4.1 Not-so-routine exams

Preventive care is a wonderful idea. This naturally applies to eyecare as well.

A routine eye exam is supposed to be yearly or biannually depending on what your insurance policy allows. It involves a physical exam of the eyes to make sure your eye sight is still 20/20. And any deviation from the previous exams is subject to additional testing and/or referral to a specialist. This specialist then also determines if any need for more treatments. What a system!

In reality, while many do enjoy routine care, others - young or middle-aged patients - show up in an eye doctor’s office often with a myriad of chief complaints, starting from blurred vision both far and near especially when driving at night, to diabetes and high blood pressure/cholesterol that are being treated, to frequent pain, tearing and photophobia, plus family history of glaucoma and AMD. And by the way: “I also need some new contacts.” In less affluent areas, even in a developed country such as the US, this is not an unusual scenario - yes, the all-inclusive not-so-routine exams. The cause? IMHO, the managed-care maze which both the patients and the doctors often must navigate together. It is a system so inflexible as to impede providing and receiving of proper care. As as result, the patients' health problems multiply.

So what do the doctors see in addition to changes in refraction, incipient cataracts, glaucoma suspects, and background diabetic retinopathy? Well, quite a bit. An interesting list, starting from the most common to somewhat rare, is shown below:

1. Dry eye and subconjunctival hemorrhage
2. Contact lens over-wear and keratoconjunctivitis
3. Medicine-induced mydriasis in children
4. Allergic conjunctivitis
5. Early arcus senilis
6. Pterygium and non-UV pinguecula
7. Undiagnosed keratoconus
8. Herpes simplex keratitis
9. Corneal dystrophy

In addition, patients who often self-refer because of alarming visual disturbances. A few common complaints are listed below:

1. Diplopia
2. Floaters/flashes/vitreous hemorrhage
3. Visual field loss/blood vessel occlusion
4. Retinal detachment
5. Macular hole/pucker

Interesting cases deserve serious comments which I will now start to post.

3.3.2 Squint (noun)

Childhood squint, i.e., strabismus or tropia is different from phoria. The latter refers to the eyes assuming a natural position when they are artificially dissociated. They resume fixation at the same point when both eyes now see at the same time. The angle of deviation, in prism diopters, can be measured quite accurately, e.g., with rotating prisms. And frequently, small amounts of prisms are prescribed to relieve extraocular-muscular strains from the need to actively maintain the binocular alignment.

In squint, the two eyes remain dissociated and misaligned, also known as crossed- or walled-eyes when the affected eye turns in or out, respectively. The deviation can be horizontal, vertical, or mixed. It can be constant or it can vary with gaze. And it can involve one or both eyes. The main cause can be either central involving the brain, or a local neuromuscular problem. So the diagnosis is best left to a professional. The deviated eye either has already developed amblyopia or has the potential to become so. Proper therapy, either patching or atropine eyedrops, must be initiated in conjunction with orthoptic re-alignment of the eyes. Often strabismus requires surgery to re-arrange the positions of the extraocular muscles; although mostly for cosmetic reasons.

There is a special case, accommodative esotropia. It is from relatively high hyperopia and when the child tries to see even at distance, accommodation kicks in and the eyes converge (cross) as a result. A pair of properly prescribed glasses or contacts can re-align the eyes without the need for surgery or orthoptics.

Also in Asian babies, because of the flat nose bridge and the thick epicanthal skin covering more of the nasal part of the eyes, there is an optical illusion of esotropia or pseudo-esotropia. You can shine a penlight about 3m away into the baby's eyes and observe the reflexes on the corneas. If the reflexes appear at the same position in each eye, then the eyes are aligned.

You may have heard of the term “vision therapy” and its putative efficacy. Historically, “vision therapy” is not very well-defined and in fact quite confusing. This much we do know: In two 2005 studies, comparing intensive office-based therapy and in-home pencil push-up exercise, the former seems to better resolve symptoms from convergence insufficiency, e.g., headaches, eye fatigue, blurred and double vision from near work. This conclusion is not without controversies, though. The claim of remedying learning disability, on the other hand, is unsupported.

More recent versions of “vision therapy” include training of re-focusing and visual perception, improvement of oculo-motor coordination and eye tracking. In fact, some professional athletes are enthusiastic supporters of this type of therapy.

As in other fields of medicine, the effectiveness of any treatment must be evidence-based. Let’s just say, much more needs to be done in the field of vision therapy.

3.3.1 Who's being lazy?

Amblyopia is commonly known as the lazy eye. Except for congenital opacities, a lazy eye is absolutely normal in structure, both inside and out, yet its vision is poor. The other eye, on the other hand, has good vision. To a child, the visual world would appear normal. And to others, nothing unusual about this child's eyes, either. For this reason, the discovery of amblyopia is almost all by accident, first noticed by an observant parent or a pediatrician.

There are three types of amblyopia:

Deprivational: this happens when there are cataracts or corneal opacities blocking the path of light into the eye. Naturally the opacities must be removed first.

Refractive: this type occurs due to a large difference between the refractive errors of the two eyes. For example, if one eye is normal or near-sighted and the other is very far-sighted, then the latter will remain unused to avoid diplopia - this then results in amblyopia. There is a subtype due to high astigmatism. It usually involves both eyes. And because part of the retina is never used fully, that part will become amblyopic and the vision will not achieve 20/20 even with the best correction.

Strabismic: In this type, the eye positions are not aligned or coordinated, so the less dominating eye becomes disused or suppressed on order of the brain. This eye then becomes amblyopic.

A “lazy” eye therefore is not an eye that does not want to contribute but rather it is prevented from doing so.

The treatment of amblyopia is really to force the amblyopic eye to see, by means of patching of the good eye, or by using atropine eyedrops to reduce the usage of the good eye. The earlier the treatment starts, the better the outcome.

The major problem with patching is the children’s resistance often from discomfort or teasing from their peers. Compliance using the atropine drops (once a day) is certainly easier and in fact the results are as good as that with eye patching. This was supported by a recent clinical study comparing these two methods: The improvement was 3.7 lines (on the visual acuity chart) in the patching group and 3.6 lines in the atropine group. And about half of each group can achieve a visual acuity of 20/25 or better.

So these are the two choices, both equally effective. Amblyopia in fact should not remain untreated. Unfortunately, we still see these cases from time to time.

3.2.3 Young-old eyes

"Tear flooded his young, old eyes..." (Calvin's Stones, Magnetic Poetry's Journal, Jan 4, 2006)

Unfortunately in the young eyes, we can find older people's problems, e.g., cataract and glaucoma. Congenital cataract and congenital glaucoma, that is. By far, these are the two major congenital anomalies of the eye.

There are inherent difficulties in examining the eyes of a tiny infant. A good example is the visual acuity which cannot be assessed accurately. Yet another is the measurement of the intraocular pressure. And often sedation is needed in order to perform a complete exam, and which often must be done in an OR setting. Refraction, on the other hand, can be done with trial-lens retinoscopy or a hand-held auto-refractor. The latter, however, is less useful if nystagmus is present. And contact lens fitting naturally requires full parental participation. Routine interactive tests, e.g., subjective refraction and visual field testing must be postponed until much later for obvious reasons.

Congenital cataract is diagnosed at birth or it can develop soon after. In 1/3 of the cases, cataract is present in only one eye. If in both eyes, then 23% of the patients have a family history in an autosomal dominant pattern. This type of congenital cataracts is frequently associated with metabolic/systemic diseases (e.g., hypolycemia, trisomy, and myotonic dystrophy). Some congenital cataracts are a result of infection in-utero, most commonly from rubella; although it can also be from a host of others including rubeola, chicken pox, cytomegalovirus, herpes simplex/zoster, poliomyelitis, influenza, Epstein-Barr virus, syphilis, and toxoplasmosis. In under-developed countries, it can be from poisons in the drinking water contaminated by industrial wastes.

Because of the early presentation, if the opacity obstructs vision and left untreated, amblyopia can develop in the affected eye, and permanent vision loss if both eyes are cataractous. The usual guideline is if the opacity is 3mm or greater and located in the path of the visual axis, then the lens must be extracted. Smaller opacities do not necessarily cause vision issues. They are often discovered by chance during an adulthood routine eye exam, to the patient's greatest surprise.

Congenital glaucoma is also present at birth; although most cases are detected during early infancy/childhood. It is caused by a malformation in the fluid drainage channels, known as the trabecular meshwork, in the eye. Very rarely it is hereditary; although it won't be surprising if some cases are. It can affect only one eye; however, in 70% of the cases, both eyes. And more in boys (65%). The increase in the intraocular pressure from fluid build-up can rupture the corneal endothelium causing entry of water into the cornea. And the eye itself enlarges in size as well. Like glaucoma in the adults, the retina can be permanently damaged.

Congenital glaucoma is treated with surgical creation of a drainage pathway. Often multiple surgeries are needed to finally stablize the intraocular pressure. As you can imagine, this requires the expertise of a pediatric ophthalmologist specializing in congenital glaucoma. A video from the University of Iowa demonstrating trabeculotomy is shown below:

http://webeye.ophth.uiowa.edu/eyeforum/cases/case42-Primary-Congenital-
Glaucoma-(Infantile-Glaucoma).htm

The eye is of course only a small part of the body which, while still in the developmental stage in the uterus, is subject to all sorts of assaults. Proper prenatal care, a healthy pregnancy, and full-term birth, can certainly go a long way towards avoiding all congenital diseases, not just cataract and glaucoma.

3.2.2 ROP

ROP, or retinopathy of prematurity, surprisingly is still quite prevalent. In older ophthalmology textbooks, ROP was referred to as retrolental fibroplasia and the cause was traced to excessive oxygen in the incubator. This occurred in the 1940s and 50s and was thought to be under control. However, with the recent advent of in-vitro fertilization and fertility drugs based on follicle-stimulating hormone and luteinizing hormone, multiple births have become relatively common. And with that, an increase of preemies. We often see on TV evening news, palm-sized infants inside the incubators with beaming parents looking on. While all lives must be celebrated, often unreported is a multitude of complications from pre-term births. The surviving babies often face a lifetime of health problems. And one of the problems is ROP.

In this day and age, excess oxygen in the incubator is no longer an issue, which is very carefully monitored. However, the development of the retina in pre-term babies is incomplete and for some reason, further development outside the womb is met with confusion. Often the blood vessels, reaching from the optic nerve to the peripheral retina, become fibrous that can pull off the retina (see the video below).

(Courtesy of National Eye Institute, NIH)

ROP is divided into 5 stages of increasing severity. Stage 5 is the most advanced that usually involves total retinal detachment. The video above illustrates such a case.

The treatment of ROP is essentially a repair, using laser, cryotherapy, or open-sky vitrectomy. We favor the more efficacious open-sky procedure in which the cornea is opened and the crystalline lens removed to expose the rest of the eye to the sky. Then the fibrous tissues are removed and the retina re-attached. The resulting aphakia, unlike that of the age-related cataract, is corrected with a contact lens first, then an IOL later in life. The visual acuity is usually quite good, often in the 20/40 - 20/60 range.

To avoid ROP and related health problems, perhaps higher-order births should be discouraged. Certainly multiple births should be managed by OBs and pediatric nurses with specialty training. They must not yet be treated as normal births.

3.2.1 Stargardt et al

There are several frequently encountered hereditary eye diseases. Most of them are autosomal recessive, i.e., both parents are carriers. They include Stargardt's Disease, Usher Syndrome, and Leber's Congenital Amaurosis (LCA), among others. Still another common occurrence is retinoblastoma, caused by a deletion of the tumor suppressor gene Rb. Rb codes for a protein crucial in the regulation of the cell cycle.

These diseases each affects a different tissue of the eye:

Stargardt's disease can be regarded as juvenile macular degeneration. Similar to AMD, the end result is a dense central scotoma. And the gene culprit is abca4. The starting age of Stargardt's is usually around adolescence. Fortunately, these patients will never lose vision entirely. Their central vision may decrease to around 20/100 - 20/400, the peripheral vision is still quite normal. So proper optical aids can be of tremendous help to these children.

Usher Syndrome involves a form of retinitis pigmentosa, together with deafness. There are three types from the most severe USH1, to less severe USH2, and more moderate USH3. So far 12 loci are known to cause Usher Syndrome and seven of them and their proteins also have been identified. For your info: Genes for USH1 are MY07A, USH1C, CDH23, PCDH15, and SANS; for USH2: USH2A; and for USH3: USH3A. It is important to differentiate the types for counseling purposes. For example, USH1 patients with profound deafness will need to learn Braille prior to age 10 before their vision totally deteriorates.

Another of the worst possible cases is LCA, in which, there is no detectable photoreceptor activity at all. And the disease usually starts at birth or during early infancy. There are now 11 types identified, each associated with a mutation. And 14 genes are now known to be involved. There is a bright side: More recently, clinical trials of gene therapy for LCA caused by mutations in the RPE65 have begun. This is based on previous successful animal studies (dogs with the same RPE65 mutations) and should be very promising. This may pave the way for future treatment of genetic eye diseases. We shall find out soon enough.

And retinoblastoma is a cancer of the pediatric eye caused by deletions or mutation of Rb in the q14 band of chromosome 13. There are two types, the first is the familial retinoblastoma, in which both copies of defective Rb are present (i.e., one from each parent). There is another, unilateral retinoblastoma which is non-hereditary and not as severe; although no less cancerous. The treatment of retinoblastoma is similar to other cancers. Often the eyes must be removed to preserve life.

Here, I should point out that the practice of pediatric eyecare carries an enormous responsibility. Indeed, in all cases, accurate diagnosis is absolutely essential.

At present, not all clinics have access to PCR machines and the tests are quite costly as well. So genetic analysis is still not as widely available as it should. We hope this situation changes in the future. For now, by studying family history and examining symptoms, and signs, the latter through ophthalmoscopic observation, fundus photography, visual fields, etc, in conjunction with electrophysiological testing, such as ERG and VER, we can still draw very accurate road maps. Furthermore, in almost all cases with residual sights, the children can also be managed successfully through low-vision care.

3.1 Pediatrics

Some babies are born with eye problems. It seems unfair. Well, it is unfair because some problems are hereditary while others are induced in-utero or from premature birth. Fortunately, with loving parental care and societal support, most if not all grow up to be well-adjusted boys and girls.

In every nation, there are schools for the blind. While some pupils indeed were born blind and require special education, many others simply need powerful optical aids such as magnifiers and telescopes to carry on visual tasks. With gene therapy and electrode implants in the offing, even those with no vision at all may one day see again. We hope, in not so distant future, schools for the blind will all close for lack of students.

We will now discuss the etiology of more prevalent eye diseases that cause vision loss in the pediatric population, e.g.,
1. Hereditary
2. Prematurity
3. Infection and poison

And in a separate category, we will examine children with compromised binocularity:
1. Amblyopia (lazy eye)
2. Strabismus

In these cases, higher-order functions such as depth perception and stereopsis are lost. While not as debilitating as the vision loss, it is still a barrier for children aspiring to many professions that require binocularity, e.g., airline pilots. Early intervention is therefore crucial.

2.3.3 Retinal lurkers

A retinal exam of the aging eye often reveals lesions in the periphery. These are best appreciated with pictures than descriptions alone. The images shown here were captured with a scanner that permits a 200-degree view of the retina (in contrast, conventional fundus cameras allow only 30 degrees).

First, let us look at an absolutely normal retina. The image below is the right eye of a happy child. There is a certain sheen to it, i.e., wet-looking, which is lost in adults. Some landmarks: you can see the blood vessels coming out from one small oval area, known as the optic disc. To the left of the optic disc is the macula. And the rest is the whole retina. It looks like a well-tended garden, certainly a pristine landscape. After a few decades, things are bound to be different. If you see anything, either extra, missing, or changed, that can be bad news.
A few examples:

1. Peripheral chorioretinal atrophy: a "window" appears at 4 o'clock position from old chorioretinitis causing loss of retinal pigment epithelium. You can see through the opening at the blood vessels underneath. This is usually regarded as a scar. Sometimes it can be an active infection; typically more central that can threaten vision.

2. Lattice degeneration: On the left periphery, a long patch of retinal degeneration with potentially troublesome holes in it. The holes may need to be lasered/sealed to avoid retinal detachment.
3. More retinal degeneration in the periphery: A common type of degeneration in the aging eye, usually benign.
4. Melanoma: a small yet dangerous cancer in the peripheral retina (the dark spot in the 7 o'clock position).
5. Retinoschisis: This is not a retinal detachment, only a separation of retinal layers. It can, however, lead to retinal detachment.
6. Leber's aneurysm: Notice in the middle of the image a microaneurysm which can rupture and result in vitreous hemorrhage. In this case, the patient does have a family history of such a problem. Blood of course must be removed or the iron in hemoglobin can be toxic to the retina.
Take-home lesson: Even when the visual acuity is 20/20, danger can and does lurk in the far periphery of the retina.

2.3.2 ARMD

ARMD or AMD = age-related macular degeneration. This is a much dreaded eye disease in the elderlies in the US.

OK, some commonly thrown around numbers first: 10% of 66-74 and 30% of >75 year-olds will develop AMD, and 80% of which will be in the dry form (and the rest, the wet form). Quite a bit of research has been done on AMD, from risk factors to genetics to therapy. Here, we'll concentrate on prevention and treatment.

First, we need to make a diagnosis. Sometimes, patients are devastated by the diagnosis of AMD as they often associate it, incorrectly, with total blindness.

Usually what alerts the clinicians to AMD is the appearance of multiple drusens in the macular area. A lone one or two, located way out in the periphery, usually does not mean much except maybe an indication of high cholesterol. The image below is the fundus photo of a right eye. To the right, the oval structure is the optic disc, from it, arteries and veins originate and extend to arc above and below the macula.

Drusens are yellowish little round objects (see above, scattering in the macular region) that contain protein and fat, probably byproducts of the immune system. It is still a mystery what causes the production of drusens. They are found between the pigment epithelium and the choroid and seem to choke off the blood supply to the macula. As a result, this retinal area atrophied (this is the dry form). In some cases, new blood vessels are invited in, to re-supply oxygen. These blood vessels upset the integrity of the macular structure and often they leak (which can be assessed with fluorescein angiography)(this is the exudative, or the neovascular, but more commonly known as the wet form). In both cases, the macular function gradually deteriorates and is finally lost. And you now have a central scotoma. A video clip illustrating the evolution of a very dense scotoma is seen below (courtesy of NEI/NIH):

It should be noted that this video compresses years of gradual change into a few seconds. There are measures you can now take immediately upon diagnosis. On the prevention front, some clear evidence is beginning to emerge. In a study concluded in late 2007, the intake of lutein and zeaxanthin seems to reduce the risk of AMD. Foods containing these nutrients include Brussels sprouts, peas, corn, zucchini, broccoli, etc. And dark leafy greens are usually good sources. A daily dose of spinach is highly recommended.

An earlier study already has found a 25% reduction of risk in developing advanced AMD, through intake of vitamin C, vitamin E, vitamin A, and zinc - later modified to vitamins C and E, lutein, and zinc. There are now several OTC versions available. To be prudent, if you have a family history of AMD, it is a good idea to pay more specific attention to nutrition.

On the medical front, the introduction of anti-angiogenics (anti-VGEF monoclonal antibodies) has opened a small albeit important door to the treatment of wet AMD. Lucentis and its far less expensive generic form, Avastin have both been found efficacious in arresting and even limited reversal of AMD. They must be injected directly into the eye, however. Pain? Not too much.

Lucentis, in conjunction with photodynamic therapy (PDT) may even be more efficacious. Only time can tell. PDT is of course based on laser light activation of an intravenously adminstered dye, Visudyne, thereby destroying new blood vessels in the macular area.

All these require multiple treatments and the main goal is really to stablize not to significantly improve the residual vision.

And in the worse case, it is still possible to re-direct the light to retinal areas outside of the damaged macula, and the patient can regain some reading abilities. This is because a different area of the retina, outside of the scotoma, can be called upon to see. We have named these areas PRLs (Preferred Retinal Loci). A special instrument SLO (Scanning Laser Ophthalmoscope) is used to first identify the PRL. Reading materials are projected directly onto the PRL, and each patient’s reading rate is then measured. The results show that the average reading speed of patients with PRL of Area 1 (below the central scotoma) is significantly faster at 72 wpm (words per minute), than Area 2 (away from both the scotoma and the optic disc) at 62 wpm, and Area 3 (between the scotoma and the optic disc) at 31 wpm. In other words, inferior PRL (Area 1), especially that with an initial point of reading located inside the PRL but away from the scotoma, is the most optimal for reading. Based on these findings, by using the SLO to train the patients to use Area 1 for more efficient reading, it can greatly improve the patients’ quality of life.

2.3.1 Worn-and-torn retina

Again, the retina cannot regenerate. What this means is if an area in the retina is destroyed, that area is gone for good. You should know that the retina is not a single-layer structure. It has 7 layers (the photoreceptors count as one) as depicted in the following histology/diagram:

(from www.thalamus.wustl.edu/course/eye3.gif)

There are always minor local repairs, for example, the rhodopsin-containing discs in the photoreceptors are replaced as needed. High school biology did teach us that there are two types of photoreceptors, the cones for day and color vision, and the rods for night vision. The cones reside in the central retina in the posterior pole (i.e., the macula). The rods, in the rest of the retina. In terms of visual acuity, the central part, i.e., the fovea, usually achieves 20/20; out in the periphery, around 20/200.

If the rods are wiped out, as in retinitis pigmentosa, then you have only the central part working, like looking through a small tube (i.e., tunnel vision). This is a true case of night blindness. And if the macula is lost, then you end up with loss of the central field, known as the central scotoma. When you look at a person's face, the nose area is now missing. Loss of different parts of the retina from, e.g., glaucoma or diabetes, then you'll have corresponding loss of the visual fields. Remember this is part of the central nervous system, left is right and up is down. A loss of the upper retina, you lose the lower visual fields.

These are generally what happened with wear and tear. And the loss of retina/visual fields is permanent. Attempts to transplant the retina are not ready for prime time just yet, if ever. Transplant of retinal cells, stem cells, or in fact gene therapy may hold more promise.

You can see why mapping the visual fields is so important in managing retinal diseases. And this is also where low-vision care comes in, so that some sight can be restored.

2.2.4 "Other" cataracts

Besides the more common age-related and diabetic cataracts, there are other unique cataracts.

A major one is toxic cataract from, for example, long-term exposure to systemic or topical steroids. Typically, the opacities are located in the posterior subcapsular region, known as, what else, the posterior subcapsular cataract (PSC). Because PSC is situated right in front of the nodal point of the ocular optical system, in the daytime when the pupils constrict, the patient's vision is worse than that at night.

Then we have radiation cataracts from ocular/orbital exposure to excessive X-ray (both dental and medical), radiation therapy, cosmic rays (in airline pilots and maybe astronauts), infrared ("the glass blower's cataract"), and most important, ultraviolet (UV) from sunlight.

Epidemiological studies have confirmed the correlation between UV exposure and the prevalence of cataracts by investigating populations residing in different climates. More on these studies in the Public Health section (to be posted in the future).

2.2.3 Diabetic cataract

Yes, diabetes mellitus causes cataracts, among other things. It is a unique biochemical issue.

Now, open your biochemistry textbook to Glucose Metabolism. You'll see that in addition to glycolysis and hexose monophosphate shunt (HMPS), there is a little known "sorbitol pathway". It has only two steps/enzymes, aldose reductase (AR) and polyol dehydrogenase (PD). AR requires the cofactor NADPH to turn glucose into its alcohol, sorbitol. NADPH is generated by HMPS and is also needed by glutathione peroxidase. PD with the cofactor NAD converts sorbitol to fructose. And NAD is called for elsewhere in glycolysis. It is under the interaction of these pathways that diabetic cataractogenesis initiates. Here is the scenario:

AR has very high Km for glucose, so it'll become active when glucose level is high as in diabetes. Glucose is then converted to sorbitol which cannot leave the lens cell. It is also not metabolized by PD fast enough because of low PD levels in the lens. Sorbitol therefore accumulates and becomes an osmogen causing water to enter the cell. In fact, during the early stages, water vacuoles or small water-filled "bubbles" are seen in the lens cortex. At the same time, AR activation will have taken away NADPH also needed by glutathione peroxidase to detoxify lipid peroxides. Excess peroxides results in extra oxidative stress mentioned in the previous post. So we now have a double whammy situation. Clinically, diabetic patients do seem to develop age-related cataracts earlier than the non-diabetics.

An obvious strategy for treating diabetic cataract is to inhibit AR. And indeed several AR inhibitors have been developed; although none has become clinically practical. The main reason is the sperm utilizes the sorbitol pathway to produce fructose, its main energy substrate. A systemic use of AR inhibitors will have unintended consequences. Perhaps the topical route, as eyedrops, can achieve the same therapeutic purpose. Another way is to control blood glucose tightly. The advantage is protein glycosylation also can be avoided. This glycation is indexed by hemoglobin A1c. In fact, glycosylation also has been proposed to be a diabetic cataractogenic factor as a direct challenge to the sorbitol pathway theory. And in addition to glucose, fructose, fructose-3-phosphate and others also have been implicated. By monitoring both A1c and blood glucose levels, perhaps diabetic cataract can be prevented. At least in theory.

The glycation scenario, however, does not agree with the vision change in the diabetics, unless one argues that lens protein glycation is reversible. It also should be noted that the lens cell fibers do not turn over as the erythrocytes. Each new generation of the latter of course will have an A1c level representing the present not the past. In fact, there is currently no evidence of reversible lens protein glycation.

Cortical cataracts are unique in that they appear like spokes on a bicycle wheel, i.e., there are clear zones inbetween that behave as pinholes. Sometimes, with the pinhole effect, the patient's vision in each eye becomes quite good. However, with both eyes together in binocular coordination, the visual axis no longer passes through the pinholes, and the patient's vision is now blocked by the opacities, i.e., lost. Yet another possibility is the patient can see through two or more adjacent clear zones resulting in double or multiple vision but only with one eye, which is to be distinguished from the true binocular double vision (diplopia), usually the result of a neurological deficit.

There are other situations where a diabetic's vision can change. Chief among them is the fluctuating glucose level. High glucose causes increasing myopia because of glucose/sorbitol/water accumulation. Once controlled, the patient's refractive error will now become less myopic. This is when the patient declares, "I can see better with my old glasses." In a way, a shift towards more hyperopia (or less myopia) is an indication of a well-regulated and stable blood glucose level. A good sign in fact.

2.2.2 "Senile" cataracts

The term "senile cataract" has been banished from the lexicon of eye diseases, for PC reasons. Now it is "age-related cataract" and it still affects people over 60.

The lens nucleus would have received a lifetime of "insults" from various sources collectively known as the aging process. And from time to time, someone will report the discovery of a gene that can be turned on or off to alter the aging of, e.g., skin cells. Since lens fibers in the nucleus and deep cortex do not have any DNAs, so there is no such control. Cataracts, i.e., lens opacities, are seen primarily in the nucleus and the cortex, so it is a one-way aging street.

(from www.eyevet.info)

In the diagram above, opacities are shown in gray (and left=anterior and right=posterior of the lens; the posterior surface is more curved than the anterior). They are usually denoted as nuclear, supranuclear (lamellar), cortical, subcapsular (both anterior and posterior), and anterior polar (including pyramidal) cataracts. The last group is seen mostly in the pediatric population.

Age-related cataracts are predominantly nuclear with yellow to brown to black pigmentation and are frequently associated with other types of cataracts. The image below is a left eye with combination nuclear (the yellowish center) and cortical (the whitish off-center spokes) cataracts:

(courtesy of NEI/NIH)

Vision tends to vary with the extent of opacification. Typically, surgery is contemplated if the best correctable visual acuity is worse than 20/40. And the refractive error does change. Pure nuclear cataracts will require more minus power because of increasing myopia. In dense nuclear cataracts, the doctor cannot see in and the patient cannot see out. Surgery is the only recourse.

Now, we'll backup a little and examine what lens opacification really means and what leads up to it. Lens cells contain a large concentration of structural proteins known as the crystallins. In decreasing order of the molecular weight, we have the alpha-, beta-, and gamma-crystallins. Opacities are seen when these proteins aggregate and scatter light. It is much like the egg white going from clear to opaque when boiled - because of protein aggregation from heat denaturation. In the lens, it is the formation of disulfide bonds between cysteine moieties. The causative factor is therefore oxidation. In fact, the aging process has now been re-defined as that of oxidative stress - from, e.g., oxygen free-radicals. Indeed, when you are X-rayed, your body is actually oxidized in the macro sense. In the lens, the source of oxidation appears to be H2O2 in the aqueous humor and lipid hydroperoxides in the cells. (Some reported presence of superoxide dismutase in the lens that can remove the highly toxic superoxide.) Normally these compounds are removed by catalase and glutathione peroxidase; however, if these enzymes become inefficient for some reason (e.g., the peroxides are in overwhelming concentrations), then the sulfhydryl groups in the crystallins form disulfide bonds and the proteins aggregate.

The question of whether molecular chaperons, a role for alpha-crystallins, have failed to oversee protein unfolding and proper folding and re-folding has not met with definitive conclusion.

So, it would appear that by avoiding oxidation, one can escape from not only cataracts but also other tissue injuries. Of course that is not entirely possible. The alternative may indeed be ingestion of anti-oxidants that truly work. The question is which ones? There have been some retrospective epidemiological studies linking some vitamins and lower cataract incidences; however, large-scale clinical trials are yet to be done.

Medical therapy is not possible at present, it'll be like un-boiling the egg. In fact, if you can turn a hard-boiled egg back to its original form, then you'll have the first step towards cataract reversal. If then, you can also revive the cells, very quickly, you'd become wealthy beyond imagination, in more ways than one.

2.2.1 The crystalline lens

It is important to understand the biochemistry of the crystalline lens, so we know why cataracts develop and how to prevent them from happening or progressing. Even though cataract surgery is performed as a routine in all developed nations, it is in fact not widely available in less developed countries, simply because people cannot afford to pay for the procedure. The WHO estimates that age-related cataracts constitute 50% of blindness in the World and in 5-10% of people over age 50. And far more women than men are blinded unnecessarily because women live longer and are less likely than men to seek/undergo surgery. Poverty is such an overriding factor!! The key strategy is therefore prevention and inexpensive medical therapy, with surgery reserved as the last resort. And at the same time, no-frills surgery also must be developed, ORs built, and personnel trained.

The crystalline lens is a tiny structure, about 9.5mm in diameter and 4.5mm in thickness. On its front, there is one single layer of cuboidal epithelial cells and the ones in the equatorial region grow into cell fibers that form the cortex. The cortex then merges into adult/juvenile nucleus which overlays the original nucleus developed during the embryonic stage. The ends of cortical cell fibers join to form a Y and an inverted Y "suture" at the front and the back of the lens, respectively. This is why we see all stars (or any point source of light) with 6 points. And the whole epithelium-cortex-nucleus is enclosed in a collagen bag known as the capsule.

The lens actually is present before the immune system develops. That is why mature cataracts must be removed before proteins leak out, to avoid a severe immune response.

So there are two types of cells, the epithelial cells and the cortical/nuclear cell fibers; only the former contain both nuclei and mitochondria. This is a good thing, otherwise when bombarded constantly by ultraviolet rays, there maybe mutations that lead to unpleasant conditions such as tumor of the lens. And in fact, there is no such thing. Further, because the lens is located inside the eye globe, somewhat remote from any source of oxygen, except that dissolved in the aqueous humor, all cells metabolize glucose anaerobically. And the ATP expenditure is mostly for maintaining ionic/osmotic balance by keeping sodium out and potassium in. Any disturbance to ATP production/consumption will have undesirable effects. And one of them is the entry of excess water into the cells which then die.

On the other hand, accommodation, i.e., lens refocusing for near vision, does not seem to require energy. Well, the ATP kind, not the physics kinetic kind. It is a passive lens re-shaping from a change in tension of the zonules, which link lens equator to the ciliary muscle. In other words, near work per se probably does not contribute to energy-related cataract formation. So, relax and read on.

Now what could be the cataractogenic factors?