In-vivo confocal microscopy is a novel diagnostic tool that allows ophthalmologists to visualize the cornea and other structures within the eye in high resolution. High resolution, in-vivo imaging of all five layers of the cornea removes the need for invasive, time-consuming, expensive and painful biopsies for patients. The five layers are the corneal epithelium, Bowman’s layer, stroma, Descemet’s membrane and the corneal endothelium.

Due to it being non-invasive (and by extension, not painful!), it has huge clinical potential to readily investigate numerous corneal diseases. It is already used in the detection and management of pathologic and infectious conditions, corneal dystrophies and ecstasies, monitoring contact lens induced corneal changes and for pre and post-surgical evaluation (PRK, LASIK and LASEK etc.), and penetrating keratoplasty. More recently, the nerves on the cornea have been studies to assess progression of certain diseases that damage corneal nerves – an example is diabetes.

At the time of the conception of Eyes2Eyes in 2021, and still to our knowledge today, there was no in-vivo Confocal Microscope in the Western Cape; in fact, there is only one of these microscopes in the whole of South Africa, which is privately owned in Gauteng. The ability to procure an in-vivo Confocal Microscope in public and private sector medical facilities is currently hindered by extensive costs (exceeding 1 million ZAR) from international manufacturers.

One of the core aims of Eyes2Eyes is to procure an in-vivo confocal microscope to improve the screening and diagnostic capacity Western Cape ophthalmology services.

Listed briefly below are five benefits of this technology for both ophthalmologists and patients:

1. Real-time imaging: Confocal microscopy provides real-time images of the cornea, allowing ophthalmologists to dynamically monitor changes in the cornea during an exam.
2. Early detection: By detecting corneal diseases and conditions in their early stages, in-vivo confocal microscopy can lead to earlier treatment and better outcomes for patients.
3. Non-invasive, improved diagnosis: Confocal microscopy provides high-resolution images of the cornea, allowing ophthalmologists to diagnose a range of corneal diseases and conditions with greater accuracy. In-vivo confocal microscopy is a non-invasive technique, allowing ophthalmologists to examine the cornea without the need for surgical procedures.
4. Reduced risk of complications: By avoiding invasive procedures, in-vivo confocal microscopy reduces the risk of complications for patients.
5. Better patient outcomes: With more accurate diagnosis and improved monitoring, patients are likely to receive more effective treatments, leading to better outcomes.

References

1. Tavakoli M, Hossain P, Malik RA. Clinical applications of corneal confocal microscopy. Clin Ophthalmol. 2008;2(2):435-445.
2. Petropoulos IN, Bitirgen G, Ferdousi M, et al. Corneal Confocal Microscopy to Image Small Nerve Fiber Degeneration: Ophthalmology Meets Neurology. Frontiers in Pain Research 2021;2.

Image

Image reproduced under CC BY4.0 open access using article reference (2).

1. Minimally invasive techniques: Advances in surgical instruments and techniques are likely to lead to more minimally invasive corneal surgeries, reducing the risk of complications and improving patient outcomes. An example of this is the femtosecond laser deep anterior lamellar keratoplasty (FSDALK). Femtosecond (FS) laser is an infrared laser with a wavelength of 1053nm. Since the pulse duration is in the 10^-15 range, there is minimal damage to the surrounding tissue whilst penetrating the cornea. The DALK technique was previously discussed under “Corneal Transplants in Ophthalmology”. Essentially, with FSDALK, instead of using a circular blade or trephine to mechanically cut a circular incision in both donor and patient, “tongue and groove” patterns can be created to ensure a good fit of the graft without any slippage. This ensures good wound apposition and theoretically should reduce astigmatism. Additionally, the laser creates a wound healing reaction which also creates good adhesion, allowing earlier stitch removal. Visual recovery is faster than a traditional method of trephination.

2. Improved imaging and diagnostic tools: Advances in imaging and diagnostic technologies, such as in-vivo confocal microscopy, will allow ophthalmologists to better visualise the cornea and diagnose corneal diseases more accurately. At present, there is no in-vivo Confocal Microscope in the Western Cape; in fact, there is only one of these microscopes in the whole of South Africa, which is privately owned in Gauteng. One of the core aims of Eyes2Eyes is to procure an in-vivo confocal microscope to improve the screening and diagnostic capacity Western Cape ophthalmology services.

3. Customised treatments: With the growth of personalised medicine, corneal surgeons are likely to increasingly tailor treatments to individual patients based on their unique anatomy and medical history. Additionally, novel treatments, such as gene therapy (discussed previously on this blog) and regenerative medicine, are increasingly being researched for corneal diseases. These therapies are especially relevant in areas of the world where there is limited capacity for donor corneas. For example, Dr Heydenrych from Eyes2Eyes demonstrated the feasibility of a new growth medium that allows for the growth and proliferation of corneal cells, limbal epithelial cells, taken from previously traumatised corneas, to form cornea epithelium that could theoretically be transplanted.
4. Increased use of robotics: Robotic systems and advanced surgical instruments are likely to be increasingly used in corneal surgery, improving the accuracy and precision of procedures. The da Vinci system (Intuitive Surgical, USA) is the current standard robotic surgical system used in the field of ophthalmology. It is a telemanipulation robot that has been utilised for performing pterygium surgery in human eyes and has been successful in ex vivo corneal surgery. Telemanipulation systems are a class of robotics that enable the operator to work remotely by a computerised human—machine interface.

5. Advancements in artificial intelligence: Artificial intelligence is likely to play a growing role in corneal surgery, helping to plan surgeries, predict outcomes, and improve patient outcomes. AI has been used to predict the outcome of keratoconus management. More recently, AI-based algorithms using corneal topographies, tomographies, and Aanterior segment optical coherence tomograph (AS-OCT) such as KeratoDetect and Ectasia Status Index (ESI) have been developed to detect early keratoconus and screen patients before refractive surgeries. For the anterior segment of the eye in general, since the diseases often involve some form of imaging, including slit-lamp photography, AS-OCT, specular microscopy, corneal tomography/topography, and in vivo confocal microscopy (IVCM), there is a huge potential to leverage the power of AI to enhance the clinical service provision in these fields.

References

1. Leonard G. Heydenrych, Donald F. du Toit & Colleen M. Aldous (2016) Eviscerated Corneas as Tissue Source for Ex Vivo Expansion of Limbal Epithelial Cells on Platelet-Rich Plasma Gels, Current Eye Research, 41:12, 1543-1547.
2. Pandey SK, Sharma V. Robotics and ophthalmology: Are we there yet?. Indian J Ophthalmol. 2019;67(7):988-994.
3. Rampat R, Deshmukh R, Chen X, et al. Artificial Intelligence in Cornea, Refractive Surgery, and Cataract: Basic Principles, Clinical Applications, and Future Directions. Asia Pac J Ophthalmol (Phila). 2021;10(3):268-281.
4. Alio JL, Abdelghany AA, Barraquer R, et al. Femtosecond Laser Assisted Deep Anterior Lamellar Keratoplasty Outcomes and Healing Patterns Compared to Manual Technique. Biomed Res Int. 2015;2015:397891.
5. Sioufi K, Zheleznyak L, MacRae S, et al. Femtosecond Lasers in Cornea & Refractive Surgery. Experimental Eye Research 2021;205:108477.

The cornea is the clear front surface of the eye. Have you ever wondered about the significance of a Cone-Shaped Cornea is, and how it could affect vision? The word keratoconus comes from the Greek words ‘keras’, meaning cornea, and ‘conus’, meaning cone, which together means ‘cone- shaped’ cornea.

Keratoconus affects all ethnicities and both sexes. The highest rates typically occur in 20- to 30-year-olds, but it is fairly common for it to be found in adolescents. It often develops in the 2^nd and 3^rd decades of life and tends to progress until the 4^th decade. While it is commonly found as an isolated eye condition, it sometimes can coexists with other eye and multi-system diseases.  

This disease is more aggressive in children than in adults and can have debilitating consequences for their vision as the condition deteriorates. Given its onset usually during their formative adolescent/adult years keratoconus can fundamentally alter the psychosocial profile of individuals. Even if their visual acuity can be corrected, patients with keratoconus are still likely to experience significant impact on their quality of life (1). The combined visual deterioration and psychological stress may debilitate patients from achieving their academic potential and contributing meaningful to their communities and economy.

Keratoconus is considered a bilateral and asymmetric (i.e. one eye is typically more severely affected than the other) (2-6) eye disease which results in the progressive thinning and steepening of the cornea leading to irregular astigmatism (i.e. irregular contouring of the cornea along its surface, affecting the way in which light enters the eye) and reduced visual acuity (i.e. less “seeing power” for the eye) (7-9). Images may also appear distorted, and the eyes may become more sensitive to glare and light.

Our understanding of the mechanism behind the development of keratoconus remains limited. The interplay between genetic and environmental factors have been associated with the cause and progression of this disease. Keratoconus progresses because of a combination of simultaneously occurring destructive and healing processes.

In the field of ophthalmology, precision and accuracy are of paramount importance when it comes to delivering medication to the delicate tissues of the eye. Traditional eye drop delivery methods have their limitations, often leading to inconsistent dosages and wastage. Piezoelectric eye drop delivery systems could theoretically offer precise, controlled, and touchless administration of medication. Piezoelectric materials have a unique property where they generate an electric charge when subjected to mechanical stress or pressure.

Advantages:

1. Precise and controlled dosage administration
2. Minimize contamination and wastage
3. Improved patient experience and compliance to eyedrops

One of the potential main advantages of piezoelectric eye drop delivery systems is their ability to provide precise and controlled dosage administration. The mechanical pressure applied to the piezoelectric material causes it to generate an electric charge, triggering the release of eye drops. This mechanism allows for accurate and consistent dosage delivery, reducing the risk of over or under medication. With traditional eye drop methods, variations in hand pressure or technique often lead to imprecise dosage, compromising the effectiveness of treatment. Overflow of the eyedrops to the surrounding structures (e.g. eyelids, eyelashes) can cause local irritation and discomfort for patients. There is also greater risk of the medication unevenly distributing to the nasolacrimal duct, which facilitates the draining of the ocular surface into the nasal passage, potentially leading to systemic absorption of the compounds inside the eyedrops, which may lead to more side-effects.

Another significant advantage of piezoelectric eye drop delivery systems is their potential to minimize contamination and wastage. Conventional eye drop bottles are prone to contamination as they come into contact with the eye’s surface, skin, and eyelashes. Additionally, the imprecise squeeze and dropper mechanisms of traditional methods often result in excessive drops being dispensed, leading to wastage. A major portion of each conventional eyedrop administered is blinked out and drained into the nasolacrimal duct system (a small drainage system connects the eye to the nose). Piezoelectric systems address these issues by offering a touchless delivery method that eliminates contamination risk and ensures efficient drug utilization. This not only enhances patient safety but also reduces overall healthcare costs.

Piezoelectric eye drop delivery systems also offer an improved patient experience compared to traditional methods. When using conventional eye drops, the patient has to incline the face almost 90° to ensure that the eye drops are administered into the eyes under gravity – this is very physically difficult for some people, especially the elderly, and especially when multiple drops are needed per day. Piezoelectric systems allow the patient to be upright during eyedrop administration. Further, the touchless and precise nature of the technology eliminates the need for direct contact with the eye, making it more comfortable for patients, especially those with sensitive or compromised ocular tissues. Moreover, the controlled release mechanism reduces the sensation of an excessive liquid flow, making the process less intrusive and more pleasant.

In summary, piezoelectric eye drop delivery systems have the potential to optimise corneal care in several ways:

1. Treatment of Ophthalmic Diseases: Conditions such as dry eye syndrome, corneal infections, and glaucoma often require frequent and precise administration of medications. Piezoelectric devices can enhance the efficacy of these treatments by ensuring consistent and accurate dosing, leading to improved outcomes for patients.
2. Post-Surgical Recovery: Following corneal surgeries, patients often need to self-administer eye drops for an extended period. Piezoelectric delivery systems can simplify this process, reducing the likelihood of mistakes and enhancing the overall recovery experience.
3. Research and Development: The ability to precisely control the dosage and delivery of medications opens up new possibilities for researchers studying corneal diseases. Piezoelectric systems can facilitate the development of innovative therapies, targeted drug delivery strategies, and improved understanding of drug interactions with the cornea.

Figure 1: An example of a piezo-electric eyedrop delivery device, discussed in further depth by Pasquale et. al (1). Reproduced via Open Access.

Sounds great. What’s the catch? More research is needed … it will take a while until these device systems become mainstream.

References:

1. Pasquale LR, Lin S, Weinreb RN, et al. Latanoprost with high precision, piezo-print microdose delivery for IOP lowering: clinical results of the PG21 study of 0.4 µg daily microdose. Clin Ophthalmol 2018;12:2451-7.
2. Yao G, Mo X, Liu S, et al. Snowflake-inspired and blink-driven flexible piezoelectric contact lenses for effective corneal injury repair. Nature Communications 2023;14:3604.
3. Shaukat H, Ali A, Bibi S, et al. A Review of the Recent Advances in Piezoelectric Materials, Energy Harvester Structures, and Their Applications in Analytical Chemistry. Applied Sciences 2023;13:1300.

Acanthamoeba Keratitis

Acanthamoeba is a genus of single-celled amoeba commonly found in water and soil environments. Some species of Acanthamoeba are also capable of causing infections in animals. Some species of Acanthamoeba are also capable of causing serious infections in humans, including brain infections, skin infections, and acanthamoeba keratitis (an eye infection that targets the cornea). Acanthamoeba keratitis affects the cornea and can cause significant pain, redness, blurred vision, sensitivity to light, and the sensation of something in the eye. It is most common in people who wear contact lenses, but anyone can get the infection. It is so painful because the outermost surface of the cornea is exquisitely sensitive – it has a nerve density that is 300–600 times that of the skin! (1). To prevent this relatively rare infection, it is so important to practice good hygiene, especially when handling contact lenses. Never use tap water on your contact lenses, because acanthamoeba can be found in tap water. Acanthamoeba can also survive in chlorinated swimming pools (2) so protecting your contact lenses with goggles if you cannot take them off completely is a good idea. If left untreated, acanthamoeba keratitis it can lead to corneal ulcers, serious vision loss and even blindness. Treatment involves the use of anti-amoebic medications and may also include surgical removal of infected tissue. Early diagnosis and prompt treatment are crucial for the best outcome – seek eye care urgently.

Bottom Image: Corneal melting and new inflammatory growth of blood vessels in a patient with Acanthamoeba keratitis. They lost vision in this eye. Reproduced via open access (3)

References

1. Zander E, Weddell G. Observations on the innervation of the cornea. J Anat. 1951;85(1):68-99.
2. Kaji Y, Hu B, Kawana K, Oshika T. Swimming with soft contact lenses: danger of acanthamoeba keratitis. The Lancet Infectious Diseases. 2005;5(6):392.
3. Lorenzo-Morales J, Khan NA & Walochnik J: An update on Acanthamoebakeratitis: diagnosis, pathogenesis and treatment. Parasite, 2015, 22, 10.

Gene therapy describes the introduction of normal genes into cells in place of missing or defective ones in order to correct genetic disorders. Gene therapy in ophthalmology has made significant advances in recent years, with numerous clinical trials showing promising results. The eye is considered a good candidate for gene therapy; it is small and compartmentalised, requires relatively small numbers of vectors/gene copies, and has special immune response features that can be favourable for gene therapy (1). Some of the key advancements in this field include:

1. Treatment for corneal dystrophies: Corneal dystrophies are a group of inherited disorders that cause progressive clouding of the cornea, leading to vision loss. Gene therapy approaches aim to replace or repair the defective gene responsible for the disease. 
2. Treatment for Retinal Diseases: Gene therapy has shown promising results in the treatment of retinal diseases such as age-related macular degeneration, retinitis pigmentosa, and Leber congenital amaurosis. Gene therapy has shown to restore vision and improve visual acuity in patients with these conditions.
3. CRISPR-Cas9 Technology: CRISPR-Cas9 technology has allowed for precise and efficient editing of specific genes, making it a powerful tool for gene therapy in ophthalmology. This technology has been used to correct mutations that cause retinal diseases, leading to improved visual function.
4. Viral Vectors: Lentiviral and adeno-associated virus (AAV) vectors have also become a popular tool in gene therapy for ocular diseases due to their ability to efficiently deliver therapeutic genes to the retina. AAV vectors in particular have been used to deliver genes to treat conditions such as retinitis pigmentosa, choroideremia, and Stargardt disease.
5. Improved Delivery Methods: Advances in delivery methods, such as the use of subretinal injections and intravitreal injections, have improved the delivery of therapeutic genes to the retina, resulting in more effective treatment of retinal diseases.

One type of gene therapy for ophthalmology has already been approved by the United States Food and Drug Administration (FDA) to treat paediatric patients with a retinal condition called Leber congenital amaurosis who have a deficiency in the RPE65 gene (2). The RPE65 gene provides instructions for making a protein called RPE65, which is involved in the production of a molecule called 11-cis-retinal, an essential component of the visual cycle that allows people to process light.

References:

1. Bennett J. Immune response following intraocular delivery of recombinant viral vectors. Gene Ther. 2003;10(11):977-82.
2. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-60.