otherwise, substances have been inferred as cataractogenic due to the identification of their epidemiological relationship with cataract. In some cases, such as chlorpromazine cataract, it is the drug or a metabolite that precipitates in the lens.

Drug induced
Corticosteroid Miotics Chloropromazine Antimitotics Alopurinol Chloroqine Amiodarone

Hereditary
Cataract present at birth and is always nuclear and may be hereditary (Figure 8). Developmental opacities, such as coronary cataract and focal dot opacities, occur during the otherwise normal development of

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Chemical
Several locally or systemically administered substances can produce cataract. These include the local effects of chemicals as in corneal chemical burns and the systemic effects, as in poisoning. Hyperbaric oxygen has been shown to cause a myopic shift and nuclear opacity with nuclear vacuoles. Cigarettes are associated with the development of nuclear cataract as the smoke contains free radicals.

Metal ions
Metals tend to deposit as granules in the capsule and anterior cortex of the pupillary area of the lens. These include: Copper (Wilson's disease) Ferrous ions (siderosis) Gold deposits as fine golden granules

Nutritional
Epidemiological studies indicate that nutrition plays a role in the development of cataract. In areas of good nutrition, cataract is more common in those of low socio-economic status, low stature and low educational achievement. The antioxidant status of persons with cataract has been shown to be reduced compared with persons without cataract.

posterior subcapsular. Ultraviolet radiation and also light in the visible blue has been implicated as a cause of cataract. The cornea passes UV in the region of 295-350u, which is absorbed by the lens. The lens also absorbs some visible blue light, especially once senile nuclear yellowing has begun. Ultraviolet creates free radicals and, in fact, cataract is more common in people with occupations that expose them to sunshine. Microwave radiation causes cataract in the experiment animal, but exposure of man to such sources as radar is considered unlikely to cause cataract. The effect is due to heating, but there may also be a specific effect due to microwaves. Laser radiation in the visible and infrared spectrum has been shown capable of causing localised opacities when used to perform iridotomies.

cataract associated with myopia is in the posterior cortex just in front of the subcapsular region at the posterior pole. Secondary glaucoma is commonly associated with cataract. Primary open angle glaucoma appears to be unassociated, but cataract becomes associated when the eye has received glaucoma surgery. Cataract is a sequel to retinal detachment surgery, especially that involving vitrectomy.

Systemic disease
The development of cataract is associated with a number of systemic diseases and with ageing. It is related to being female (female to male ratio 3:2), which may possibly be related to the reduction in female hormones after menopause. Furthermore, people with cataract have a reduced life expectation. The systemic disorders include cardiovascular disease, diabetic, renal and gastro-intestinal (diarrhoea). There is a 12-fold relative risk for cataract in renal failure, which may be due to urea accumulation leading to carbamylation of lens protein. Cataract occurs rarely with a number of skin disorders (dermatogenic cataract). The association between cataract and skin disease is understandable because both the lens and the skin are derived from the surface epithelium of the embryo.

Complicated cataract
Cataract consequent to eye disease is described as complicated cataract. The lens is dependent on the health of the eye for its metabolism and so is affected when the eye cannot supply oxygen and nutrients, or when toxic substances are produced. Complicated cataract occurs in: Glaucoma Tumours Inflammation Ischaemia Retinal disease and myopia Infection Post-surgical Hypotony

Physical dehydration
Cataract occurs in association with chronic diarrhoea.

Summary
Cataract formation is explained by a number of indentifiable mechanisms, leading to the different morphological types of cataract. An understanding of the basics of cataract will help in the evaluation of cataract in the individual patient.

Traumatic cataract
The lens may receive physical damage from concussion of the eye, by penetration of the eye and lens with a sharp object or by a high velocity foreign body. Electric shock is another rare cause. The transparency of the lens may be affected by physical energy in a number of ways. The classical flower-shaped cataract is pathognomonic of trauma (Figure 7). The flower shape probably originates from the tearing apart of the lens fibre tips from the suture lines in axial region of the cortex.

Complicated cataracts tend to be either nuclear or subcapsular. The complicated

ABOUT THE AUTHOR

Nicholas Phelps Brown has been involved for many years in cataract research, initially at Moorfields Eye Hospital, where he was a consultant, and subsequently as the Director of the Clinical Cataract Research Unit Oxford. He has recently retired from Oxford and now continues his private practice in Harley Street.

Radiation Ionising radiation

X-rays, gamma rays, rays and neutrons are cataractogenic. The effect is on the germinal epithelium. Mitosis is initially inhibited and this is followed by abnormal mitosis producing a granular debris in place of normal fibres. These granules pass to the subcapsular region to aggregate at the posterior pole (Figure 9).

Non-ionising radiation
Infrared radiation was well known to cause cataract in glass-blowers. The mechanism is believed to have been by energy absorption in the iris pigment epithelium causing a localised temperature rise. The cataract is

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Please note there is only one correct answer Multiple choice questions Mechanisms of cataract formation MCQs

1. Which one of the following statements is incorrect? The lens is transparent mainly because: a. the lens fibres are well separated b. the lens protein molecules are similar in size c. the lens protein molecules are close together d. the lens fibres have an ordered arrangement 2. Which one of the following statements is correct? Light scattering occurs in the lens mainly because: a. the protein molecules become fragmented b. the protein molecules become linked together to form aggregates c. the protein molecules become closer together d. the protein concentration becomes increased 3. Which one of the following statements is correct? The structural difference between age-related nuclear cataract and agerelated cortical cataract is: a. nuclear cataract scatter is due to protein aggregates and brunescence b. cortical cataract scatter is due only to lens membrane changes c. cortical cataract is due to the formation of granular material in place of lens fibres d. brunescence of the nucleus causes browning but not scatter 4. The basic mechanism of cataract formation may involve all of the following expect:

a. b. c. d.

the opacification of previously clear lens fibres the formation of new opaque fibres fibrous metaplasia malignant metaplasia

a. b. c. d.

Acute diabetic cataract Congenital nuclear cataract Age-related cortical cataract Age-related posterior subcapsular cataract

5. Posterior subcapsular cataract occurs in relation to all of the following except: a. ageing b. adult diabetes c. radiation d. smoking 6. Which one of the following is not a cause of cataract? a. Smoking b. Ionising radiation c. High anti-oxidant status d. Dehydration 7. Which one of the following has not been found to accumulate in the lens? a. Lead b. Chlorpromazine c. Cadmium d. Cholesterol 8. The tendency to a particular type of cataract is determined by a number of clinical factors. Which one of these factors is not associated with a tendency to a particular type of cataract? a. Heredity b. Trauma c. Ionising radiation d. Diabetes in the adult 9. Which of the following cataracts is not influenced by heredity?

10. Which one of the following drugs is not associated with causing cataract? a. Ibuprofen b. Corticosteroid c. Miotics d. Alopurinol 11. Which one of the following eye conditions is not associated with complicated cataract? a. Retinitis pigmentosa b. Uveitis c. Primary open angle glaucoma d. Herpes zoster 12. All of the following are factors in the degredation of lens protein in man except: a. x-rays b. urea c. microwaves d. corticosteroids

An answer return form is included in this issue. It should be completed and returned to: CPD Initiatives (c2983e), OT, Victoria House, 178180 Fleet Road, Fleet, Hampshire, GU51 4DA by May 2, 2001.

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Multiple choice answers - Paediatric cataract

Here are the correct answers to CPD module 3 part 3, which appeared in our March 9 issue.
1. Hypoglycaemia in an infant is most likely to give rise to all of the following except: a. cataract b. convulsions c. permanent brain damage d. skeletal dysplasia d is the correct answer Hypoglycaemia of whatever cause may give rise to lens opacities in the child. The majority of babies with hypoglycaemia will also have convulsions. Hypoglycaemia may also cause permanent brain damage. 2. Oil droplet cataracts are associated with which disorder? a. Galactosaemia b. Mannosidosis c. Trauma d. Glucose-6-phosphate dehydrogenase deficiency a is the correct answer Galactosaemia is a metabolic disorder in which the childs body cannot metabolise milk and milk products. The baby will have vomiting and diarrhoea, and develops typical oil droplet cataracts which are easily seen by examining the red reflex. 3. Which one of the following statements is incorrect regarding cataract? a. Short stature may be associated with cataract b. Cataracts which result from the metabolic abnormality known as galactosaemia can be reversible c. Congenital cataracts are most easily seen by looking at the red reflex in the first week of life d. In babies with dense congenital cataract it is best to wait until the child is at least five years old before considering surgery d is the correct answer IOLs have been implanted into the eyes of babies as young as four weeks of age. Given that cataract in early childhood, if not picked up early and managed appropriately, can have devastating visual consequences, it is not best to wait until the child is at least five years old before considering surgery. The child must be referred immediately for appropriate management. Short stature may be associated with cataract e.g. Marinesco-Sjogrens syndrome. Oil droplet cataracts caused by galactosaemia are reversible as the lens returns to normal following removal of dairy products from the diet. A simple examination of the red reflex in the newborn child allows the diagnosis of cataract to be made. 4. Which one of the following statements is correct regarding cataract? a. Contact lenses are contraindicated in children under six weeks old b. Leukocoria is always a benign ocular sign which warrants routine referral c. Steroid-induced cataracts are reversible on discontinuing steroid therapy d. Microphthalmos may be a contraindication of contact lens wear d is the correct answer Progression of steroid induced cataract will be halted following cessation of treatment although the cataract is not reversible. Leukocoria is not always a benign sign, as it may indicate a malignant retinal tumour which requires an urgent referral. If a child has not had an IOL inserted and is therefore aphakic, contact lenses are fitted as soon as possible after surgery. Microphthalmos may contraindicate contact lens wear and so the child will be given aphakic spectacles. 5. a. b. c. d. Steroid induced cataracts are typically: lamellar anterior polar cortical posterior subcapsular

d is the correct answer Steroid induced cataracts are typically posterior subcapsular. 6. Which one of the following statements is correct? a. Children who have had surgery for unilateral cataract have a much better visual outcome than children who have had surgery for bilateral cataracts b. When a very young infant is having an IOL implanted, the power of the IOL is calculated to make the child myopic c. Management of ambyopia is essential in improving visual function d. Bilateral cataracts are often operated on simultaneously

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