Cataract: Clinical Types
NATHAN G. CONGDON, MARGARET A. CHANG, PAUL BOTELHO, WALTER J. STARK and MANUEL B. DATILES III
Table Of Contents
POSTERIOR SUBCAPSULAR CATARACT
OTHER, LESS-FREQUENT AGE-RELATED ANATOMIC CATARACT TYPES
OTHER CLINICAL CATARACT TYPES
CATARACT ASSOCIATED WITH PRIMARY OCULAR DISEASES
CATARACT ASSOCIATED WITH SYSTEMIC DISEASES
CATARACT ASSOCIATED WITH METABOLIC DISORDERS
CATARACT ASSOCIATED WITH RENAL DISEASE
CATARACT ASSOCIATED WITH CUTANEOUS DISEASE
CATARACT ASSOCIATED WITH CONNECTIVE TISSUE AND SKELETAL DISORDERS
CATARACT ASSOCIATED WITH CENTRAL NERVOUS SYSTEM DISEASE
CATARACTS CAUSED BY ENVIRONMENTAL EXPOSURE: RADIATION AND PHARMACEUTICALS
CATARACTS CAUSED BY ELECTRIC SHOCK
OTHER RELATED CONDITIONS OF THE LENS
|Of the various clinical types of cataracts known today, the majority are
age-related cataracts. It has been estimated that more than 75% of
persons older than 75 years have lens opacities.1 Therefore, the first part of this chapter addresses the various types
of age-related cataracts, and the second part is concerned with the less-common
types of cataracts. Table 1 serves as a classification of the various types of cataracts and as a
general outline of this chapter.
A cataract is commonly defined as any opacity in the ocular lens, and a wide variety of descriptive terms have been used by clinicians to describe these opacities. In this chapter, we mention and attempt to clarify some of the more commonly used descriptive terms, but for the most part we describe the various types of cataracts in terms of their anatomic location.
|During the Middle Ages, Arabian physicians called the diffuse white appearance (Fig. 1) of total cataracts nuzul-el-ma, which means “a flowing down of water” or “blue water.” The
Carthaginian monk Constantius Africanus, of the Monte Cassino
Monastery, translated the ancient Arabic manuscripts into medieval
Latin and applied the word cataracta, meaning “to rush down, as a waterfall.”2 In modern times, the development of devices that allow the lens to be
examined at high magnification (e.g., the slit-lamp biomicroscope) has helped reveal many early changes
that can occur in the human lens. Patients' increasing visual demands, as
well as advances in the field of cataract surgery, have resulted
in earlier removal of cataracts, and this has made the waterfall-like
appearance of advanced cataracts a rarity.|
The lens maintains its clarity because of its architectural structure and composition. The lens fibers are laid down in specific arrays and are composed mainly of crystallin proteins. When biochemical or physicochemical changes develop that disrupt the architecture or result in the formation of molecules larger than 1,000 nm (10,000 Å), the affected area loses its transparency and opacity results.3
However, the resulting opacity must be located at or near the visual axis for it to affect vision and become clinically important. Very often peripheral cataracts develop without affecting the visual acuity of the patient, and are therefore considered clinically benign. These opacities may exist for many years, even decades, without necessitating any treatment other than optical correction.
Age-related cataracts appear in late adulthood and may cause a painless progressive loss of vision over the course of several years. Cataract is the leading cause of low vision in the United States4 and of blindness in the world.5 To date, studies on possible medical treatments for cataracts have not proved them to be safe and effective in humans.6
When the patient's visual function becomes compromised by the cataract, the only effective treatment available today is surgical extraction and replacement of the cataractous lens with an intraocular lens. Various studies have suggested that cataract surgery is one of the most cost-effective surgical interventions.7,8 The techniques used for the surgical extraction of cataracts are constantly being refined and improved. In the last decade, the frequency of cataract extraction has increased to more than one million per year in the United States alone, and it has become the most commonly performed surgical procedure for Medicare beneficiaries.9 An estimated 20.5 million Americans 40 years and older (17.2%) have cataract, and approximately 6.1 million Americans (5.1%) have undergone cataract surgery.1
In recent attempts to develop a more uniform classification, clinical researchers have used the anatomic locations of lens opacities as a means of classifying cataracts based on photographic standards. The current consensus divides age-related cataracts into three major pure anatomic types (cortical, nuclear, and posterior subcapsular) and mixed types (combinations of these three). Classification schemes such as the Lens Opacities Classification System (LOCS) II10 and III,11 the Oxford Cataract Classification System,12 and the systems used in the Beaver Dam Eye Study,13 at Johns Hopkins,14 and in the Age Related Eye Diseases Study15 use photographic standards to further subdivide each major type into grades. These grades are based either on density and color (in the case of nuclear cataract) or the anatomic area affected by opacity (in the cases of cortical cataract and posterior subcapsular cataract (PSC)). One can directly grade the patient's lens as seen with the slit-lamp (clinical grading), or evaluate photographs of the lens being studied (photographic grading). In addition, an automated grading system that uses densitometry was recently developed.16,17
|Nuclear cataracts are the most common subtype in most European-derived
populations.18 Studies have documented a gradual increase in optical density of the nucleus
with increasing age in normal adults with 20/20 vision (Fig. 2).19|
Nuclear cataracts tend to progress slowly. The refractive index of the lens changes as the nucleus progressively hardens, which usually results in increasing myopia.20,21 In some patients this is accompanied by optical distortion, especially of distant images, while near vision remains unaffected. A nuclear cataract is best seen with the narrow-beam direct illumination employed by the slit-lamp, which reveals the color and generalized haze or opalescence of the nucleus. In the early stages, the two halves (cotyledons) of the embryonic nucleus remain visible (Fig. 3). Later the entire nucleus appears as a homogeneous mass in contrast to the cortex (Fig. 4). Retroillumination may show the “oil droplet” effect (Fig. 5). Sometimes one may notice crystals in the lens nucleus (known as a Christmas tree cataract; Fig. 6A and B).
Nuclear cataracts are associated with physiochemical changes in the lens structural proteins (α-, β-, and γ-crystallins). These proteins undergo oxidation, nonenzymatic glycosylation, proteolysis, deamidation, phosphorylation, and carbamylation, which lead to the aggregation and formation of high-molecular-weight proteins. It was recently proposed22 that α-crystallin may play a role as a molecular chaperon in preventing the aggregation of protein. These high-molecular-weight (>1,000 nm) protein aggregates interfere with light transmission and cause light scattering in nuclear cataracts. Chemical modification of the nuclear lens protein also leads to yellowing, followed by browning and, in advanced stages, blackening.23 Whether these color changes are related to the cataract or are independent of it is still being debated and investigated. Recent studies have also suggested that phase separation inhibitors (PSIs) may play a role in maintaining a clear nucleus, and that the loss of these PSIs may lead to nuclear cataract formation.24
|The cortical cataract is often the most common subtype of opacity seen
in African-derived populations.18 The cortical layer is approximately 2 mm thick anterior and posterior
to the nucleus in adults, and its metabolically active new cortical fibers
are continuously laid down by the bow region cells. The cortical
layer is less compact than the nucleus and is therefore more prone to
becoming overhydrated as the result of an electrolyte imbalance. This
may eventually lead to disruption of the lens cortical fibers, as demonstrated
in diabetes25 (Fig. 7) and galactosemia.26 It has therefore been proposed that this type of cataract may be partly
caused by osmotic stress. Early changes may include signs such as vacuoles, water
clefts, and lamellar separation (Fig. 8). These changes may come and go over time, but eventually they may
lead to damage and irreversible opacification of some fibers. Recent
studies have also suggested that an abnormality of the maturation process
of the lens fibers may lead to subsequent poor development of the
primary, secondary, and tertiary sutures, resulting in the formation
of cortical cataracts.27|
Cortical opacities have been clinically observed to develop earliest in the inferior half of the lens, especially the lower nasal quadrant.28 Epidemiologic29 and laboratory studies30 have suggested that cortical cataracts may be caused by ultraviolet rays from sunlight. The supraorbital margins may block the ultraviolet rays from falling over the upper part of the lens, thus making cortical cataract less frequent in the upper quadrants. Eventually these opacities also develop in the periphery in other quadrants, resulting in a circular array of spokes and peripheral cuneiform opacities (Fig. 9). Bands of central cortical fibers may become prominent and opacify centrally (Fig. 10). However, most cortical cataracts remain in the periphery for many years, even decades, before the central axis of the lens becomes involved, causing loss of vision late in the development of the cataract.
It has been observed that some individuals may have cortical opacities covering the entire anterior cortical and posterior cortical area (Fig. 11), and yet have 20/40 or better Snellen visual acuity under standard testing conditions. However, these patients may have severe disability glare such that under simulated bright lights their visual acuity may decrease to 20/80 or worse.31 They may also have decreased contrast sensitivity. These individuals tend to do well indoors but have difficulty driving during bright, sunny days, and at night because of oncoming headlights. Treatment in these cases must be decided on an individual basis, and surgery may be indicated when the expected benefits outweigh the surgical risks.
This type of cataract is best seen with retroillumination, which gives an enhanced picture of the cortical spokes and vacuoles by the shadows they cast as the light is reflected back by the fundus. Direct illumination helps clarify the level of the opacities (see discussion in the Posterior Subcapsular Cataract section below).
|POSTERIOR SUBCAPSULAR CATARACT|
|The PSC is the least prevalent subtype in most population-based studies.18 These cataracts often occur in combination with nuclear or cortical cataracts
in the later stages. They are easily noticed on retroillumination
because they are usually located centrally, and may interfere with
funduscopy (Fig. 12). In early stages, patients usually complain of subjective symptoms
such as glare disability32 and difficulty focusing on near objects. This is because when the pupil
constricts during accommodation, the light entering the eye becomes
concentrated centrally, where the PSC is also located. This causes light
scattering and interferes with the ability of the eye to focus an image
on the macula. In addition, these opacities lie at or near the nodal
point of the eye, further interfering with focusing of the image on
One can examine this type of cataract with direct illumination, using the narrow and broad beams of the slit-lamp to show the characteristic granular inner surface immediately in front of the posterior capsule (Fig. 13). The problem with this technique, however, is that patients may not tolerate any prolonged direct illumination because of the glare. Retroillumination is therefore more useful for revealing the outline of the opacity, since it is usually seen as an “island” in the center of the posterior capsule, which is further highlighted by the shadow cast by the opacities.33 However, in the early stages of this type of cataract, the dust-like particles that might be noticeable in the central posterior subcapsular area with direct illumination disappear or are difficult to see with retroillumination (Fig. 14). Eventually this “dusting” becomes dense enough to cast a shadow and thus appear on retroillumination. The smooth orange background of the fundus helps to highlight the rough, irregular pseudopodia-like edges of the central opacity. In advanced stages, the PSC may become a thick, calcified plaque (Fig. 15). During surgery, excessively vigorous scraping or vacuuming of the calcified opacity can lead to rupture of the posterior capsule. Usually, small remnants that are left behind after surgery are reabsorbed and do not interfere with vision; otherwise, they are easily treated with a neodymium : yttrium (Nd:YAG) aluminum garnet laser. Pathologic evidence suggests that most PSCs result from the migration of bow region cells into the potential space (along with accumulated cellular debris) between the posterior capsule and the cortex.34–36
PSC may also result from irradiation or steroid ingestion, or it may be associated with diabetes, high myopia,37–41 retinal degeneration (e.g., retinitis pigmentosa),42,43 and gyrate atrophy.44,45 In some cases, the PSC eventually may be pushed to the cortex as new fibers are laid down and the offending agent is no longer present (Fig. 16A and B).
|Sometimes more than one of the above-described varieties of cataract will
occur together in a lens (Fig. 17). In general, a cataract will start as a pure type but eventually
become mixed as the other lens regions become involved in the degenerative
|OTHER, LESS-FREQUENT AGE-RELATED ANATOMIC CATARACT TYPES|
CAPSULAR (INCLUDING POLAR) CATARACTS
The lens capsule may develop localized opacities in age-related cataracts. However, these opacities are more often associated with persistent pupillary membranes or epicapsular stars, and they may also occur in uveitis in association with posterior synechiae or secondary to injury caused by drugs, radiation, or trauma. Capsular thickening may also occur in heat (glassblowers') cataract, and localized thickening may occur in both Lowe's syndrome and Miller's syndrome.46
Localized central capsular cataracts (polar cataracts) can occur in the anterior and posterior capsules and are usually congenital, although they may also occur secondary to trauma. Polar cataracts (Fig. 18) are usually dense, localized, and nonprogressive. Because they are stable, many patients may be able to tolerate them and may retain good or adequate vision with conservative treatment (e.g., dilation of the pupil, wearing sunglasses on bright days, and optical correction).
ANTERIOR SUBCAPSULAR CATARACTS
Anterior subcapsular cataracts (Fig. 19) result from the aberrant differentiation and growth of lens epithelial cells to form fibrotic plaques.47–49 Immunolabeling studies of anterior subcapsular cataracts have revealed cytoskeletal and extracellular matrix proteins that are not normally expressed by the lens.50,51Transforming growth factor beta (TGF-β) has been shown to induce anterior subcapsular cataracts in animal models.47,48,52,53 Anterior subcapsular cataracts have been reported following ocular trauma and in association with atopic dermatitis.48,54,55 Pure anterior subcapsular cataracts may be more common in the Korean population.50
LENS EPITHELIAL DECOMPENSATION
In some cases the entire anterior lens epithelium is observed to be edematous with resulting generalized haze (Fig. 20A). This is usually followed within a short period of time (a few months to 1 year) by the development of cortical cataracts and PSCs that mature quickly and cause severe, rapid loss of vision (Fig. 20B).
Retrodots are round, translucent opacities that usually occur in the deep cortex or perinuclear region. It has been proposed that they contain calcium oxalate, probably from ascorbic acid.46 In general, they do not seem to affect vision until a mixed cataract appears (nuclear or cortical), and patients may have these retrodots for years and still retain good vision (Fig. 21).
Advanced cataracts are usually mixed cataracts that reach the mature stage. A cataract is termed “mature” if the cortex and nucleus are so opaque that one can no longer see the red reflex; at this stage the lens looks white (hence the appellation “waterfall” or “cataract”)2 (see Fig. 1). In even more advanced cases, the white cortex becomes so liquefied that one can see the outline of the brown nucleus floating free inside the lens, which usually settles down with gravity when the patient rests for a while. This is called a morgagnian cataract (Fig. 22). If the lens is noticeably swollen, the cataract is called an intumescent cataract. If the lens appears silvery white and desiccated, with some leakage of the cortical fluid, it is called a hypermature cataract (Fig. 23). As mentioned above, these advanced stages are now rarely seen in the United States but are still fairly common in less-developed countries where surgical treatment is not readily available.
Surgery on these advanced cases must be done carefully because the lens capsule and zonules can easily break during manipulation. When carefully performed, however, both intra- and extracapsular extraction techniques have successfully achieved complete restoration of sight for patients with advanced cataracts.
Before we leave the topic of age-related cataracts, we should point out that the mortality rates of patients who have cataract or have undergone cataract surgery may be elevated compared to matched controls.56 This has been interpreted to indicate that the presence of an advanced cataract may reflect a generalized state of decreased health in the patient. In addition, recent studies have also suggested that body mass is indirectly related to the incidence of cataracts. Again, this may indicate that a person's state of health is an important factor in cataract formation.57–59
|OTHER CLINICAL CATARACT TYPES|
CONGENITAL AND JUVENILE CATARACTS
By definition, congenital cataracts are detected at birth, whereas juvenile cataracts develop during the first 12 years of life. Both range from mild and benign to advanced and sight-threatening. Congenital cataracts are an important cause of blindness in children.60 Approximately one-third of congenital and juvenile cataracts are inherited. A wide degree of variation is seen in the morphologic characteristics of these cataracts. In the following paragraphs we present a morphologic classification of congenital cataracts.
I. Total or Complete Cataracts
Total or complete cataracts are completely opaque or hazy at birth. Most of these are associated with systemic disorders or abnormalities such as galactosemia, rubella, and Lowe's syndrome. They may also be hereditary (autosomal-dominant (AD) or autosomal-recessive (AR)) (Fig. 24).
II. Partial or Incomplete Cataracts
A. ANTERIOR AND POSTERIOR POLAR CATARACTS
(see Fig. 18). These cataracts involve the lens capsule in the anterior or posterior pole of the lens. They are sometimes associated with a localized anatomic abnormality in the region. For example, posterior polar cataracts commonly occur in cases of posterior lenticonus. They may cause more visual symptoms because they are closer to the nodal point of the eye; however, they are usually stable, and patients may do well with conservative measures. Anterior polar cataracts may be associated with absence of the lens capsule. Anterior and posterior polar cataracts are associated with abnormalities in the gene that encodes the major intrinsic protein of the lens fiber (chromosome 12q3), which is inherited as an AD trait. Posterior polar cataract may also be associated with AD defects in α-2 crystallin (chromosome 21q22.3) and γ-D crystallin (chromosome 2q33-q35).
B. ZONULAR CATARACT
In this type of cataract, only a region or zone of the lens is opaque. They may be stationary, but may also progress. There are various subtypes, as described below:1. Lamellar. This is the most common type of congenital cataract. Such cases are usually bilateral and symmetric, and the density of opacification may vary considerably (Fig. 25A and B). Less opaque lamellar cataracts may be compatible with good vision and minimal medical intervention (e.g., optical correction and therapeutic mydriasis). These cataracts may be inherited as an AD trait through defects in γ-C and γ-D crystallin (chromosome 2q33-q35), but in some cases they may be attributed to a transient intrauterine toxic agent that affects only the layer of cells that develop at the time of fetal exposure.
2. Stellate. These cataracts affect the region of the sutures. They may be Y-shaped if the cataract occurs in the intrauterine stage of development, since the sutures have this configuration during this period. Anterior sutural cataracts are Y-shaped, and posterior sutural cataracts are shaped like an inverted Y. Sutural cataracts that develop later on have a more stellate shape (Fig. 26), in keeping with the shape of the sutures after birth. Stellate cataracts can be inherited in an AD pattern through mutations in the β-B1 crystallin (chromosome 22q11.2-q12.1) and the major intrinsic protein of the lens fiber (chromosome 12q3).
3. Nuclear (Fig. 27). These cataracts are usually bilateral and involve the fetal or embryonal nucleus. They may be inherited as an AD, AR, or X-linked trait. The known loci of genetic mutation include α-1 crystallin (chromosome 21q22.3), γ-C crystallin (chromosome 2q33-q35), and γ-D crystallin (chromosome 2q33-q35), all of which are AD.
4. Coronary (Fig. 28). These cataracts are radial, club-shaped discrete opacities that are located in the cortex. They are called “coronary” because they resemble the top of a crown. Because of their peripheral location, they do not decrease visual acuity. Coronary cataracts are dominantly inherited and have been described in cases of Down's syndrome, glutathione peroxidase deficiency (chromosome Xq28), and myotonic dystrophy.
5. Cerulean. These cataracts consist of small, discrete opacities that have a distinct bluish hue (see Fig. 29). They are located in the cortex, are nonprogressive, and do not cause visual symptoms. They may be present together with other congenital cataracts. Others are dominantly inherited through mutations in γ-D crystallin (chromosome 2q33-q35).
C. MEMBRANOUS CATARACTS
These cataracts are thin but dense and contain fibrous tissue. They may occur when lens proteins are reabsorbed (e.g., traumatized lens; see following section), such that the anterior and posterior lens capsules fuse and produce a dense membrane. They are also associated with defects in type II collagen (chromosome 12q13.11-q13.2).
|Cataracts can occur secondary to trauma to the lens.61 The morphologic characteristics differ between cataracts caused by blunt trauma and cataracts secondary to penetrating trauma. Cataracts secondary to blunt trauma often have a rosette-shaped
appearance (Fig. 30) or are of the PSC variety. In cataracts secondary to penetrating
trauma, the size of the opening in the lens capsule determines the morphology
of the cataract. When the opening is large, the whole lens may
become cataractous. When the opening is small, it may sometimes seal
by itself and leave behind an opacity that is localized to the site of
|CATARACT ASSOCIATED WITH PRIMARY OCULAR DISEASES|
|Cataracts can occur secondary to a large number of intraocular diseases. Intraocular
inflammation is the most common cause of this type of cataract. These
cataracts are typically of the PSC variety. PSCs seen in
retinitis pigmentosa (Fig. 31), gyrate atrophy (Fig. 32), and Usher's syndrome (Fig. 33) show finger-like projections. In persistent hyperplastic primary
vitreous, the PSC is often associated with abnormal blood vessels from
the hyaloid system that arborize from the posterior pole of the lens. Cataracts
seen in retinal anoxia and anterior segment necrosis are thought
to occur due to interference with the nutrient supplies of the
lens. This leads to decreased anabolism, increased catabolism and acidity, and
necrosis. The cataracts in these conditions are also of the PSC
type. An acute increase in intraocular pressure can cause focal necrosis
of the subcapsular epithelium and localized, fleck-like opacities (glaukomflecken). These opacities are initially located immediately under the capsule, but
when new fibers are laid down they slowly become buried in the
lens. Their presence indicates that the patient has experienced an
acute increase in intraocular pressure. The premature occurrence of PSC
and possibly nuclear-type cataracts has been noted in eyes with high
myopia (Fig. 34).37–41|
|CATARACT ASSOCIATED WITH SYSTEMIC DISEASES|
|The systemic conditions associated with cataract formation can be grouped
into five broad categories (see Table 1):
|CATARACT ASSOCIATED WITH METABOLIC DISORDERS|
Diabetes mellitus is a significant risk factor for cataract formation. It has been reported that cataracts reach visual significance 10 years earlier in the presence of diabetes than they would otherwise.65,66
Sorbitol does not readily pass through the cell membranes, and is therefore trapped inside the lens, causing an osmotic imbalance. This results in the influx of water into the lens to balance the osmotic pressure, which causes the lens fibers to swell and eventually rupture. This cataract type has been demonstrated in experimental animals and has been completely prevented in animal models with the use of various potent aldose reductase inhibitors.68–70 However, aldose reductase enzyme levels in human lenses have been found to be lower than in animal models of diabetic cataract, and so far the few aldose reductase inhibitors that have been tested (in a limited way) have not been shown to have much effect on human diabetic cataracts.
Another possible mechanism of cataract formation in patients with diabetes is overaction of the proteolytic enzyme calpain 2. This intracellular cysteine protease, in the setting of elevated lens calcium 2+ levels, was found to be cataractogenic in several diabetic animal models.71,72,73 Calpain 2 has been identified in human lenses, and was reported by one study to be the major calpain expressed in epithelial cells of human lenses with cortical cataracts.74,75
Other potential causes of increased cataract formation in diabetes include elevated lens advanced glycated end-products found in human subjects compared to controls,65 and oxyradical-induced lens DNA changes with apoptosis in a diabetic animal model (with a protective effect from pyruvate).76
Transient changes in refraction, which may be either a myopic or a hyperopic shift, may accompany this swelling in some diabetic patients. Diabetics also exhibit a decreased amplitude of accommodation.
Two types of cataracts result from diabetes. The first one is the true diabetic (snowflake) cataract, which is quite rare. It is usually bilateral, occurs rapidly, and is usually related to very high, uncontrolled levels of serum glucose in young type II diabetics. The word “snowflake” is used to describe these cataracts because in the early stages one notices multiple white anterior and posterior subcapsular and cortical opacities, as well as vacuoles (Fig. 37). Later, as more lens fibers become involved, water clefts appear (Fig. 38) in the cortex, and the lens becomes swollen and opaque. This closely mimics what occurs in experimental animals, as mentioned above. The second, more common type is the age-related diabetic cataract, which occurs in type I or II diabetics. It is very similar to other age-related cataracts, and may present as a cortical, posterior subcapsular (Fig. 39), or (less frequently) nuclear cataract. These cataracts have an earlier onset than other age-related cataracts, and patients with such cataracts undergo cataract surgery sooner. These cataracts may result from osmotic causes and increased glycosylation of lens proteins, in addition to the other mechanisms that lead to age-related cataract (e.g., oxidation and phase separation).
Galactosemia, which refers to a group of AR inborn errors of galactose metabolism, is a well-recognized cause of cataract in infants.77 Classic galactosemia is due to a deficiency in galactose-1-phosphate uridyltransferase (GALT) activity. Affected patients may develop significant neurologic abnormalities, including mental and motor retardation, dyspraxia, and hypergonadotropic hypogonadism, in addition to cataract formation. By contrast, numerous case series of galactokinase deficiency, a less common cause of galactosemia, have reported isolated cataract formation.78–80 As in diabetic cataract formation, galactosemic cataracts occur as a result of osmotic swelling of lens fibers secondary to a metabolic abnormality: as serum galactose accumulates, it enters the lens and is converted to the sugar alcohol galactitol by the enzyme aldose reductase. Because galactitol does not pass readily through cell membranes, it accumulates in the lens, resulting in the entry of water to correct the osmotic imbalance. This leads to swelling and rupture of lens fibers and cataract formation. As in diabetic animal experiments, galactosemic animal experiments have shown that these cataracts can be prevented completely with the use of potent aldose reductase inhibitors.81 Reversal of these cataracts is known to occur if galactose is removed from the diet.
Reduced activity of GALT has been proposed as a risk factor for the development of idiopathic cataract formation. Several studies have shown an increased rate of isolated cataract formation in heterozygotes for classic galactosemia, as well as homozygotes with the less severe Duarte or Los Angeles variant.82–87
Although galactokinase enzyme mutations are known to cause congenital cataracts, recent studies suggest that the Osaka variant of galactokinase is associated with modestly increased rates of formation of age-related cataracts.80 Given that galactokinase thus appears to be associated with both congenital and age-related cataracts, future research investigating other loci associated with congenital cataracts may likewise shed light on the pathogenesis of age-related cataracts.
Cataracts secondary to hypocalcemia show fine, discrete white dots in the perinuclear zone. Patients with hypoparathyroidism/hypocalcemia also have skeletal abnormalities, such as frontal bossing and increased osteoporotic changes, as well as a serum calcium-to-phosphorus ratio that is well below normal
LOWE'S (OCULOCEREBRORENAL) SYNDROME
Wilson's disease, which is characterized by increased serum copper levels and the deposition of copper in basement membranes throughout the body, causes a kind of lenticular opacity called sunflower cataract. This is characterized by a fine, powdery deposition of copper just underneath the lens capsule, which gives it a brilliant yellow, brown, or red sheen. The deposition is more concentrated in the pupillary area and is disc-like centrally. Extending from this disc-like area are radiating petal-like deposits (hence, the sunflower appearance). These cataracts do not interfere with vision and may resolve with systemic therapy for the increased copper levels.89
Fabry's disease occurs secondary to an abnormality in lipid metabolism, and is characterized by feathery opacities radiating in the posterior subcapsular regions.90 These cataracts are mild and seldom cause significant visual symptoms
In 90% of patients with homocystinuria, the zonules show abnormalities leading to a subluxation of the lens that is often in the inferonasal direction.91 Occasionally, congenital cataract is associated with this condition.92 Patients with homocystinuria have thrombotic tendencies and must be monitored carefully when they are under general anesthesia
Refsum's disease, whic is a condition of abnormal lipid metabolism, is often associated with PSCs.93 Patients with this disease have an atypical pigmentary degeneration of the retina.
|CATARACT ASSOCIATED WITH RENAL DISEASE|
|Patients with Lowe's or Alport's syndrome are known to have cataracts. Ocular manifestations (most commonly anterior lenticonus) occur in approximately 15% of patients with Alport's syndrome.94 Often there is a localized posterior polar opacity associated with the conic area. The opacity or sometimes the severe irregular astigmatism induced by the lenticonus can cause disabling visual symptoms, which often necessitate cataract extraction.|
|CATARACT ASSOCIATED WITH CUTANEOUS DISEASE|
|That lenticular changes should act in consort with cutaneous changes in
some cutaneous disorders is not surprising given their common ectodermal
origin. Lenticular changes are common in Rothmund's syndrome, atopic
dermatitis, and Werner's syndrome, and may be seen in incomplete
forms of congenital ectodermal dysplasia.92 The features of these cataracts are outlined along with their respective
clinical conditions as follows:|
Atopic dermatitis: Cataracts occur in 8% to 10% of cases, are bilateral, develop in the third to fifth decade of life, and usually are in the form of a dense anterior or posterior subcapsular plaque with radiating opacities into the cortex. Eventually complete opacification of the lens is seen.
Rothmund's syndrome: Cataracts are of the zonular type and typically develop between 2 and 4 years of age. They are bilateral, occur mainly in girls, develop as punctate opacities, and evolve rapidly.
Werner's syndrome: Cataracts commence with the formation of striae that are located in the posterior cortical and subcapsular areas, and have a metallic sheen. They develop during the second or third decades of life, rapidly become intumescent, and progress to total opacification of the lens.
Congenital ectodermal dysplasia: The complete forms of this disorder are not usually associated with cataract. In incomplete forms of the disease, however, congenital cataract may be seen along with other ocular disorders, such as Rieger's anomaly and vitreous fibrosis.
|CATARACT ASSOCIATED WITH CONNECTIVE TISSUE AND SKELETAL DISORDERS|
|Myotonic dystrophy and Stickler's, Conradi's, and Marfan's
syndromes are all associated with cataract. The features of these cataracts
are outlined along with their respective clinical conditions
Conradi's syndrome: Cataracts are associated with two of the three genetic types of this syndrome. In the lethal, AR type, the cataracts are congenital, dense, and symmetric. A milder, asymmetric, acquired cataract is the only ocular finding in the X-linked dominant type. No cataracts are associated with the AD type.95
Myotonic dystrophy: Cataracts are an essential part of the constellation of signs seen in this condition. They usually commence in the second or third decade of life and show a diffuse layer of dust-like, multicolored, punctate, and flaky opacities that may be located in the perinuclear zone or the posterior subcapsular area. They may remain stable for many years before progressing. The posterior subcapsular opacity may enlarge and increase in density, and an anterior subcapsular opacity may develop. The sutures may also opacify, causing a stellate opacity. Finally, the lens becomes diffusely opaque. Myotonic dystrophy is a well recognized cause of presenile cataract (Fig. 41), and should be suspected in patients with systemic features of the condition and the typical cataracts described above. These patients may also have associated ocular disorders, such as pigmentary changes in the retina, ocular hypotension,96 ptosis, and abnormal pupillary responses.
Marfan's syndrome: Marfan's syndrome is an AD disorder that affects the cardiovascular, musculoskeletal, and ocular systems. The causative defective gene located on the long arm of chromosome 15 codes for fibrillin 1, the main constitutive protein of the elastic tissue.97,98In one study, up to 70% of patients with Marfan's syndrome were found to have ectopic lentis.99 Dislocation of the lens (Fig. 42) has been positively correlated with increased axial length, which is a very common ocular abnormality in this syndrome. Localized opacities of the lens may also be present. The defective fibrillin 1 protein may be more susceptible to degradation by matrix metalloproteases, resulting in zonular instability.100,101 It has been proposed that the superotemporal subluxation may be due to UV-B light that is preferentially focused in the inferonasal quadrant, leading to decreased fibrillin expression in this location.102
Weill-Marchesani syndrome (WMS): WMS is a systemic connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and characteristic ocular findings. These include microspherophakia (Fig. 43A and B), ectopic lentis, cataract formation, severe myopia, and acute or chronic glaucoma.103–105 Both AD and AR modes of inheritance have been reported in familial cases of WMS.106,107 A review of all published case reports of WMS found clinical homogeneity and genetic heterogeneity in WMS.105 Of note, AR cases were more commonly associated with microsherophakia (94% AR, 74% AD, Fischer 0.007) while ectopic lentis was present in a greater percentage of AD cases (84% AD, 64% AR, Fischer 0.016). Wirtz et al108 reported linkage of the AD form of WMS to the fibrillin-1 gene located on chromosome 15q21.1. A frame fibrillin-1 gene deletion in AD WMS was also identified.109 Underscoring the genetic heterogeneity of WMS was the recent identification of ADAMTS10 mutation in AR WMS. Three distinct mutations involving the ADAMTS10 gene on chromosome 19p13.3-p13.2 were identified in two consanguineous families and one sporadic case of WMS.110 ADAMTS10 is a member of the extracellular matrix protease family, and is believed to be anchored to the extracellular matrix through interactions with aggregan or other matrix components.111,112 A close interaction between fibrillin-1 and ADAMTS10 has been suggested as the explanation for the similarities in phenotypic expression found among genetic heterogeneous cases of WMS.110
Stickler syndrome: Stickler syndrome, an AD disorder of connective tissue proteins, has multiple manifestations that affect the ophthalmic, orofacial, auditory, and articular systems. Micrognathia, depressed nasal bridge, and flat midface are the most commonly found orofacial features, and they tend to become less evident with age. Midline clefting may be of variable severity, ranging from a cleft soft palate to the Pierre-Robin sequence. Deafness may be present secondary to ossicle defects or sensorineural deficits. Joint hyperextensibility with later degenerative osteoarthropathy is also common.113,114 The most prominent ophthalmic manifestations are abnormalities of vitreous formation and architecture, and congenitally high myopia, which predispose to giant retinal tear formation and retinal detachment. Patients with Stickler syndrome may be more at risk of early-onset nuclear sclerosis and posterior subcapsular opacification.113 Congenital cortical cataracts may be present. These tend to be nonprogressive, and may have a curved113 or “wedge and fleck”114 distribution.
|CATARACT ASSOCIATED WITH CENTRAL NERVOUS SYSTEM DISEASE|
|Cataracts have been described in conditions associated with anomalies of the brain, such as Little's disease, microencephaly, and Marinesco-Sjogren's syndrome. The characteristic features of such anomalies are congenital spinocerebellar ataxia, oligophrenia, and occasionally congenital cataract.92 Neurofibromatosis type 2 (bilateral acoustic neuroma) is associated with cortical cataract and PSC (see Fig. 36).63,64|
|CATARACTS CAUSED BY ENVIRONMENTAL EXPOSURE: RADIATION AND PHARMACEUTICALS|
CATARACTS DUE TO IONIZING RADIATION
Continuous exposure to many of the wavelengths in the electromagnetic spectrum (e.g., x-rays, ultraviolet rays, microwaves, and infrared rays) can cause cataracts.115,116 An increased rate of cataract formation has been reported in astronauts and airline pilots.117–119 Often a latent period of 9 to 12 months or more exists between exposure to ionizing radiation and the onset of cataract. These cataracts are PSCs (Fig. 44) and classically show multiple vacuoles, as well as an evenly feathery appearance and weblike fringes. Ionizing radiation affects the germinative equatorial epithelium. The damaged cells form an abnormal plaque, which first appears at the posterior pole and progressively shows enlargement.
CATARACTS SECONDARY TO PHARMACEUTICAL AGENTS
A large number of medications are known to induce cataracts (see Table 1). The following is a list of the more commonly used pharmaceuticals, along with the characteristics of their associated cataracts:
Corticosteroids: Both topically applied and systemically administered corticosteroids can cause cataract.120,121 The factors involved in the development of typical PSCs include 1) inhibition of the sodium-potassium-ATPase pump mechanism, which increases the permeability of the lens to cations;122 and 2) conformational changes in specific amino groups of the lens crystallins, which lead to the development of disulfide bonds and protein aggregation.123
Other possible mechanisms include a decreased expression of cadherin (a family of cell–cell adhesion molecules that control the calcium-dependent cell adhesion of lens proteins that are necessary to prevent cataract formation),124,125 binding of corticosteroids to lens proteins forming lysine-ketosteroid adducts that cause aggregation of lens crystallin proteins,126 or corticosteroid-induced oxidative stress caused by accelerated gluconeogenesis, with reduced levels of glutathione sulphate attributed to the possible inhibition of glucose-6-phosphate dehydrogenase.127–130
A genetic predisposition to the cataractogenic effect of corticosteroids has been proposed to explain the apparently exaggerated effect seen in some persons as opposed to others. These cataracts commence at the posterior pole and progress to form PSCs with dense central opacity and a feathery fringe (Fig. 45).
Hydrocarbons and substituted hydrocarbons: Naphthalene, dinitrophenol, p-dichlorobenzene, and other orally ingested compounds belonging to this group have been reported to cause cataracts (however, vapors from p-dichlorobenzene have not been found to be cataractogenic).131 Dinitrophenol, which was previously prescribed for obesity, is notorious for causing cataracts because it has a directly toxic effect. Bilateral cataracts develop after only a few months and are characterized by fine, grayish opacities in the anterior cortex, with a lusterless appearance of the anterior capsule. Golden granular opacities with a polychromatic specular reflection also appear in the posterior cortex. These opacities rapidly progress to a mature cataract. Most of the studies on naphthalene-induced cataracts were based on experiments in rat and rabbit models, and reports of naphthalene-induced cataracts in humans are anecdotal. Naphthalene-induced cataracts have been studied as a possible model for human age-related cortical cataracts, and aldose reductase inhibitors have been shown to prevent these cataracts in animal models.132,133
Miotics: Chronic use of all long-acting cholinesterase inhibitors (e.g., echothiophate iodide [phospholine iodide] and demecarium bromide) can produce anterior subcapsular vacuoles. Continued use of these strong miotics may cause posterior subcapsular and nuclear changes.131 Pilocarpine is also associated with cataract formation, but the changes are less marked and require more time to develop than those induced by the stronger miotics.134 The mechanism of cataract formation remains unclear.
Phenothiazines: This refers to a group of antipsychotic drugs, of which chlorpromazine is the most widely used. Fine, granular deposits are seen in the palpebral portion of the cornea and conjunctiva. In the lens, a dust-like granular pattern may develop in the pupillary area beneath the anterior capsule.133 These pigmented deposits may progress to a stellate pattern following the suture lines, but usually they are not visually significant. Development of these opacities appears to be dose related. Although it has been thought that these opacities do not lead to formation of an ordinary cataract, it has been proposed that these drugs may accelerate any predisposition to lens opacification from solar radiation because of their ability to form photosensitive products. Recent studies have also shown that phenothiazine use is a risk factor that results in the need for cataract surgery.135,136
Psoralen-ultraviolet A (PUVA) therapy: Psoralen is used to treat psoriasis and vitiligo, usually in conjunction with long-wave (320 to 400 nm) ultraviolet radiation.137,138 The notion of a possible association between PUVA and cataracts is based on experimental animal studies in which excessively large doses of psoralen (methoxsalen) were administered. A number of studies on humans have shown that cataract development is a rare occurrence in association with PUVA therapy. It is also possible that concomitant ultraviolet exposure may have an additive cataractogenic effect.
Statins: Statins have proved to be beneficial in a number of cardiovascular diseases, and their usage is increasing throughout the world. There has been concern that statins may induce cataract. Animal studies have shown an increased risk of lens opacity with large doses of statins, and a dose-dependent increase in cataract formation has been found in dogs.139–141 Thus far, no strong evidence has linked statin usage to increased lens opacity in humans.142–147 A large case-control study using data from the United Kingdom's General Practice Research Database found no significant risk of cataract with statin use, but did find an increased risk of cataract with concomitant use of simvastatin and erythromycin.148 This finding was not reproduced in a second, larger study using the same database.149 Long-term studies of statin use in humans will be necessary to determine whether chronic use may lead to a cumulative risk of lens opacity.
|CATARACTS CAUSED BY ELECTRIC SHOCK|
|Clinical cases of lenticular opacification following shock from a high-tension conductor,150 lightning,151 and even electric shock therapy have been reported. The exact pathogenesis of these cataracts is unknown, but it is thought that direct coagulation of proteins and osmotic changes following damage to the subcapsular epithelium are responsible. These cataracts are typically anterior and posterior subcapsular, and have a coarse, fern-like appearance. They impair vision significantly because of the dispersive properties of the coarse opacities, and often necessitate surgical removal.|
|OTHER RELATED CONDITIONS OF THE LENS|
DISLOCATION OF THE LENS (ECTOPIA LENTIS)
In ectopia lentis, the lens may be dislocated completely (luxated) into the anterior (Fig. 46), posterior, or vitreous chambers. It may be congenital, developmental, or acquired. Before Daviel performed the first cataract extraction in 1748, the popular method for treating cataract was “couching,” or the deliberate posterior dislocation of the lens into the vitreous chamber in order to clear the pupil and restore vision. This cleared the pupillary axis to enable the patient to see again, and long-term results were variable.152
The lens may also be partially displaced (subluxated) in patients who have Marfan's syndrome or have been subjected to trauma (Fig. 47). Such patients may complain of decreased or fluctuating vision and monocular diplopia. The findings include iridodonesis (tremulous iris) and irregular astigmatism.
LENTICONUS AND LENTIGLOBUS
Lenticonus is a cone-shaped deformation of the anterior or posterior lens surface. Posterior lenticonus (Figs. 48 and 49) is more common than anterior lenticonus, and is usually unilateral and polar. This deformation results in a marked distortion of images and subsequent poor vision. Posterior lenticonus may be associated with extremely thin posterior lens capsules, and polishing of the posterior capsule should be avoided during cataract surgery.
Lentiglobus is a spheric deformation of the lens surface. Posterior lentiglobus is more common than anterior lentiglobus, and is often associated with posterior polar cataracts.
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