- Part 4

One of the most difficult things in health care, both for patients and doctors, is dealing with diseases and conditions that have no treatment. The most common condition like this that I encounter is dry macular degeneration.

Last week The Lancet published a preliminary report from 2 studies using human embryonic stem cells (hESCs) for treatment of macular degeneration. The studies, from Steven Schwartz at UCLA’s Jules Stein Eye Institute, are funded and partially run by a private company, Advanced Cell Technology. They are the first human trials using transplanted hESCs for macular disease.

Stem cells are cells that have the ability to replicate and produce more stem cells, and have the ability to develop (or differentiate) into specialized types of cells. Stem cells can be found in embryos (human embryonic stem cells or hESCs), as well as adult bodies (somatic stem cells eg in bone marrow and umbilical blood). hESCs are more potent, in other words they are able to turn into a wider variety of specialized cells, which is why much research has been focussed on finding clinical applications for them.

In these studies stem cells were turned into retinal pigment epithelial (RPE) cells and then transplanted by injection into the patient’s eyes, under the retina, during a surgical procedure. Two patients have been treated so far. One patient has dry macular degeneration, the other has Stargardt Disease. In both patients the cells survived and persisted, there were no complications, and in one patient vision may have improved.

The main barriers to the use of hESCs are concerns about safety (the potential for teratoma formation, abnormal cell growth and rejection), and ethics (hESCs are derived from human embryos). This report is part of a series of trials to assess whether the technology is safe, and what treatment effect may be possible. So far the fact the stem cells can survive in the eye without causing problems makes the results very promising.

But apart from ethical concerns regarding the origin of hESCs, there is reason to question partial reporting of such preliminary results. This report is very early. Results from only 2 patients were reported, and according to ClinicalTrials.gov both these studies are still recruiting patients. The findings were reported on Tuesday, the day after their online publication, in the Business section of The New York Times, which also reported a 23% rise in Advanced Cell Technology’s share price. Although the investigators from UCLA declared no conflict of interest and retained full responsibility for the decision to publish the findings, the study’s sponsors were involved in every other aspect of the study. Is it possible that commercial considerations play a role in the decision to release very early data?

Nevertheless the study is ongoing, and these early results are very exciting, giving patients, families and doctors affected by these conditions reason to be hopeful.

The Australian campaign has obviously been very effective. The graphic photo of an eye with lids held apart with a speculum brings the message home, although the damage smoking does lies deeper, unseen in the photo, and half of Australia’s smokers still haven’t got the message.

Smoking is associated with a wide variety of eye diseases, both directly and through increasing the effects of a patient’s genetic susceptibility. The most important of these is macular degeneration (AMD). Smokers have 4 times the risk of non-smokers of developing the disease, and a smoker’s “second-hand” smoke increases the risk of family members developing AMD. There are a number of reasons for the increase in risk. Nicotine itself has been shown to cause over-expression of VEGF, a protein that stimulates new blood vessel proliferation, and has been shown to block PEDF, a protein that suppresses abnormal blood vessel proliferation. The proliferation of abnormal “new” blood vessels is what leads to the aggressive “wet” form of AMD. Tobacco smoke also reduces anti-oxidants, reducing the capacity of the macula to respond to toxic and other damage.

Cigarette smoke increases the risk of cataract development, dry eye syndrome, visual loss from thyroid eye disease, and recent studies have shown that it increases the risk and severity of ocular inflammation.

We need to encourage our smoking patients to quit for the sake of their eyesight, and support them when they try. The Federal government is currently fighting “big tobacco” in the high court, trying to get plain packaging through. Tobacco companies are worried about the loss of their brand identity. But to your eye, all cigarettes are branded the same.

Article: Steven D Schwartz et al. Embryonic stem cell trials for macular degeneration: a preliminary report, The Lancet, Available online 24 January 2012, ISSN 0140-6736, 10.1016/S0140-6736(12)60028-2.

2011 seems to me to have gone especially quickly, and to have been perhaps especially portentous. Devastating floods in Brisbane and south Queensland, tsunami in Japan, earthquake in New Zealand. The Arab Spring led to changes of government in Tunisia, Egypt and Libya, pledges of reform in Yemen, and is ongoing in several other countries. We need to wait and see where these developments lead.

It’s hard, if not impossible, to pick the most important development of 2011 for eye health. I’ve discussed some of them in this blog. One very exciting study that is ongoing, but which is due to be completed this month, is a trial of L-Dopa for vision improvement in Albinism, led by Dr Gail Summers at the University of Minnesota.

Albinism is a group of inherited conditions in which genes that control melanin pigment production are affected and don’t function normally. The most heavily pigmented tissues in the body are the skin, hair and eyes, and these tissues are affected in people with albinism to a greater or lesser extent.

In the eye, albinism leads to reduced pigment in the iris and choroid, failure of normal development of the macula, instability of gaze-holding (nystagmus), and abnormal optic nerve “wiring”. The result of these changes is reduced vision, particularly at distance, and many people with albinism are “legally blind”, or have severe visual impairment. So far treatment is really limited to optical and visual rehabilitation, correcting near- or far-sightedness with eyeglasses, skin and eye protection from the sun, and surgical realignment of strabismus.

L-Dopa (or levodopa) is a precursor molecule for the neurotransmitters dopamine, noradrenaline and adrenaline. It is used in the treatment of Parkinson’s Disease and has been trialled in the past, without success, in the treatment of amblyopia. The rationale for its use in Professor Summer’s study is that providing levodopa to the retina of a patient with albinism may lead to increased melanin production, and improved vision.

I’m very excited about the possibility that we may be able to offer hope of improvement in vision to people with albinism, and I will be waiting to see where these developments lead.

Many diseases that affect the health of the body as a whole can damage the eyes or cause changes in the eyes that doctors and optometrists can detect. The best known of these are probably diabetes and high blood pressure, but there are others.

One that is often overlooked is xanthelasma (plural xanthelasmata). Some people are prone to develop small yellowish lumps on the skin of the eyelids that are due to the accumulation of cholesterol (photo). They are known to occur in people with high blood cholesterol (hypercholesterolemia or hyperlipidemia), but also occur in people whose cholesterol levels are normal. If a patient’s cholesterol level is normal then xanthelasmata have usually been considered a cosmetic blemish only, that are easy to treat by excision. The true importance of them has been unclear until now.

A major study from Denmark published last month in the British Medical Journal (BMJ) showed that whether or not a patient’s cholesterol level was high, having xanthelasmata was associated with an increased risk of ischemic heart disease and heart attack, severe atherosclerosis and death. 12,745 people were followed from 1976-8 until 2009 (the average follow-up time was 22 years), making this the largest study so far to look at this issue.

The explanation for why xanthelasma is an independent risk factor for atherosclerosis and heart disease is not clear, but it is likely that people with xanthelasma have a greater tendency to deposit cholesterol in tissues of the body than people without them, regardless of the actual level of cholesterol in the blood. People with xanthelasmata may benefit from lifestyle changes to reduce other cardiovascular risks, and may benefit from treatment to lower so-called “bad” cholesterol (low density lipoprotein or LDL).

Xanthelasma is easily diagnosed without special equipment, so it doesn’t need a visit to an optometrist or ophthalmologist, but we now know that when GPs, optometrists, ophthalmologists or dermatologists notice it, it’s significance is more than skin-deep.

(M Christofferson et al. Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study. BMJ 2011; 343.)

Around 1.7 million Australians have diabetes, and almost 6000 children under 14 have type 1 diabetes. Half of Australia’s diabetics probably don’t know they have it.

Diabetes is a group of metabolic diseases that have in common abnormal blood glucose control. Glucose is the body’s energy currency. The energy we absorb from the protein, carbohydrate and fats that we eat is converted to glucose for transport around the body. Some of this is used immediately, some of it is stored in muscle or the liver as glycogen, and some is stored as fat. The distribution of glucose to the cells of the body is regulated by the hormone insulin, so that the concentration of glucose in the blood is normally pretty finely tuned. In diabetes the body either doesn’t produce enough insulin, or the cells respond poorly to insulin, so that the level of glucose in the blood is too high.

Long-term high glucose concentrations in the blood can lead to kidney disease and renal failure, peripheral nerve damage and non-healing foot ulcers, cardiovascular disease with heart attack and stroke, and blindness from diabetic retinopathy. In diabetic retinopathy high blood glucose can cause some blood vessels in the retina (the delicate “seeing” tissue in the eye) to leak, leading to swelling and reduced central vision, and it can cause some vessels to close off, starving the retina of oxygen. The retina responds by creating new blood vessels, but the new vessels are abnormal and can bleed and scar, leading to retinal detachment and blindness.

A land-mark study published almost 20 years ago in the New England Journal of Medicine, “The Diabetes Control and Complications Trial” (DCCT), showed clearly that tight control of blood glucose can reduce the risk of complications of diabetes, especially diabetic retinopathy. But tight control is a balance between keeping glucose low enough to prevent damage, and high enough so that the body has the glucose it needs to function.

Diabetes Australia is a not-for-profit organization dedicated to supporting people with diabetes, and supporting the scientists and doctors involved in diabetes research. Much research is focussed on improving management of diabetes, and looking for a cure, and this needs ongoing funding. But raising community awareness, ensuring that the half of diabetics who don’t know they have it can get diagnosed and treated, and advocating for the lifestyle changes that may help some people avoid diabetes is also a big job, and a vital one.

The Wilson HTM Brisbane to the Gold Coast Cycle Challenge (http://b2gc.bq.org.au/) is raising money and attention for Diabetes Australia – Queensland and the Heart Foundation. I’ll be riding with a team from Queensland Eye Hospital. Please join us or consider making a donation to Diabetes Australia (https://www.diabetesaustralia.com.au/Donate/) or the Heart Foundation.

The Lions Clubs have had a long tradition of supporting eye care. I have been very grateful to the Aspley Lions Club in particular for their support in the development and implementation of our Telemedicine program for Retinopathy of Prematurity screening at the Mater Mothers Hospital.

One Lions project I’d like to draw attention to is Recycle for Sight. This is a project that collects used spectacles and sunglasses and then distributes them to people in need, especially to children in developing countries. Over the last 15 years the project has delivered 2.5 million pairs of glasses to countries in Africa, Europe, Middle East, Asia and the Pacific.

The program helps not only the people receiving glasses, but those involved in the project. It depends not only on general volunteers, but also on people under Community Service Orders, trainees under Work for the Dole, and people with Mutual Obligation requirements. They have centres in the Helena Jones Half Way House (for women reintegrating into the Community) and Numinbah Women’s Correctional Institution.

At Northside Eye Specialists we have a collection box for used spectacles and sunglasses, and we are pleased to contribute to the program by forwarding these to Lions Recycle for Sight.

People often ask me why they need a current referral to see an ophthalmologist. The bureaucratic answer is that without a referral you can’t access the medicare rebate, but this may actually be the least important reason. Many people find it hard to remember details of their medical history, or their current (and past) medications. And it may not be immediately obvious which of these details are significant for their eye health.

This was brought home to me the other day when I performed cataract surgery on someone who had been taking Tamsulosin. He hadn’t recalled this medication when I’d talked to him, but thankfully it was recorded on his referral.

Tamsulosin, available in Australia as Flowmaxtra (CSL), is used to treat Benign Prostatic Hyperplasia (BPH), a condition that affects middle aged and older men by causing urinary hesitancy, painful urination, and even urinary retention. What could this possibly have to do with cataracts? Well, Flowmaxtra can cause the iris to behave oddly during cataract surgery, sometimes with catastrophic consequences, in what is known as the “intraoperative floppy iris syndrome” (IFIS). IFIS can lead to serious sight-threatening complications because cataract surgery is technically complex, and each subsequent step depends on the success of the previous step. A population-based study performed two years ago in Canada, which included all men over 66 that had cataract surgery in Ontario over a 5-year period, found that complications occurred more than twice as often in men using Tamsulosin. More than 50 000 scripts are written for it annually in Australia.

The American Society of Cataract and Refractive Surgery (ASCRS), which I belong to, has tried to encourage GPs and Urologists to consider other medications for BPH, or to refer prospective patients for an eye examination so that if necessary their cataracts can be removed prior to starting the drug.

But the most important thing is that the ophthalmologist be aware if a patient with cataracts uses Flowmaxtra. The good news is that if the ophthalmologist knows a patient is using Flowmaxtra, steps can be taken to avoid or limit the risks associated with IFIS. And this is a great reason to have a current referral.

(CM Bell et al. Association Between Tamsulosin and Serious Ophthalmic Adverse Events in Older Men Following Cataract Surgery. JAMA 2009; 301(19): 1991-1996.)

Multiple Sclerosis (MS) is an inflammatory disease in which a person’s immune system attacks their central nervous system. It most commonly affects young people, with an average age at diagnosis of just 30 years. There is no cure, and it can cause progressive neurological deterioration, affecting mobility, vision and sometimes cognition. About 20,000 Australians have MS.

People with the first signs of MS frequently come to the attention of an optometrist, or an ophthalmologist like me, because one of the more common initial symptoms is loss of vision or blurring of vision due to optic neuritis. Overall, around half of people with MS experience an episode of optic neuritis at some point, and half of people experiencing optic neuritis for the first time will go on to develop MS. Other visual symptoms, such as double vision, can also occur, though this happens less commonly. Patients with MS need to have their care guided by a neurologist, although physiotherapists, occupational therapists and other heath care professionals often need to be involved as well.

Since I was a medical student the management of MS has changed dramatically, and continues to do so. One aspect of this change is the development of new drugs, the so-called “Disease-Modifying Drugs” (DMDs), which have made a huge advance in the outlook for patients with MS. Recently in Australia a number of oral DMDs (eg Cladribine and Fingolimod) have been approved by the Therapeutic Goods Administration (TGA). MS is a multifactorial disease, and people with MS have different stages, different symptoms and different responses to medications, so the role of some of the newer medications is not yet clear. In particular, the balance between risk and benefits is still being assessed. But the quantity and quality of research into this condition is hopeful.

Another aspect of the change in MS management is increased public awareness, in particular an increased awareness of the special needs of younger patients with complex and changing neurological problems. Organizations like MS Australia and youngcare are at the vanguard of this increasing awareness and action.

These organizations deserve our support. The annual “Brissie to the Bay” bike ride is run in support of MS Australia – QLD and the Queensland Eye Hospital is supporting this event by posting a team. I’m riding out with them; hopefully I’ll be riding back too. I urge everyone to consider joining the ride or donating to either MS Australia – QLD or youngcare, or both!

Last week the New England Journal of Medicine published the study eye care professionals have long been waiting for, comparing treatments for macular degeneration (AMD). The CATT study (“Comparison of Age-Related Macular Degeneration Treatments Trials”) was funded by the American National Eye Institute (NEI) to compare Lucentis and Avastin head-to-head in the treatment of AMD.

AMD is the leading cause of blindness in Australia and affects 1 in 7 people over 50. The most aggressive form, “wet” AMD, was for years effectively untreatable, until Lucentis was developed. Lucentis is a monoclonal antibody fragment (Fab) that binds to a protein called VEGF. We need VEGF to produce new blood vessels in the body, but when it is over-produced it can cause diseases such as AMD, proliferative diabetic retinopathy and retinopathy of prematurity. While ophthalmologists were waiting for the FDA (the US regulatory body controlling medicines) to approve Lucentis, they began using Avastin, a Fab that comes from the same parent molecule as Lucentis, and which is usually used in cancer treatment. They found it worked very well for AMD.

Most ophthalmologists have long believed that Avastin is as good as Lucentis for treating AMD, and it is considerably cheaper (US$50 compared to US$2000 per dose), but since Lucentis gained approval and PBS listing in Australia it has been far more widely prescribed. Avastin remains unapproved for AMD and in Australia its ophthalmic use is limited to management of diabetic retinopathy and retinal vein occlusion, and in public hospitals where PBS benefits don’t apply. The makers of Lucentis insist that Lucentis is better, although a year’s treatment with Lucentis costs more than US$20,000 and a year’s treatment with Avastin costs around US$400.

Wouldn’t you think that the makers of Avastin would try and show that it is equally good and seek to have it approved for use in AMD? Well, here’s the problem: Lucentis and Avastin were both developed by Genentech (based in San Francisco but now owned by Swiss giant Roche), although Lucentis is sold in Australia by Novartis. Since Genentech spent US$1.2 billion developing Lucentis, it is simply not in their interests to encourage the use of a drug that costs 40 times less. When Avastin is used in cancer treatment much larger doses are given, and Genentech already earns around US$2.5 billion annually from its sale.

So it has been left to the publicly-funded NEI to produce the first good randomised controlled trial (RCT) of Lucentis v Avastin, the CATT. It’s a very well designed study that recruited 1208 patients, and compared the two drugs across two regimens. They came out equal in their ability to treat AMD and restore or maintain vision. There were slightly more hospitalizations in the Avastin patients (24% compared to 19%), and this needs more study.

Both drugs work very well in the management of “wet” AMD, and have revolutionized the treatment of patients with this debilitating disease. We now know that they are equally good. But the importance of this study also extends to the public health sphere, where politicians and health bureaucrats need to try to do more and more with less and less. There were almost 130,000 scripts for Lucentis dispensed in Australia in 2010, costing the Australian taxpayer more than $220 million through the PBS subsidy. If the same patients were treated with Avastin, an additional $214 million dollars would have been available for other health problems. Perhaps for disability support services, mental health, or indigenous eye care?

It also brings into sharp focus the complex nature of our relationship with the pharmaceutical industry, whether as doctors, optometrists or patients. We need the industry to invest in Research & Development, and the industry needs to be able to realize a profit to justify that initial investment, or new drug development will decline. But we can’t always rely on the industry to deliver value, and conflicts of interest can occur. We need to be aware that pharmaceutical companies are still primarily answerable to their shareholders, not to their customers, our patients.

(Article citation: The CATT Research Group. Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration. N Engl J Med. 2011 Apr 28. [Epub ahead of print])

After last night’s “A Current Affair” story about laser cataract surgery I expect to be fielding a lot of questions next week.

The program, which was heavily promoted using a “sixty second surgery” sound bite, reported the use of Alcon’s LenSx femtosecond laser for cataract surgery in Sydney.

The ACA website promo says:

“Cataract eye surgery is one of the most successful procedures in medicine, but imagine if the same procedure took a painless 60 seconds. A revolutionary new machine has just arrived in Australia to restore vision, which offers a non-invasive procedure and remarkable results with no pain.“

Well, you need to keep using your imagination.

The story was misleading for a number of reasons. There has been no change in pain control, which remains excellent, and cataract surgery does not now take 60 seconds. In fact, using the new laser actually takes longer because patients having femto cataract surgery are essentially having two procedures. First, they have the laser procedure in the laser room, which replaces the initial difficult but relatively brief part of the current standard operation. Then, because the laser doesn’t actually remove the cataract, they are moved to the operating theatre, where the cataract is removed and the lens implant inserted. This second part remains essentially unchanged. The surgeon that was featured used a machine that has been around for 7 years to remove the cataract, and as you could see it still works very well.

Does the new laser make the procedure safer, as the ACA surgeon said? Well, it might. And that’s as far as you can go at present. There is simply no evidence yet that femto surgery is safer. There have been about a thousand cataract operations using the femtosecond laser worldwide, and as the infection rate using the current standard technique is less than 1/1000 we are nowhere near seeing the numbers required to compare one technique to another. The marketers tell us that the wounds created are more precise than those made with a knife, and that this will lead to reduced wound leakage. Since wound leakage is a risk factor for infection, they suggest that the infection risk will be lower. Is there any evidence to support this? Not yet. It is speculation.

As I said in my previous blog the new technology is certainly very exciting. So far it looks like the main benefit will be more accurate lens position, and this may mean less patients needing distance glasses after surgery. It may have the power to make a wonderful, miraculous operation even better. But we need to be very careful of crafty spin.

The American Society of Cataract and Refractive Surgery (ASCRS) conference was in San Diego last week, and most of the hype and excitement was centred around Femtosecond Laser-Assisted Cataract Surgery. Although only one machine is in commercial use in the USA (the LenSx), the marketing drive is in full swing and this is set to continue, as three other companies are readying to launch their machines over the next 12 months (OptiMedica’s Catalys, Lensar, and Technolas Customlens from Germany). Alcon recently bought LenSx for more than $360 million, so it’s unsurprising that they’re trying to push home the advantage of being first on the market.

I went to an event in San Diego presented by Alcon in which a packed theatre was wowed with a laser light show before being shown videos of the femto in action, with commentary from five prominent American surgeons. Although only two of the five surgeons have the laser in their operating theatres and fewer than 1000 patients worldwide have had the surgery, the consensus was that this is the biggest advance in the safety and efficacy of cataract surgery to come around in 2 decades. Strong stuff. Are they right?

Well, it’s simply way too early to judge. Certainly, the technology in the femto systems is amazing. They can cut extremely precise wounds, and cut perfect repeatable circular openings in the 20-micron anterior lens capsule (capsulotomy) every time. This precision, greater than can be performed by any surgeon’s hands, may ultimately prove to improve visual outcomes, but so far there is no direct evidence that this is the case. Likewise, the implications for safety are all indirect and speculative, and unproven.

Femtosecond lasers were introduced into refractive surgery around 10 years ago. After a decade, they still haven’t supplanted steel blades for all patients or all surgeons, despite their stated benefits. It’s now recognized that in some settings they are safer and reduce complications, but that they also introduce different complications. Femto technology is not cheap to purchase (around $500 000 up front for the machine) or to use (companies charge a fee-per-use, known as a “click fee”), and they take significantly longer. All of this means that femto-assisted cataract surgery will be substantially more expensive than current state-of-the-art cataract surgery.

Will it be safer? In the hands of an experienced surgeon modern cataract surgery is amongst the safest medical interventions ever devised. It will take some time and a lot of data before anyone can say that the supposed advantages of femtosecond laser cataract surgery are real, rather than imagined. There is no femto cataract laser in Queensland yet. I’m looking forward to seeing more data on safety and efficacy, and to trialling the femto when it becomes available in Brisbane.

Dr Michael Forrest

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