Eye gene therapy

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The status of global research and future perspectives of the treatment

WHAT IS GENE THERAPY?

Gene therapy is a procedure that allows the transfer of genetic material (a functional copy of the gene) from a healthy cell to a diseased one, in order to treat a pathology in which one or more genes are absent or defective (mutated). As a consequence, first of all we need to identify the genes or set of genes that are responsible for the genetic disease itself. dna-animazione.gif

HOW DOES GENE THERAPY WORK?

In genetic diseases, gene therapy consists of replacing a defective gene inside the DNA of a cell with a functional gene, by using a viral vector (generally an adenovirus, or flu virus). Such vectors, which have been deactivated (unable to replicate themselves) and emptied of their genetic content in advance, are used as a “Trojan horse” to deliver the healthy gene(s). In this way, the functional copy of the gene(s) integrates into the genome of the diseased person and makes a sufficient quantity of one or more proteins, thus correcting the genetic defect at its source. This procedure is called “transfection”.

WHICH EYE DISEASES CAN BE TREATED WITH GENE THERAPY?

It’s first application in the ophthalmological field has been in the treatment of Leber’s congenital amaurosis, a severe hereditary disorder that is transmitted, in the majority of cases, in an autosomal recessive way: two parents who are both healthy carriers have a 25% chance of transmitting the disease to their children in each pregnancy.

However, the cases of autosomal dominant transmission are rare: in this case, the sole affected parent has a 50% chance to transmit the disease to their children.

Leber’s congenital amaurosis begins with the loss of vision in early childhood, followed by complete blindness at around 20-30 years of age. It could be caused by a mutation of the RPE65 gene, which is one of at least 19 genes that are responsible for the disease. This gene controls the production of an enzyme, which is responsible for the retinoid cycle that captures light. If the enzyme production is not correctly performed, retinal photoreceptors (cones and rods) run out of their stock and undergo a progressive degeneration until they loose their function.

Another experimental success has been achieved for choroideremia (a disease of the choroid, a vascular layer of the eye that feeds the retina through its blood vessels). On 16 January 2014, a large team of researchers published the results of a preliminary study conducted on six people, in the magazine The Lancet, which produced very encouraging results. During the experiments, an improvement of sight was achieved in all the treated patients, who were followed for six months after the injections – performed under the central area of the retina – through which the “diseased” genes had been replaced.

An important letter was published on Nature in 2018 by a team of researchers: 6 out of 14 people affected by choroideremia gained at least one line of vision on the optitype after subretinical injections cointaining the healthy genes.

WHICH TRIALS HAVE BEEN CARRIED OUT?

For Leber’s Congenital Amaurosis, a trial on animals was carried out initially, before a trial on 31 people was conducted between 2012 and 2015. This research – which was published on The Lancet in 2017 – produced positive results (7-9% of the cases) and in December of the same year a medicine (which is administered via subretinal injection) was approved by the FDA.

The healthy gene replaces the diseased gene: the RPE65 gene to be precise. The deactivated flu virus is used as a viral vector to introduce the healthy gene. This way, the production of an enzyme that restores the correct functioning of photoreceptors has been induced.

Moreover, an important study on choroideremia was published by the journal Nature in 2018, as previously mentioned.

HAVE THERE BEEN ANY OTHER TRIALS ON HUMANS?

Yes. In particular, trials have been carried out at Pennsylvania University and at the Children’s Hospital of Philadelphia (US), where half of the patients were no longer deemed legally blind after a single subretinal injection. The scientific results were published on The New England Journal of Medicine in 2008 and the following year on The Lancet.

To treat Leber’s congenital amaurosis, the “healthy” copy of the defective gene (the RPE65 gene, which synthesizes a protein that enters in the retinoid cycle and is essential for the correct functioning of the retina) must be injected under the retina. So far, functional vision tests have shown a partial vision recovery, particularly in younger patients. This result shows that the earlier gene therapy is administered, the greater the chance that a patient’s retina won’t deteriorate completely and will react positively to the treatment.

The retinal degeneration caused by Leber’s congenital amaurosis is related to the mutation of some 20 genes overall. For this reason, their role in the development of the disease should be evaluated. The University of Campania Luigi Vanvitelli (formerly known as the Second University of Naples) and TIGEM (Telethon) are also conducting fruitful research on Leber’s congenital amaurosis: not only children, but also patients aged 27-28 can read letters from a distance of 50 cm and are no longer considered legally blind.

Such improvement can be achieved in half of the cases. However, in 2015 a team of researchers showed that after three years, photoreceptors die with the same frequency both in treated and untreated retinas. Unfortunately a progressive loss of vision was detected in two people almost six years after the treatment, while the same problem had occurred to a third person after four years and a half.

In any case, long term results are not stable, at least according to The New England Journal of Medicine (2015).

CAN GENE THERAPY TREAT RETINITIS PIGMENTOSA?

At the time of writing, retinitis pigmentosa is considered an incurable disease. In the United States, researchers have carried out some studies on lab rats, by performing subretinal injections of healthy genes transported by nanoparticles. Such genes, once penetrated in the DNA of the retinal cells, replace the defective genes that cause retinitis. In this way, degeneration of essential photoreceptors for the central vision was slowed down in at least one specimen. This experimental research could have interesting developments for humans. The problem is that there are several forms of the disease and, overall, some 70 genes at least are involved, which cannot be fully corrected at present (only the RPE65 gene can be replaced, which could be decisive in only 1-2% of retinitis pigmentosa cases). [Scientific references: [The Lancet, Clinical Trials, Ophthalmology]] retinitepigmentosa-visione_1_-photospipd2adfccbc7188845549708a116b40997.jpg

CAN GENE THERAPY TREAT AGE-RELATED MACULAR DEGENERATION?

In principle, it could be possible but the therapy is only experimental and it is interesting mainly for the dry form of AMD (presently incurable). Researchers at Tufts University School of Medicine (USA) carried out a study that uses an enzyme, which allows the replacement of the diseased genes with healthy copies by cutting up the DNA. The enzyme in question is the PEG-POD. Once the healthy gene has been introduced, the enzyme acts like “molecular scissors” to cut the DNA up in the right places. The aim is to repair the genetic code of patients with age-related macular degeneration (AMD).

In February, 2019 an 80-year-old English woman with the atrophic form of the eye disease (dry AMD) reported being treated with gene therapy at the Oxford Eye Hospital: she is the first one of the 10 patients who are participating in an experimentation organized by the famous British university of Oxford that aims to block or at least slow down the evolution of the retinal degenerative disease (learn more).

However, further studies will be certainly needed and, at present, no therapy is available on a clinical level, but only experimental treatments are underway.

WHAT IS THE UTILITY OF GENE THERAPY?

amd-umida-fundus-2.jpgThe results of the first scientific experiments obtained by applying gene therapy lay the foundations for its application not only to retinal diseases existing from birth, but also to other more common retinal degenerations, such as age-related macular degeneration. In fact, the knowledge of the mechanisms at the origins of genetic diseases is fundamental to pave the way for new therapeutic strategies. In the case of ocular genetic diseases, in which a small number of genes are involved, gene therapy has produced extraordinary and encouraging results, even though further research is required for large-scale clinical application.

IS IT CURRENTLY POSSIBLE TO RECEIVE GENE THERAPY IN HOSPITAL?

At present, it is not a common occurrence. In recent years, researchers have been trying to overcome or contain the limits of gene therapy, namely the safety of the procedure, which is particularly delicate due to the use of viral vectors, the efficiency of the transfer and the possible immune reaction that can cause the elimination of the genetically modified cells, thus cancelling the effects of the gene therapy itself. Researchers are also trying to optimize gene transferring procedures and develop new therapeutic protocols for the treatment of several hereditary diseases. Surely, this is a “frontier” approach that appears to be very promising.

Stem cells

occhio con limbus

WHAT ARE STEM CELLS?

Stem cells are called “immature” because their main characteristic is that of being able to specialize, in other words, being able to become any tissue and organ of our body. Unfortunately not every tissue of the human body is provided with an area in which stem cells can be produced when we are adults, while at the initial stage of the embryo’s development, all tissue has the ability to produce stem cells. Stem cells can be metaphorically considered “baby cells” that potentially can regenerate countless parts of the body.

WHAT ARE THE DIFFERENT TYPES OF STEM CELLS?

There are 4 different types of stem cells:

  • totipotent: they can become any cell of the organism (muscular, nervous, etc.);
  • pluripotent: they can evolve in many cell types, but not in all;
  • multipotent: they only specialize in a certain type of cell (i.e. nerve cells);
  • unipotential: they only generate a certain type of cell (i.e cornea, liver, etc.)

Stem cells are also divided between somatic (improperly called “adult”: they are not yet specialized – they are multipotent – and are generally found among the cells in a specific tissue), and embryonic stem cells (early stages of development following fertilization).

HOW ARE STEM CELLS OBTAINED?

The embryo is the source of stem cells par excellence, but the study and use of embryonic stem cells is restricted for ethical reasons, even in countries where it is permitted. As the embryo develops, its cells specialize and loose their ability to transform into any type of cell. However, if you want to give an unborn child the possibility of having some “spare cells” (such as blood, muscular or nerve cells), there is at least the possibility of storing and preserving them freezing the umbilical cord (although there are a number of limits). Stems cells are also found in the amniotic fluid.

There is also the possibility of obtaining stem cells from adult cells; this technique, developed for the first time in Japan in 2006 (by the Nobel Prize winner for medicine, S.Yamanaka), requires “genetic reprogramming”. Some genes can be used to start a rejuvenation of the adult cell, which returns to the stem stage (as if going back in time); once this rejuvenation is started, the same genes that functioned as a “trigger” are removed from the DNA. Given the complexity of the procedure, some teams of researchers have been able to do without those genes, eliminating the risks associated with their use.

Reprogrammed stem cells (iPS) are pluripotent and represent an important frontier of regenerative medicine. In 2009 the University of Wisconsin-Madison published on PNAS the results of some research, which claimed that it was possible to transform adult skin cells into human retinal stem cells after appropriate genetic reprogramming. In the future, these rejuvenated cells will be able to, at least in principle, be used to repair the retina, which can be affected by degenerative diseases particularly in old age. However, at the time of writing, unfortunately this result has not yet been achieved.

In 2012 the Columbia University (U.S.) published a study in Molecular Medicine in which the researchers claimed to have improved the sight of blind test animals using human skin cells that had been reprogrammed (until they had become retinal stem cells).

In September 2017 an apparently very rigorous Chinese study was published on the use of embryonic stem cells in retinitis pigmentosa patients [Liu Y, Chen SJ, Li SY, Qu LH, Meng XH, Wang Y, Xu HW, Liang ZQ, Yin ZQ, “[Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients“, Stem Cell Res. Ther. 2017 Sep 29;8(1):209. doi: 10.1186/s13287-017-0661-8]]: the researchers claim to have succeeded, using appropriately treated stem cells conveyed through subretinal injections, to modestly improve their vision in blind mice (genetically modified).

ARE THERE STEM CELLS IN ADULTS?

Yes, stem cells can be obtained from an adult, for example, from the bone marrow (hematopoietic stem cells=blood cell producers), from the adipose tissue (fat) and from a series of specific areas dedicated to the production of stem cells themselves. Regarding the eyes, in particular, on the cornea there is a specific area called limbus (which has the shape of a ring and is located at the border between the transparent front part of the eye, i.e. the cornea, and the white part, i.e. the sclera).

Embryonic stem cells can be obtained by in vitro fertilization in the countries where it is permitted. The problem is that this technique has a precise time limit: up to 5 days from test tube fertilization. Alternatively, in some countries (such as Spain) it is possible to use supernumerary embryos, namely those that are not implanted in the uterus after artificial fertilization. If they are frozen they can “live” for a few years, representing a real stock of embryonic stem cells.

HOW DO STEM CELLS DEVELOP?


Let’s take into consideration the embryonic stem cells that are obtained from a fertilized embryo. These cells can divide and duplicate themselves for a long time, but without differentiation. Therefore, stem cells can generate embryonic germ layers even after being cultured for a virtually indefinite period of time. The 3 types of germ layers originating from stem cells are: ectoderm, mesoderm and endoderm. The ectoderm gives rise not only to the brain, the nerves of the spine and the other nerve cells, but also to the hair, skin and teeth, as well as to the sensory cells of the eye, ear, nose and mouth…The mesoderm, on the other hand, gives rise to the muscles, blood, blood vessels, connective tissue and the heart. Finally the endoderm gives rise to the pancreas, the stomach and the liver, to which the lungs and germ cells (ovules and spermatozoa) should be added.

WHAT POSSIBILITIES DO STEM CELLS OFFER?

On the one hand, it is possible to produce cells and tissues that can be implanted. On the other hand, the study of stem cells makes it possible to better understand the prevention and treatment of genetic disorders. Finally, toxicity tests for some medicines can also be performed more easily. There are many diseases that stem cells can help cure: from Parkinson’s to Alzheimer’s, from heart attacks to retinal damage.

According to the scientific journal Nature, “adult stem cells have already had clinical success, such as in bone-marrow transplantation for leukaemia treatment, growing new skin layers to treat burns and regenerating corneas”. There is also the potential for retinal regeneration, but at present, even in the U.S., it hasn’t been possible to achieve this ambitious result. Treatment proposals without effective scientific validation must never be taken into consideration.

WHAT ARE THE PROSPECTS FOR THE FUTURE?

Stem cells can not only give rise to any type of tissue, but in principle, could also allow us to “manufacture” an entire spare organ, which would not cause any form of rejection, being made of cells from the body of the person receiving it. In theory, many degenerative diseases could be treated in this way one day (potentially even retinal diseases). Stem cells are a virtually unlimited reserve of nerve cells, muscle cells, blood cells, etc.

ARE STEM CELLS A MIRACLE?

Probably, defining stem cells as a miracle today is an exaggeration as their clinical use is still very limited. However, if scientific research were to confirm all expectations, then their use would have really enormous potential, allowing the repair of tissues for which today there is no cure.

However, the British Medical Journal warns against therapies that go beyond official science as well as marketing sites and writes bluntly that “the marketing of unproven stem cell therapies has the potential to harm patients and to harm the reputation of stem cell science”. [Murdoch B, Zarzeczny A, Caulfield T, “[Exploiting science? A systematic analysis of complementary and alternative medicine clinic websites’ marketing of stem cell therapies“, BMJ Open. 2018 Feb 28;8(2):e019414. doi: 10.1136/bmjopen-2017-019414]] So you have to be careful about potential risks and even possible scams.

WHAT ARE THE RISKS?

A possible risk is that a tumour could be induced: the uncontrolled proliferation of stem cells can potentially cause cancer. Furthermore, we have to be careful of stem cells treatments that have not been validated by scientific results. There’s also the risk that reprogrammed adult stem cells may not work exactly like embryonic ones: they are almost the same, but not perfectly identical. For instance, heart cells do not coordinate with each other if they have been induced from adult cells, while their beat occurs in unison if they are developed from embryonic cells.

It cannot be ruled out that an experimental, non-approved stem cells treatment aimed at regenerating the retina, for example, could even cause blindness (this is what happened to three people in the U.S. while an attempt was being made to treat AMD) [Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL, “[Vision Loss after Intravitreal Injection of Autologous ‘Stem Cells’ for AMD“, N Engl J Med. 2017, Mar 16;376(11):1047-1053. doi: 10.1056/NEJMoa1609583]], while only in one case in Japan has stabilization been achieved with reprogrammed stem cells (Yamanaka S, Takahashi M et al., NEJM, 2016). At an ophthalmic level, only the use of corneal stem cells to regenerate the eye surface is currently permitted, while worldwide there is still no clinically approved treatment on human beings that leads to the recovery of sight after retinal damage through the use of stem cells.

IN WHICH CASES CAN STEMS CELLS BE USED FOR THE EYES?

With reference to the eyes, the use of stem cells mainly concerns the cornea (already possible) and the retina (not yet possible, as previously stated).

At the retinal level the first experiment on human beings was started in Japan in 2014, on a group of six visually impaired people suffering from AMD (the wet form of age-related macular degeneration that reduced their visual acuity to less then 1/10). Researchers had wished to recover about a tenth of the patients’ visual acuity in this way. The experimental protocol, which uses adult cells genetically reprogrammed back to the stem cell stage (iPS), was approved by the Japanese Ministry of Health in July 2013. In the trial, skin cells (fibroblasts) were “rejuvenated” by manipulating their DNA and then developed up to the stage of retinal cells (retinal pigmented epithelium).

However, this approach suffered a setback before the completion of the foreseen 3-year-period: in May 2015 the trial was temporarily suspended at the Riken Research Institute. [Ken Garber, “[RIKEN suspends first clinical trial involving induced pluripotent stem cells“, Nature Biotechnology 33, 890–891 (2015) doi:10.1038/nbt0915-890, Published online 08 September 2015]].

Furthermore, at the time of writing, a study involving people affected by the dry form of AMD and a retinal genetic disease (Stargardt’s maculopathy) is underway in the U.S. This experimental study, carried out using embryonic stem cells, has apparently produced encouraging results (regenerating the retina, at least partially, in more than half of the cases). However, such results have yet to be confirmed and their duration will have to be verified.

HOW DO CORNEAL STEM CELLS WORK?

The corneal limbus (the border of the cornea and the bulbar conjunctiva) is where natural corneal stem cells reside, which serve as a reserve for the regeneration and proliferation of the corneal epithelium. Epithelial stem cells have virtually unlimited potential for cell division. In fact, following stimulus from growth factors, these cells differentiate into ”transit-amplifying cells”, which then replicate and further differentiate until they reach a state of final maturation.

In a healthy subject, it is therefore evident that the presence of efficient stem cells at the corneal limbus level, allows the repair of corneal damage caused by traumatic, infectious and inflammatory phenomena of medium and mild degree. Unfortunately, when a disease or corneal trauma causes an alteration to limbal stem cells leading to a decrease in their number, there is a so-called deficit or limbal insufficiency: as a result, the cornea is no longer able to repair its surface epithelium, which could lead to serious complications that can jeopardize sight. In these cases, great progress has been made by scientific research in recent years: through limbal stem cell transplantations, the corneal epithelium has recovered its ability to regenerate, even if the results are not always satisfactory. However, stem cell transplantation alone does not lead to the recovery of a visual acuity comparable to that prior to trauma, but it is the combination of stem cell transplantation and other surgical procedures (cornea transplantation) that can often give the possibility of improving a patient’s sight, restoring transparency to the damaged cornea.

WHAT ARE THE REAL PERSPECTIVES THAT STEM CELLS OFFER FOR THE RETINA?

It seems that even the adult human retina is endowed with stem cells: extensive research has allowed us to locate these cells in the most peripheral region of the retina itself. In fact, they can be found in the pars plana and pars plicata, where they are present in an indicative measure of one cell for every 500. Retinal stem cells have been identified from the first months after birth to 70 years of age. Even today their field of application is widely experimental, but important studies have been carried out: among other things, attempts have been made to regenerate retinal photoreceptors through their implantation in stem form; however the complexity of the retinal structure and the mechanisms used for vision are obstacles not easily overcome.

In a study published in April 2013 in Cell Research it is claimed that, “multipotent retinal stem cells (RSCs) from the adult mouse retina …] are capable of producing functional photoreceptor cells”, that is to say, they are able to restore sensitivity to light in blind test animals. Another rigorous study on retinal stem cells was published in the journal [The Lancet in October 2014. It stated that visual improvements were found at an experimental level in 10 out of 18 eyes. In this study the subjects were human beings affected by the dry form of age-related macular degeneration (AMD) and Stargardt’s maculopathy. In some of these subjects, the visus improved after 3-12 months from the implantation of human embryonic stem cells.

An experimental project has allowed to obtain encouraging results in London on patients suffering from the AMD exudative form (which apparently did not respond to other therapies) using stem cells. More specifically, Moorfields Eye Hospital wrote, March 19, 2018 – following phase 1 clinical studies of an embryonic stem cell-derived retinal pigment epithelium patch – that “the first patients to receive a new treatment derived from stem cells for people with wet age-related macular degeneration (AMD) have regained reading vision”. The same hospital also writes that “the patients were monitored for 12 months and reported improvements to their vision. They went from not being able to read at all even with glasses, to reading 60-80 words per minute with normal reading glasses” [Read also: da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, Vernon A, Daniels JT, Nommiste B, Hasan SM, Gooljar SB, Carr AF, Vugler A, Ramsden CM, Bictash M, Fenster M, Steer J, Harbinson T, Wilbrey A, Tufail A, Feng G, Whitlock M, Robson AG, Holder GE, Sagoo MS, Loudon PT, Whiting P, Coffey PJ, “[Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration“, Nat Biotechnol. 2018 Apr;36(4):328-337. doi: 10.1038/nbt.4114. Epub 2018 Mar 19]].

In the conclusion of an article published in the American Journal of Ophthalmology in 2017 (Rao, Rajesh C. et al., “Stem cells for retinal disease: a perspective on the promise and perils“), however it is stated:

Stem/progenitor cell-based interventions have the potential to address blinding retinal diseases that affect hundreds of millions worldwide. Yet no Food and Drug Administration-approved stem cell therapies for retinal disease exist. Although some early-phase trial data are promising, reports of blinding complications from cell interventions remain troubling.

Therefore it will be necessary to ensure that these treatments don’t cause any harm to human health, possibly by developing, in the future, safe and effective therapies.

Researchers in the U.S. are currently carrying out the largest official experiment on stem cells that are being used to treat several pathologies and ocular traumas (affecting the retina and/or the optic nerve): it involves 500 people and, after starting in 2016, will continue until at least 2021. This vast sponsored research uses human stem cells taken from bone marrow. According to some studies that have already been published during the trial, there have been positive results in some patients, but this must be confirmed by further research.

WHAT CAN WE REALLY HOPE FOR?

The hope is that, at least in the future, stem cells can be used to treat several degenerative diseases that, at present, are some of the main causes of blindness (retinitis pigmentosa, age-related macular degeneration, etc.). In the case of genetic degenerative diseases, great potential is given to the combined use of gene therapy (injection of the correct gene under the retina) and stem cells (for example reprogrammed adult ones).

John Gurdon, who won the Nobel Prize for medicine in 2012, said that “there are very solid perspectives” for the treatment of retinal degeneration with adult stem cells. However, it will be necessary to wait for further studies to be carried out, before a large-scale clinical application is possible, provided that all the phases of the experiments on human beings are successful.

Read also (it. version): “Vista salvata con le staminali”, “Staminali riprogrammate contro la cecità”, “Usa, rigenerata la retina centrale con staminali embrionali

To deepen: consult the website of the Italian Society of Ophthalmology (SOI).

Sitegraphy and bibliography

Refractive surgery

Laser apparecchiatura

For the correction of myopia, astigmatism, hypermetropia and presbyopia

What is it?

Laser technology allows the surgical correction of the most common vision defects or refractive errors (myopia, astigmatism and hypermetropia) and, in some cases, even presbyopia. As a beam of coherent light, the laser can reshape the cornea: the transparent front part of the eye covering the iris is, in fact, a natural lens, whose focusing ability (“dioptric power”) can be improved.

How can a refractive error be corrected?

The cornea accounts for about 60% of the eye’s total refractive power (40 diopters): it can change the direction of light beams, converging them towards the retina, due to its curvature. By altering corneal thickness, laser refractive surgery aims at cornea_per_glossario-ok-2.jpgensuring that images come into focus on the retina. In short, we could say that we must flatten the cornea to correct myopia, whereas we need to increase its curvature to correct hypermetropia.

What are the main techniques?

There are three techniques that are currently the most widespread:

a) Lasik: a small “flap” is created on the cornea, by cutting horizontally through laser_apparecchio_1_-photospip075548d6a5f2df7b61e6ca7b1cc1cdba.jpgthe corneal epithelium, Bowman’s layer and superficial stroma. This action can be performed with a precision scalpel called microkeratome, or with another high precision high speed laser (femtosecond laser). After folding the flap back, the cornea is made thinner with an excimer laser and then the flap is repositioned.

  • Advantages: Lasik surgery is usually not painful and sight is recovered immediately after the treatment.
  • Disadvantages: creating the flap is a risky procedure and its success largely depends on a surgeon’s technical ability. The flap could still be slightly raised after one year, thus never fully adhering to the stoma below; in this case, an accidental shift can occur after a trauma. Infectious contaminations can also occur under the flap itself.

b) PRK (PhotoRefractive Keratectomy): with this procedure, the laser alters the curvature of the anterior cornea after the removal of the corneal epithelium (the most external layer of the cornea). After the surgery, patients are required to use soft contact lenses with no refractive power, which are intended to protect their eyes while the cornea’s outermost layer regenerates (re-epithelialization takes 4-5 days).

  • Advantages: PRK is the easiest procedure, from a technical point of view. The absence of a surgical flap also reduces long term complications.
  • Disadvantages: post-surgery pain and increased risk of developing post-surgery corneal opacity.

c) Lasek: this procedure is substantially comparable to PRK, as both techniques imply the removal of corneal epithelium. However, while the PRK procedure entirely removes it, the epithelium is repositioned over the eye after the LASEK treatment. With this technique, the corneal epithelium is first lifted, then a laser beam reshapes the cornea to achieve the desired refractive results and, at the end, the epithelium flap is put back into place (protected by a contact lens). The repositioned epithelium protects the regenerating one, but its accidental shift doesn’t compromise the surgical result.

Which errors can be treated by excimer laser?

Myopia, hypermetropia and astigmatism (which can be associated to other refractive errors) and, in recent years, also presbyopia (to be evaluated with great care). A larger amount of corneal tissue must be removed to correct astigmatism and myopia compared to hypermetropia, for the same diopters.

WHY CHOOSE ONE TECHNIQUE OVER ANOTHER?

The choice pertains to the ophthalmologist who performs the surgery. Generally speaking, LASIK is preferred for slight-moderate myopia, whereas PRK and LASEK are chosen in the case of high myopia.

WHEN IS THE SURGERY CONTRAINDICATED?

Refractive surgery aims to correct refractive errors by reshaping the cornea through a reduction of its thickness. One of the main contraindication is a cornea which is too thin. Therefore its thickness must always be measured before surgery (corneal pachymetry).

Another contraindication is ocular dryness. The quantity of secreted tears can be evaluated through a test of lacrimation and people with dry eyes can be excluded. Also, all pathologies that affect the cornea represent a limit to laser refractive surgery, particularly in people affected by keratoconus.

Myopia can be treated successfully and without risks up to 10-12 dioptres; beyond these values the risks for the eye become serious; the same is for hypermetropia that is greater than 5-6 dioptres, for which laser treatment is not always totally successful.

WHEN SHOULD YOU HAVE SURGERY?

The best age to undergo refractive surgery is between 25 and 40 years of age. Refractive errors can significantly worsen before 25 years of age, therefore nullifying the effects of the treatment. After 40 years of age, the onset of presbyopia increases the risks of suffering from dry eye syndrome, with a higher chance of developing a burning sensation after surgery. Also, the refractive error must be stable for at least 1-2 years prior to surgery.

ARE THERE PERSONS FOR WHOM LASER SURGERY IS PARTICULARLY RECOMMENDED?

People who use contact lenses inappropriately tend to contract infections, and therefore could benefit from ambulatory surgery. However, certain categories of people may experience more problems from wearing contact lenses or eyeglasses – because of their job, hobby or sport – than from undergoing laser surgery.

In some visually impaired people, there’s a considerable difference between the two eyes; this situation cannot be completely corrected with eyeglasses, because our brain doesn’t tolerate differences greater than 3 dioptres. In these cases, the possible solutions are laser refractive surgery or the correct use of contact lenses.

In conclusion, refractive surgery not only has aesthetic purposes (eliminating the use of eyeglasses) but also functional ones. However, it is generally considered a form of cosmetic surgery and is only paid for by the National Health System in some specific cases, i.e. when there is a strong difference of visus between the two eyes (severe anisometropia) or in the case of intolerance to contact lenses.[[At the moment of writing, the criteria for laser surgery to be considered a medical-surgical treatment are:

  • Anisometropia greater than 4 diopters of spherical equivalent (difference between the two eyes), which should not have been caused by previous refractive surgery, and only after after verifying the presence of single binocular vision (when intolerance to contact lenses has been certified);
  • Astigmatism of at least 4 diopters
  • Strong differences between the visus of the two eyes due to previous interventions (limited to the operated eye and not caused by refractive surgery), in order to “level” the two eyes
  • Photo-therapeutic keratectomy (PTK) performed for corneal opacities, corneal tumors, scars, irregular astigmatism, corneal dystrophies and unfortunate outcomes of refractive surgery
  • Trauma consequences or anatomical malformations such as to prevent the application of glasses (only in the cases where intolerance to corneal contact lenses has been certified).

Please note that the certification to contact lenses intolerance – when required – must be issued by a public institution other than the one in which the intervention is performed. Amongst other things, the documentation must be accompanied by photographs.]]

CAN EYES RECOVER FROM MYOPIA?

No, but myopia can be corrected. A myopic eye stays that way, but after surgery, a patient can see clearly (even though a second laser surgery can sometimes be necessary). This means that problems with the retina, eye pressure and other issues are not eliminated by refractive surgery. People with retinal problems, who undergo regular check-ups every year, must continue to do so even if they can see clearly after refractive surgery. Short-sighted people are used to seeing well at a close distance. Refractive surgery makes them emmetropic, that is to say without any apparent visual impairment. However, after the age of 40 presbyopia isn’t compensated by myopia and patients will see clearly at a close distance only by using eyeglasses (a likely event in any case, since refractive errors tend to physiologically worsen with age).

WHAT NEEDS TO BE DONE BEFORE SURGERY?

The use of contact lenses must be avoided for as long as possible before surgery. The length of the interruption depends on the patient’s eye; but in any case, surgery cannot be performed until two weeks from the interruption. Contact lenses can deform the cornea and cause problems. Patients should frequent environments that can favor ocular infection in the days before the surgery; in fact, even a simple conjunctivitis could undermine the result. Exposure to strong wind must be avoided at all costs (i.e. going on a motorbike without protection), as well as contact with people affected by infective conjunctivitis or keratitis. occhio_miope_con_immagine-web-eng.jpg

WHAT NEEDS TO BE DONE AFTER SURGERY?

Refractive surgery lasts a few minutes and its results are immediate. After surgery, a patient gets up from the surgical table and can generally see clearly. This is why postoperative risks and the doctor’s recommendations are sometimes undervalued. On the contrary, it is extremely important to follow the doctor’s prescriptions closely and adhere to their therapy with regularity and precision.

In the period following the operation, the eye is more delicate. A possible infection could jeopardise the surgical result and cause severe consequences. Patients should avoid outdoor activities, smoky environments, using motorbikes or scooters and going to the swimming pool (as chlorine causes eye irritation). Reading, using a computer, going to the cinema and watching TV is perfectly fine. Keeping the eyes well hydrated is essential and artificial tears should frequently be applied. Eye drops dosage also depends on the environment: working spaces are often very dry, due to heating in winter and air conditioning in summer, causing the tear film to evaporate too quickly.

WHAT TYPE OF ANESTHESIA IS USED?

Refractive surgery with excimer lasers requires topical anesthesia: anesthetic eye drops are instilled on the ocular surface. Patients undergoing surgery won’t feel any pain. They will have to stare at a light (called “mira”). This kind of anesthesia doesn’t inhibit ocular movements and patients must keep their eyes as still as possible.

HOW SURE CAN PATIENTS BE OF NO LONGER NEEDING THEIR GLASSES?

It is possible, but not guaranteed, that patients will no longer need glasses after surgery. If the surgery is successful, there should be no problem, at least in the short term. However there is no assurance that the refractive defect will be completely eliminated, as many factors come into play. Furthermore the refractive error could return (i.e. myopia), even if with reduced intensity compared to the level prior to surgery. In this case a second surgical intervention could be necessary, although it is possible that it will not permanently eliminate the refractive error and patients may still need eyeglasses or contact lenses. To give an idea of the incidence of myopic regression, out of a sample of 90 eyes with about -8 diopters on average (before surgery), six months after the laser surgery was completed, a measurement of -1.5 diopters was recorded (considering only people with a myopic regression).

WHAT ARE THE POSSIBLE RISKS?

According to the Food and Drug Administration (FDA), the highest US government body for the protection and promotion of public health, the following side effects may occur (or even real eye damage in the worst cases):

  • Ocular dryness (dry eye syndrome), “which can be severe”. In fact, after surgery, it may be necessary to frequently instill artificial tears and use humectants (eye gel), even though there was no need of them before
  • The use of eyeglasses or contact lenses may still be necessary after laser surgery (even though with a lower prescription). In fact it is not always possible to eliminate the refractive error. According to a study published on the American Journal of Ophthalmology “up to 28% of patients who undergo refractive surgery continue to experience a worsening of their sight” (in the case of lasik surgery for myopia)
  • The risk of experiencing halos, glare, starburst (star-shaped light vision) and double vision, all visual problems “that could be debilitating”
  • According to the FDA, the “loss of sight” can occur in extreme cases. Although very rare, this is anyway a possibility.

WHAT IS WRITTEN IN THE INFORMED CONSENT THAT YOU SUBSCRIBE TO IN ITALY?

In brief, the informed consent approved by the Italian Society of Ophthalmology (SOI), reads as follows:
1. Refractive errors (myopia, hypermetropia and astigmatism) “can be corrected with a wide margin of safety and precision by excimer lasers”
2. “Refractive surgery aims to only correct refractive errors and does not alter other pathologies that may be associated to such visual defects”
3. Refractive surgery will not improve eyesight any better than what can be achieved through the use of eyeglasses or contact lenses
4. The intervention cannot guarantee the best vision possible without eyeglasses. In some cases a small “retouch” could be necessary to optimize the result
5. “In the case of myopic patients aged above 45 years, the complete elimination of myopia will result in the immediate need for an optical correction for farsightedness” (to correct presbyopia, previously compensated by myopia)
6. Even if the surgery is correctly performed, unpredictable individual factors, which are “unrelated to a surgeon’s skill and laser precision, can affect the recovery and therefore the results. As a consequence, it is not possible to guarantee with absolute certainty the planned result”
7. Not all individuals and not all eyes are suitable to laser surgery on the cornea. In fact, people affected by certain general or systemic diseases (immunosuppression, autoimmune diseases, infectious diseases, diabetes, epilepsy, etc) or in the presence of certain general conditions (pacemaker, professional exposure to UV or blue light, pregnancy, breast feeding) and people taking a series of drugs (hypotensive, contraceptives, hormones, amiodarone, chloroquine, drugs against migraine, anti-acne) that can affect postoperative recovery and make the surgery result unpredictable; therefore the advisability to undergo refractive surgery should be carefully assessed on a case-by-case basis.
There are various eye diseases and conditions (high degenerative myopia, shallow anterior chamber, glaucoma, cataract, recurrent anterior and posterior ocular inflammations, burns consequences, ocular surface disease such as dry eye and all palpebral anomalies), and in particular affecting the cornea (keratitis, corneal ectasia, keratoconus, keratoglobus, endothelial dystrophy), that can condition or even compromise the progression of the refractive error after surgery, making the result unpredictable. For this reason, the possibility of surgery must be carefully assessed in person
8. “The cornea is the structure that will be thinned by the surgery, therefore it must have a thickness which is appropriate to the extent of the error to be corrected and to the diameter of the optical area to be treated, which is necessary to ensure complete coverage of the pupil even in poor lighting conditions”
9. After surgery (PRK, lasik, lasek) “the patient is required to apply with extreme care the prescribed eye drop medications, and according to the indicated modalities”. In fact “negligence in following the postoperative therapy and in undergoing specialist check-ups can affect the final refractive result and cause complications”.

WHAT ARE THE MAIN COMPLICATIONS OF EXCIMER LASER SURGERY?

According to the Italian Society of Ophthalmology (as written in the informed consent approved in Italy in 2011) the possible complications/problems are:

  • Infection: it is an extremely rare complication. In the case of an infection that is resistant to antibiotics and where there is reduced immunity”, the situation may be a serious one and lead to the loss of sight or even of the eye. This eventuality is so exceptional that it is impossible to evaluate its frequency”
  • Decentered treatment (the cornea is not reshaped in the right place): extremely rare with contemporary lasers, which are equipped with a centering control system
  • Incomplete refractive results: over or under correction are possible, in particular after the correction of high refractive errors. A second procedure can be performed, if necessary
  • Inadequate optical area: “when the diameter of the pupil in low lighting conditions is wider than the diameter of the flap, night glare may occur, which can make driving at night very difficult. This situation may occur also when using topical medications (i.e. vasoconstrictor eye drops) or general medications (antimotion sickness substances [= such as antiemetics for travel sickness)] that can dilate the pupil”
  • Dry eye: this syndrome may occur for some months after surgery, requiring the application of artificial tears several times per day. This is the most frequent complication of all the laser techniques, and in particular for lasik; it usually disappears or significantly decreases within one year from surgery (but it is not guaranteed).

Other extremely rare complications listed in the document include

  • Formation of corneal ulcers (lesions of the ocular surface)
  • Non-specific diffuse interstitial keratitis
  • Corneal colliquation (disintegration of the cornea)
  • Other unknown complications may occur: the outcome of long term studies may reveal additional risks that are unknown at present.

PRK and Lasek specific complication:

  • Re-epithelialization (which is the reconstitution of superficial corneal tissue) may be delayed due to the nature and conformation of the patient’s epithelium
  • After the intervention, a loss of clarity of the cornea may occur at various degrees (corneal haze) and it could be associated to an irregular corneal surface in the most serious cases. “Such opacity – the SOI writes – is generally reversible in a variable time (even several months) and compromises correct vision. Sometimes a second laser surgery could be necessary to smooth the corneal surface (PTK)”.

Lasik specific complications:

  • Incomplete, damaged and decentralized corneal flap: in this case, the flap will be repositioned and the surgeon may decide to postpone the surgery for several months. However, this eventuality “ is extremely rare today”, the SOI assures
  • Diffuse lamellar keratitis (also known as Sands of the Sahara) of varying severity: it heals without any inconvenience if promptly and properly treated. Careful evaluation after surgery is necessary to prevent it.

WHAT SHOULD YOU KNOW, IN BRIEF?

According to the Italian Society of Ophthalmology, your ophthalmologist must explain, amongst other things, that:

1. Excimer laser surgery is used to reduce the dependence on eyeglasses and contact lenses

2. Excimer laser treatment does not eliminate the need of eyeglasses or contact lenses in all cases

3. Excimer laser treatment does not cure other eye diseases

4. Excimer laser treatment does not stop the (physiological) progression of myopia

5. Complications are possible, especially if the prescribed therapies are not followed and follow-up examinations are not performed

6. After the correction of short-sightedness, a pair of glasses for farsightedness may be immediately necessary.

Notes
Shojaei A, Eslani M, Vali Y, Mansouri M, Dadman N, Yaseri M., “Effect of timolol on refractive outcomes in eyes with myopic regression after laser in situ keratomileusis: a prospective randomized clinical trial“, Am J Ophthalmol. 2012 Nov;154(5):790-798.e1. doi: 10.1016/j.ajo.2012.05.013. Epub 2012 Aug 28.

“FDA warns against improper advertising, promotion of lasers intended for LASIK corrective eye surgery“, FDA, 18 Dec 2012.

Retinal laser-therapy

retina_light_per_web.jpg

Laser treatment of retinal diseases

HOW DOES IT WORK?

laserterapia_retinica.jpgThe retinal laser (argon laser) is generally used to “burn” areas of the diseased retina. However, in some cases, it is used to fix the healthy retina around pathological areas (holes or lesions). The aim is to obtain scars that reinforce the retina at its more delicate points.

WHAT IS THE ARGON LASER?

It is a kind of laser whose light beam – generated thanks to the argon, a noble gas – has a thermal action: by heating the area on which the instrument is pointed, a series of diseases of the retina can be treated (by virtue of a phenomenon called photocoagulation).

WHEN IS IT USED?

diabete-retina_malata-web.jpgThe argon laser is used to treat:

  • Diabetic retinopathy (ischemic forms). In the case of a reduced supply of blood and, as a consequence, of oxygen to certain retinal areas, new blood vessels develop to compensate for the reduced supply, causing severe damage (proliferative diabetic retinopathy). In this case, an argon laser is used to “kill” the areas of diseased tissue.
  • Macular edemas (collection of fluid under the central area of the retina): these are the result of an inflammatory process and/or blood vessel alterations. Also in this case, the laser works by destroying the zones that “issue the command” to create new blood vessels (secreting a growth factor called VEGF).
  • Peripheral retinal degenerations and breaks. In these cases, there is a high risk of retinal detachment. Through the action of the laser, the retina is burned in proximity to any tear or potentially dangerous degeneration. The scar that is created after the laser treatment acts as a welding, reinforcing the retina.
  • Retinal Vein Occlusion. In this case, new vessels can develop, which tend to invade other areas (iridocorneal angle), causing a severe kind of glaucoma (called “neovascular”).
  • Retinopathy of Prematurity (ROP). Laser surgery is used to prevent the growth of new retinal blood vessels, which are harmful for eyesight, through the “destruction” of the damaged areas of the retina, due to a reduced supply of blood and oxygen (ischemic areas). An Australian study published in 2013 reported a 93% success rate in laser treatments on very young infants (10 months old). [References: Gunn, D. J., Cartwright, D. W., Yuen, S. A. and Gole, G. A. (2013), “Treatment of retinopathy of prematurity in extremely premature infants over an 18-year period“, [Clinical & Experimental Ophthalmology, 41: 159–166. doi: 10.1111/j.1442-9071.2012.02839]]

HOW IS THE TREATMENT PERFORMED?

The eye of the patient, who must have first signed the informed consent to the treatment, is temporarily anesthetized with drops of local anesthetic. Then a contact lens is applied with suitable treatment filters. The doctor will then target the areas of the retina to be treated. During the procedure, the patient may feel a slight pain comparable to small bites or punctures, depending on the energy used with the laser. At the end of the treatment, the lens is removed, lubricating eye drops and an antibiotic are instilled and then the patient can go home.

WHICH PRECAUTIONS SHOULD BE TAKEN BEFORE AND AFTER THE TREATMENT?

In the days prior to surgery, there are no particular indications to follow but the ones linked to the disease for which the laser treatment is performed. On the day of the surgery and in the following days (the number varies depending on the disease) it is important not to exert oneself: for this reason the doctor may request absolute rest. It is important to properly hydrate oneself and, if requested, take mineral salt supplements to better hydrate the vitreous body.

WHAT SIDE EFFECTS COULD BE EXPERIENCED?

When the periphery of the retina is treated, no vision problems related to the surgery are experienced by the patient. However, in the treatment of the macula (the central area of the retina which is responsible for distinct vision), a damage that may be perceived by the patient can occur: since a small part of the retina is burned, the tissue is no longer able to transmit light; in this case the advantages outweigh the disadvantages, even if a minor damage is created to treat a more serious one. The most frequent, but less severe side effect, may be a reddening of the eye due to the use of a contact lens during the surgery; this problem can spontaneously resolve itself within a few days or be calmed down with the use of lubricating eye drops and/or antibiotics, in the case of a mild corneal abrasion.

WHAT IS RECOMMENDED AFTER THE TREATMENT?

Apart from rest, proper hydration is important during the first 15-20 days after argon laser treatment. It is recommended to drink about 1.5 litres of water every day: as the laser acts by heating the retina and piercing through the eyeball, the liquid that is found here is inevitably heated. As a consequence, the quantity of the vitreous body, being composed for the major part by water, is reduced. Dehydration causes a contraction of the vitreous body, leading to an increased risk of vitreous-retinal tractions and peripheral retinal tears.