7.23 Singapore sling

Please, Singapore is pronounced Sin-ga-po', not Sin-ga-poah. And Singapore sling is a "mysteriously refreshing drink" in the tropical sun, not a run-of-the-mill cocktail at your local pub. There are many imitations, though. For DIYers, this one, from drinkmixer.com, is quite genuine:

1 oz gin
1/2 oz cherry brandy
4 oz pineapple juice
1/2 oz lime juice
1/4 oz Cointreau® orange liqueur
1/4 oz benedictine herbal liqueur
1/3 oz grenadine syrup
1 dash Angostura® bitters
Combine all in a shaker, fill with ice and shake until the shaker is well frosted. Strain into a tall glass and garnish with a slice of pineapple and cherry. No tiny umbrellas of course.

Better yet, go down to the Long Bar at Raffles Hotel, sit in the rattan wicker chair and have the sling with roasted-in-shell peanuts. You'll forget where you are.

Ah, but we do remember: Singapore is a prefect place to investigate the pattern of cataract formation. The Merlion City is sitting practically on the equator (1°N) with 12 hours each of day and night, with an annual temperature average of 26.7°C and a UV index of 10-13. These couldn't be good for the eyes? Yet, sunglasses and broad-rimmed hats are apparently not in fashion (see image below).

See, only one guy with sunglasses and none wears a hat.

The Merlion? Here-lah:

So, in a study on 550 Chinese Singaporeans of older than 50 years, only 26.1% are found without cataracts. More specifically, 47.3% of the 50-60 age group are without cataracts; although the rate drops down to 11.7% in the 60-70 group. And everybody has cataracts if older than 70.

Compared with a group of Japanese (884 participants) residing in Noto Peninsula - which has an average temperature of 21.3°C with 1/2 the UV radiation of S'pore - cataract prevalence in the 50-60 Singaporeans is similar to that of the 70-80 age group in Japan, i.e., a decade earlier. In addition, nuclear cataract prevalence in the 50-60 Singaporeans was 9 times higher than the same age group in Japan. One can argue that besides geography, there are differences in culture, e.g., diet, outdoor activities, etc that may also be contributing factors. The principal factors are, however, still ambient temperature and UV index.

In fact, in cooler places like Iceland, with an average temperature of 4.4°C and 1/5 of UV index of S'pore, 39% of 60-70 year-olds are still cataract-free (study population=993). If race is a major factor, then all Caucasians no matter where they live should have identical cataract prevalence. This is not the case: Melbourne residents in fact have higher cataract prevalence than Icelanders.

Further, the prevalence of nuclear cataracts in Sumatra, another high temperature locale, is similar to that of S'pore suggesting the high ambient temperature, not race is a major factor.

Does it really matter to have high cataract prevalence? It does from the viewpoint of loss of productivity and the costs for cataract extraction. It is much simpler to practice prevention - clearly a job for the eye doctors.

Have another sip and plan.

(A more detailed version of this post, written in Chinese, is available here.)

7.22 One, two, or three eyes

(Yang Jian, the 3-eyed god-general)

In Homer's Odyssey, Book 9, Mr Odysseus ran into Mr Polyphemus, a cyclops. The one-eyed giant ate a few of Odysseus's crew before losing his eye to Mr O's trickery. In Chinese mythology, The Investiture of the Gods (封神演義), Chapter 97, Yang Jian (楊戩) was born with three eyes; the third, sitting vertically on the forehead, can see beyond space and time.

While it is possible for a vertebrate embryo to develop only one eye, the three-eyed variety probably does not exist because this will require a fundamental re-structure of the cerebrum into three 1/3 brains. If we want to venture a guess, General Yang's third eye was most likely either a birthmark or a nevus that looked like an eye.

Cyclopes result from a problem with the prosencephalon which normally divides into right and left brains. Failing so, only one eye forms in the place where the nose is supposed to be. Cyclopes are mostly stillborns, so it was highly unusual for Polyphemus to even grow up, but then his Dad probably intervened (as far as life-support).

Actually, a close inspection reveals a complicated origin for each tissue in the eye. For those who for some reason must know, here is a quick summary:

Neuroectoderm: the retina, epithelium of the ciliary body/iris, and optic nerve
Surface ectoderm: the lens and corneal epithelium
The surrounding mesenchyme (neural crest origin): the sclera, the remainder of the cornea, the choroid, ciliary body/iris, and blood vessels

In the vertebrates, the development of the eye is through several invagination processes with precise timing. Any insults from microbes or toxins can of course cause mutations and congenital eye diseases. (See previous posts under Pediatrics.)

Here is something new and interesting: The development of the lens maybe controlled by the Six3 gene which in turn regulates Pax6, the master gene for eye development. The presence of gene product of Six3 does precede that of Pax6. In fact, problem with Six3 leads to holoprosencephaly. And the worse case? Yes, Mr Polyphemus the Cyclops and a kitten named Cy (see image below).

(Cy the kitten, the only living cyclops ever, even if for only one day - from cbsnews.com)

So Six3, in effect, initiates the whole cascade of gene activation in the development of the eye. We wonder why Poseidon did not see this coming.

7.21 Never say never?

(Warner Bros, 1983)

After years of education by sci-fi movies and TV shows, some members of the general public actually believe eye transplant is a reality. Well, it is not, not yet anyway. And is it just a pipe dream or shall we quote Mr James Bond, "Never say never again" in view of the tremendous progress in recent medical research?

If it is possible to transplant anything at all, the candidates must have been blinded by an incurable eye disease yet still with some residual, functional neural (visual) activity. And the procedures must of course subject to the IRB approval.

Now, let's review what the major obstacles may be, one scenario at a time - an FAQ of sorts:

1. Transplant the whole eyeball?

Sure, assuming we can keep the donor eyeballs alive, or more important, for the tissues, especially the cornea, lens, and the retina, to remain functional after transplant. The eyeballs must be kept at 0-4°C; although the best way is probably to connect the arteries, branching from the ophthalmic artery, to a miniature circulator using oxygenated artificial blood enriched with 5.5mM glucose, so that the ocular group of arteries can continue to supply and sustain tissue metabolism.

Now we come to the second problem: how to reconnect the optic nerve.

Picture an undersea fiberoptic cable that got severed during a major earthquake. Do you then retrieve the cable, and reconnect the many thousands of fibers one by one? No, you'd replace the entire section. The optic nerve has 1 million nerve fibers. And at present, there is no way of joining two damaged nerve fibers to make it one functional unit. Also, unlike the undersea cables, the optic nerve is not an isolated section with connectors at both ends, so you cannot replace the optic nerve itself.

Assuming you can somehow coax the nerve fibers to repair their cell membranes and join end to end, it probably won't be the whole 1 million fibers. Then it depends on how many are revived which will then determine the visual field size and the attainable visual acuity.

After all the above, the visual cortex will need to exercise all its plasticity to interpret the images, since it now receives signals from most definitely mis-wired optic nerve fibers. Whether this is possible is still anybody's guess.

Last but not least, the extraocular muscles must be re-attached so that the eye can move according to the direction of gaze. This is cosmetically important as well.

So, transplanting the whole eyeball seems a bit impractical, at least for now.

2. Transplant the retina?

OK. The full-thickness retina or just the photoreceptor layer? The whole retina or just the macula?

First, the retinal viability and the reconnection of "wires" (this time with the optic nerve) are both still the major obstacles. The image below is a whole mount retina specially stained for the retinal ganglion cell fibers (downloaded from webvision.med.utah.edu). You can see numerous fibers all converging toward the optic disc (the black "hole" in the center) and each one must be re-connected with its corresponding fiber in the optic nerve. Technically, with open-sky vitrectomy, perhaps the whole thickness retina/macula can be replaced in toto, but not the photoreceptor layer itself (remember it faces posteriorly the pigment epithelium) - it is simply a humanly impossible task.

Still a bit unrealistic, this retinal transplant deal. But then as in eye transplant, it may just be a matter of figuring out how to fuse nerve fibers through some clever means. And other innovations may then follow.

3. What about electronics?

Ah, now we enter the realm of practicality. A project led by Dr Eberhart Zrenner of Tübingen and Regensburg universities in Germany has implanted retinal chips in patients with retinitis pigmentosa (see image below - from The Economist, 7 June, 2007).

This chip is composed of 1,540 photodiodes which, when stimulated by light, send electric pulses to retinal ganglion cells and the excitation is transmitted all the way to the visual cortex. So now we have roughly 40 x 40 pixels that cover most of the visual field. The patients can differentiate black and white as well as some shapes. For some, this is already a huge difference.

For patients without a semi-functional eye, the alternative is to implant electrodes directly into the visual cortex. The electrodes are connected to a spectacle-mounted digital camera which functions as the eye. As with retinal chips, the resolution is quite low (around 15 x 16 pixels) and the patients can only "see" white dots on black background.

These artificial sensors no doubt will further improve so that the resolution may become high enough with little power requirement and that each implanted chip can last a lifetime. There are also attempts to teach other senses such as auditory and taste to receive and interpret electronic visual signals - with varying degrees of success.

The electronics are not a bad first step towards bionic vision - a popular notion ever since the debut of the "Six Million Dollar Man" series (ABC TV) in 1978.

4. Stem cells?

Yes, this can be very promising especially for replenishing photoreceptor cells lost to retinal degeneration. Previous attempts of directly injecting retinal cells from young rabbits into the adult rabbit eyes have produced intriguing results: There was incorporation of the photoreceptors in the the retina that formed "rosettes". Photoreceptors were present at the luminal side of the rosettes surrounded by layers corresponding to inner layers of the normal retina. So the transplanted retinal "bits" appear to have a natural tendency to self re-organize. Stem cells grown into retinal cells, when implanted, will most likely behave the same way.

The potential problems in stem cell transplants are surgical injury, tumor formation, and vector-mediated infection. These can be avoided as the transplant process evolves. The biggest hurdle in stem cell research seems political, at least at the present time.

5. No more gene therapy?

Not at all. In fact, this research is proceeding in great earnest. As previously posted, gene therapy has already been tested in Leber's congenital amaurosis (LCA) to correct a defective RPE65 gene. This project was carried out last year at University College London Institute of Ophthalmology and Moorfields Eye Hospital, led by Prof Robin Ali with Drs James Bainbridge and Tony Moore. If successful, it will no doubt lead and change the way of genetic eye disease treatment.

Hmm, James Bond maybe right after all.

7.20 Mr Sulu, take us home

(Star Trek IV, The Voyage Home, 1986)

You all remember the Star Trek movie, "The Wrath of Khan (1982)", in which Captain James Tiberius Kirk receives a pair of reading glasses as a birthday present from Dr Leonard (Bones) H McCoy. Kirk proceeds to lament rather unconvincingly the onslaught of old age. Presumably, by the 23rd Century, presbyopia has already been eradicated. Unfortunately, Capt Kirk is allergic to Retinax V - the medicine for treating Presbyopia, or "老花眼old blurry eyes" in Chinese and "老眼old eyes" in Japanese. The keyword: "old".

Funny the script did not follow the more creative vein as that for Captain Jean-Luc Picard who chooses to be bald (Ha!!) There is perhaps a lack of imagination on the screen writers' part. Because even now, there are invasive ways of manipulating presbyopia. Not that this is necessary, a pair of inexpensive OTC readers, bifocals including bifocal contacts, or monovision correction of various kinds (from LASIK to contact lenses, to spectacles) all can quickly resolve the issue.

Presbyopia is an age-related loss of crystalline lens deformability for focusing at near. This was described by Thomas Young (1773-1829) in 1793. To explain the process, he had invoked the elasticity theory. The Young's Modulus (stress = E x strain) is dependent on the material. In the case of accommodation, the lens capsule appears the candidate (see image below). Young's argument was that the capsule elasticity had diminished during aging. Indeed, recent measurements confirmed that the Modulus was about 6 × 10⁷ dyn/cm² in children which decreased to 3 × 10⁷ dyn/cm² at age 60, and to 1·5 × 10⁷ dyn/cm² in extreme old age. Similar to tired old rubber bands which cannot resume the original lengths when the tension is released.

(Lens capsule is the outer most layer which envelops the whole lens
- it is the faint band to the left (anterior to) the single-cell-layer epithelium in the above image)

That is not the whole story, though. There are three parts involved in the accommodation process (see below, 1-3):

(1: The zonules; 2: the crystalline lens; and 3: ciliary muscle)

The ciliary muscle must first contract to allow a decrease in the tension of the zonules, so the capsule can re-shape the lens. Does the ciliary muscle change with aging as well? Not the contractility. It appears the diameter of the ciliary muscle ring does decrease owing to a configurational change. The overall result is the zonules no longer have enough space to relax. And the weakened capsule also can no longer deform the lens as much as before. Did the lens diameter increase with aging also? Some say no; although the only way to make sure is to do a large-scale high-resolution MRI of the eye, because the lens is hiding behind the iris, inaccessible through optical means. The zonules? It is assumed, but never quantified, that the zonular fiber elasticity also changes with time.

Loose ends galore, indeed.

So, how can presbyopia be manipulated surgically? At least in theory, the ciliary muscle ring can be re-positioned to create more space for the zonules. This procedure has already been attempted; although the outcome is still unclear. Alternatively, Conductive Keratoplasty (CK), using radiofrequency to heat and shrink collagen fibers in the cornea, can be done. This to steepen the curvature of the appropriate area of the cornea, so that more plus power is produced for near tasks. CK takes about 3 min and is done to only one eye - a monovision correction as well. It seems to work for some, for a limited duration anyway (about 4-7 years). Interested parties are urged to consult their own eye doctors.

It's been 26 years since "The Wrath of Khan" and we still don't know the composition and the mechanism of effect of Retinax. Well, the sci-fi writers have already pointed the way, perhaps pharmacological researchers can now take us home - to a presbyopia-free world.

7.19 Headaches

(Skrik, 1893, Edvard Munch - from headaches?)

Headaches are an interesting clinical entity. They are quite common yet with very few outward signs useful for diagnosis (except maybe temporal arteritis, see below). Plus the potential causative factors are many. Of course, we are talking real serious headaches, not those from muscular tension or sinus congestion; both of which most people are well aware of and who can often self-treat.

Most times, headaches can be diagnosed based on chief complaints, for example, in migraine and cluster headaches. One of the migraine prodromes, the occurrence of auras is quite well-known. [Note, however, in ocular migraines, auras do not lead to headaches.] And cluster headaches can last quite a few days; the patients often need to rest/recuperate in a dark and quiet place.

Patients with persistent headaches who show up in an eye doctor's office, are often referrals from the PCPs. The purpose is see if any of these apply: athenopia, angle-closure glaucoma, temporal arteritis, pseudotumor cerebri, pituitary tumor, etc. The PCPs may also plan, in addition to a complete physical to rule out hypertension, migraines, etc, neurological and radiological consults to ensure absence of space-occupying or vascular lesions, hemorrhages in the brain, or even meningitis. It is a multi-disciplinary process of elimination that can therefore be quite time-consuming.

From an eye doctor's perspective, any patients with headaches are suspected of having one of the following until proven otherwise:

Beyond the routine headaches checklist (throbbing/sharp/dull, where, when, how long, how bad, how treated), the first exam is to see if asthenopia is a contributing factor. Asthenopia is simply headaches caused by eye strain or uncorrected refractive error. The strain can occur when the eyes are forced to constantly re-focus, further worsened by insufficient accommodative reserve - typically in progressive hyperopia and/or incipient presbyopia, and much less well-known, in uncorrected astigmatism. The patient's complain of pain is usually vague; although it mostly refers to heaviness in and around the eyes. The symptoms disappear as soon as the refractive error is properly corrected. A good example is to switch from spherical equivalent to toric contact lenses for a full astigmatism correction. And the accommodative lag or insufficiency is remedied by applying more plus (or less minus) power. Asthenopia is, however, never truly debilitating, nor is it sight- or life-threatening.

Often the patient with acute angle-closure glaucoma attack ends up in the ER department of a hospital. Because the symptoms can include headaches, nausea, and vomiting. During attacks, the eyes show steamy corneas with limbal flush and often a distorted pupil as well (see image below):

As in acute angle-closure, patients with chronic narrow-angle glaucoma often complain of "brow aches". The cause is a true increase of pressure in the eye that can be readily measured with a tonometer. At the slit-lamp, gonioscopy is also performed to assess the angle - to see if the aqueous drainage is dangerously obstructed. Both hypotensive agents and laser iridotomy maybe needed to normalize the IOP to get to the origin of this type of headaches and prevent the visual field loss.

Temporal arteritis usually afflicts the elderly. It is a manifestation of a systemic giant cell arteritis that can sometimes lead to death. Usually the inflamed temporal artery can be seen snaking under the skin (shown in image below). The temple area is quite tender, certainly sensitive to touch, and painful while chewing. The blood supply to the optic nerve and the retina also can be compromised, causing irreversible loss of vision. Definitive diagnosis is based on erythrocyte sedimentation rate (ESR) and temporal artery biopsy. The treatment of choice is naturally the use of systemic steroids which can reduce the inflammation rather quickly.

Then we have the pseudotumor cerebri. As the name indicates, this is not a real tumor inside the cranium, but an increase in intracranial pressure owing to the presence of excess cerebrospinal fluid (CSF). Usually the patient is a slightly over-weight woman of child-bearing age. Birth control pills, vitamin A, and tetracyclines are all risk factors. Because of the increase in the intracranial pressure as in hypertension, sometimes papilledema is seen (shown below). Papilledema is a swelling of the optic disc, so the disc margin is now raised and the demarcation blurred. These can be seen very easily with a hand-held ophthalmoscope.

Definitive diagnosis is lumbar puncture together with neuro-imaging, the latter to rule out brain tumor. There are other visual disturbances such as blurred vision and diplopia. In fact, these visual symptoms are the reason why the patients are referred to the eye doctors in the first place.

Speaking of brain tumor, pituitary adenomas that impinge upon the optic chiasm can cause bilateral hemifield loss. Which can be picked up by performing simple confrontation visual field tests. Definitive diagnosis is brain MRI. The MR image below is a T1-weighted coronal scan showing a large hyperintense area (arrows), i.e., the pituitary tumor.

Headaches are of course a prominent feature of pituitary adenoma. They also can be the only manifest, and to the surprise of many eye doctors, without involving any visual field loss. Needless to say, pituitary tumors must be removed (usually through the nose to reach the base of the brain where the pituitary gland is).

Diagnosis and treatment of headaches can be exciting and rewarding - particularly if a potentially sight- and/or life-threatening lesion is the root cause. Fortunately, most cases are benign, stress-induced variety.

7.18 Nip and tuck

(From pachealthholdings.com)

Cosmetic eye surgery has always been very popular. In Asia, for example, double-upper-lid surgery (see above) is a perennial ladies' favorite - for a more "spirited" look, allegedly. In the US, the low insurance reimbursement rates for other procedures have forced surgeons to seek additional sources of revenue. And medically unnecessary cosmetic surgery is paid out of pocket by the patients. It is therefore a perfect solution, especially if the surgical outcome meets the expectation of the patients. Botox injection to remove the wrinkles and thermo-lasers to re-surface the skin are now common place.

Medical necessity simply means whatever is "reasonable and necessary for the diagnosis or treatment of illness, injury, or to improve the function of a malformed body member" - according to Medicare. So the double-lid surgery cited above does not qualify. Also excluded is the "bags under the eyes" which are simply too common to merit any especial attention. They are essentially pockets of fatty tissues which can be removed and the skin tightened with the basic Z-plasty. Some of course opt for the procedure to look younger. Sometimes, however, the "bags" are from accumulation of fluids, as part of a general fluid retention, then the underlying problem(s) should be addressed instead.

There are many medically necessary cosmetic surgeries for the eye/orbit, usually performed by specially-trained hospital-based plastic surgeons. To name a few: ptosis repair, excision of cancer of the lid-margins, orbital decompression for Graves' Disease, patching of fractured orbital bones, prosthetics implants, reconstruction of facial deformity, repair of tear drainage system, and pterygium removal. This list probably should alert you that not all plastic surgeons are trained or qualified to operate on the eye and orbit.

A few examples of the eye plastics are presented below:

The most common procedure is probably that for repairing ptosis, i.e., drooping eyelids, that can interfere with vision.
In the case pictured above (notice also the bags under the eyes), clearly the visual field of the right eye is severely limited. The levator or Muller's muscle is therefore shortened to lift the upper lid. Ptosis can be bilateral. It can be congenital or acquired. The latter as a result of Cranial Nerve III palsy or myathenia gravis; both of which accompanied by double vision.

Very few people know how a prosthetic eye is fashioned. It actually requires the implant of a sphere made of porous polyethylene into the orbit to replace the enucleated eye - porous to allow migration of cells into it. Then the 4 straight rectus muscles are re-attached and the sphere covered with conjunctival tissue. After proper healing, an acrylic shell with the painted iris is then inserted (see image below).
The outcome is, without exception, quite striking. It is not uncommon for a novice eye doctor trying to examine the prosthetic eye, to the great bemusement of the patient.

Graves' disease, commonly known as hyperthyroidism, can cause enlargement of the extraocular muscles or increasing volume of the orbital fat (both within and without the EOM cone). This increase forces the eyeballs to bulge out - not only cosmetically undesirable but often the vision may be compromised. It is therefore necessary to decompress the orbit, by removing part of either the orbital bones or the fatty tissues, or both.

Very simplistically put, ocular/orbital plastics is practiced by very talented artists who happen to be skilled surgeons.

7.17 Wink, wink

("The Wink" - Seinfeld: Season 7, Episode 114, 12 Oct 1995)

The fans of the 1990s "a [TV] show about nothing" known as "Seinfeld" will readily recall "the Wink" episode. In which, a bit of grapefruit juice was accidentally squirted into George Costanza's left eye causing George to wink at inopportune moments.

First, a little info on first-aid: Any time when acid or alkali is splashed onto the eye, the most important first action is to rinse the open eye with copious amount of normal saline, or tap water if saline solution is not available. A few liter or more is generally needed. Then seek immediate medical attention so that the anterior structure of the eye can be preserved. Acid and alkali burns are different. Acid causes protein denaturation on contact. The denatured protein sometimes can form a barrier to prevent further acid erosion. On the other hand, alkali can penetrate deep into ocular tissues. Alkali burn is long-lasting and far more difficult to manage. In either case, saline/water rinsing is the crucial first step.

Back to "Seinfeld". The pH of grapefruit juice is around 3, mild in comparison to, e.g., HCl; although it does cause some discomfort for the eye. Tear fluid in the eye is poorly buffered yet its pH usually stays at a comfortable 7.4, until disturbed. George's winking or twitching, known as myokymia, is from acidic irritation to the nerve endings of the orbicularis oculi muscle in the lower eyelid (occasionally, the upper eyelid can be affected). Myokymia usually resolves itself. In very annoying cases, anti-histamine eyedrops can be used to slow down the muscle contraction. The best one Livostin unfortunately is no longer in production, probably lost out to Botox injection?

There is another uncontrollable winking, know as the Marcus-Gunn jaw-winking syndrome, in which the patient's eye (or eyes) twitches when chewing or suckling. In this case, there is a wiring problem: the eyelid levator muscle, instead of being innervated by a branch of Cranial Nerve III, is now by the motor branch of Cranial Nerve V. It can be regarded as a birth defect; although nothing untoward is involved.

More persistent and chronic twitching of the eyelids of both eyes is known as blepharospasm. It has been noted for years that blepharospasm seems to predate the onset of Parkinson's disease. Recent findings suggest that indeed if there is a lesion in substantia nigra, then Parkinson's eventually does develop. Others report that L-DOPA used to treat Parkinson's can cause blepharospasm. Sort of a lose-lose situation. Other possibilities include the usual suspects: fatigue, dry eye, stress, too much caffeine, etc.

Truly debilitating eye twitching involves half the face, i.e., hemifacial spasm or Meige's Syndrome, that can severely curtail both speech and eating. It is usually a result of inflammation of the facial nerve (Cranial Nerve VII), a sequela of Bell's palsy, or from a tumor or blood vessel pressing on the facial nerve. This can be treated with muscle relaxants, Botox injection, or neurosurgical repair.

Indeed, a wink is not quite just twitching of the eyelid.