NGF treatment (Cenegermin) in corneal ulcer due to radiation exposure
Two independent, multicentre, randomised, double-masked, vehicle-controlled clinical studies demonstrated the efficacy and safety of Cenegermin in patients affected by moderate or severe NK that were refractory to other non-surgical treatments. In both studies patients received Cenegermin 6 times daily in the affected eye for 8 weeks [1, 2].
Highlights on Corneal Infections
Infectious keratitis are a major cause of blindness and visual impairment globally. The prompt identification of the pathogen organism and an early targeted therapy are crucial to control the infection, but often difficult to obtain. New tools in diagnosis and treatment are the following.
Diagnostic Investigation
Cultural exam remains the prevalent diagnostic procedure. However other approaches can be effective to identify the causative organism or to have a faster response.
In vivo confocal microscopy is helpful to identify fungal hyphae or Acanthamoeba cysts [3].
PCR (Polymerase Chain Reaction) is useful especially to identify Acanthamoeba and Herpesviridae DNA [4]. Ultimately, the use of Next Generation Sequencing (NGS) has been suggested. NGS includes a number of different modern sequencing technologies that allow to sequence DNA and RNA very quickly. These techniques can be advantageous particularly for organisms that are difficult to culture such as atypical or anaerobic bacteria [5].
Collagen Cross-Linking (CXL) for Corneal Infections
CXL is a procedure which uses UV light and a photosensitizer (riboflavin) to strengthen chemical bonds in the cornea. The main indication for CXL is to prevent the progression of keratoconus or other ectatic disorders, however, it has been recently proposed to treat corneal infections. In fact, several study has shown that CXL has some antimicrobial effects and has the potential to inhibit enzymatic degradation and corneal melting [6].
There is no agreement yet about when and how to employ CXL to treat keratitis, however, several papers showed the efficacy in bacterial cases whereas there is less evidence in fungal and Acanthamoeba cases [7, 8]. Furthermore, CXL should be avoided in patient with history of herpes because the virus can be activated by ultraviolet light [9].
Further studies are needed to determine the optimized CXL protocol and define the indications in corneal infections treatment.
Povidone-Iodine (PVI) and Corneal Infections
PVI is a well known disinfectant and antiseptic agent. Thanks to its broad spectrum of microbicidal activity with no reports of resistance or anaphylaxis, and its reasonable cost, it is widely used in ophthalmic surgery [10]. In addiction, PVI has been shown to be active against Acanthamoeba in vitro and it does not induce resistance or cross-resistance to antibiotics [11].
A recent study conducted in India and Philippines on 172 patients affected by bacterial keratitis, showed no significant difference between the effect of topical PVI 1.25% and topical antibiotics available in developing countries (0.3% ciprofloxacin or neomycin-polymyxin b-gramicidin) [12].
Suggesting that PVI (widely available and inexpensive) should be considered for treatment of bacterial keratitis in countries with limited access to antibiotic therapy.
Additionally, povidone iodine contact lens disinfection systems has been proven effective against a variety of pathogenic microorganisms and may aid in the prevention of potentially sight threatening microbial keratitis [13, 14].
Dry Eye Disease
Dry eye etiology
Aqueous deficient | Evaporative | ||
|---|---|---|---|
Sjogren Syndrome DED: Primary Secondary | Non-Sjogren Syndrome DED: Lacrimal deficiency Lacrimal gland duct obstruction Reflex block Systemic drugs | Intrinsic: Meibomian oil deficiency Disorders of lid aperture Low blink rate Drug action Accutane | Extrinsic: Vitamin A deficiency Topical drugs preservatives Contact lens Ocular surface disease |
The definition of dry eye is still under continual revision. According to the 2017 Report of International Dry Eye Workshop, DED is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.
Classic clinical tests are tear break-up time, Schirmer test, corneal esthesiometry, and dye staining.
Newer diagnostic tests measure tear film osmolarity, matrix metalloproteinases levels, and lipid composition. Advanced imaging has also allowed us to measure tear film meniscus height (by OCT), ocular surface health (epithelium and nerve quality by in vivo confocal microscopy), and tear film evaporation (by noninvasive tear break-up time).
There are numerous treatments for DED , depending on the causes. The more common include artificial tears, gel or oinments, tear conserving interventions such as punctal plugs, topical ophthalmic steroids and tetracycline.
Topical cyclosporine-A inhibits T cell activation and decrease IL-6 and HLA-DR. It has been the only pharmacologic treatment specifically approved for DED by the Food and Drug Administration (FDA), but it is discontinued by most patients as it causes burning sensation in the eye.
In 2016 lifitegrast has been approved by the FDA as therapeutic option for dry eye too, as it affects the T-cell-mediated inflammatory pathways, inhibiting the release of cytokines, interferon d, tumor necrosis factor alpha (TNF-α), and other interleukins [15, 16].
Neurostimulation is another important addition to our armamentarium in DED treatment to stimulate natural tear production using electrical stimulation. The intranasal neurostimolator was shown to be safe and effective for temporarily increasing tear production in adult patients [17].
Corneal Transplants
Evolution from penetrating keratoplasty to lamellar corneal transplant
Deep anterior lamellar keratoplasty (DALK) is replacing penetrating keratoplasty for disorders affecting the corneal stromal layers, while eliminating the risk of endothelial rejection, providing longer graft survival, avoiding an open sky procedure and offering stronger postoperative wound resistance.
Endothelial keratoplasty selectively replaces the corneal endothelium in patients with endothelial disease and results in more rapid and predictable visual outcomes.
Other emerging therapies are ocular surface reconstruction and artificial cornea (keratoprosthesis) surgery, which have become more widely performed because of the advances in these techniques. Together, these advances have resulted in improved outcomes, and have expanded the number of cases of corneal blindness that can now be treated successfully.
Comparison between corneal transplant techniques
Indications | Advantages | Disadvantages | |
|---|---|---|---|
PK | Suitable for all indications | – Fast learning curve | – Open-sky surgery related risks |
– Relatively fast procedure | – Progressive endothelial cell loss | ||
– Less expensive procedure | – High glaucoma risk | ||
– Considerable rejection rate | |||
– High postoperative astigmatism | |||
DALK | – Corneal ectasia (Keratoconus, pellucid marginal degeneration, keratoglobus, post-laser-assisted in situ keratomileusis ectasia, recurrence of ectasia in previous PK) | – Spares the host endothelium | – Steep learning curve |
– Corneal stromal dystrophies when the endothelium is not affected (macular corneal dystrophy, granular corneal dystrophy, lattice corneal dystrophy and Avellino dystrophy) | – Less rejection risk | – Stroma interface can affect the visual outcome (manual dissection techniques) | |
– Corneal scarring (secondary to trauma, infection, chemical injury) | – No endothelial rejection | – Time consuming procedure | |
– Corneal melting (autoimmune, neurotrophic or infectious) | – Long term graft survival | – Postoperative astigmatism similar to PK | |
– Descemetoceles | – Less intraoperative complications | ||
– Penetrating corneal wound without loss of substance | – Early suture removal | ||
– Fungi or Acanthamoeba stromal keratitis unresponsive to medical treatment | – Stronger postoperative wound resistance | ||
EK | – Endothelial dystrophy (Fuchs endothelial dystrophy, posterior polymorphous dystrophy and congenital hereditary endothelial dystrophy) | – Spares the healthy stroma | – More difficult learning curve |
– Iridocorneal endothelial syndrome | – Less rejection risk | – Donor selection and manipulation | |
– Bullous keratopathy (iatrogenic, post-traumatic or post-infective) | – Early and better visual recovery | – Stroma interface can affect the visual outcome in DSAEK | |
– Endothelial failure of a prior corneal transplant | – No induced astigmatism | ||
– Fewer suture and wound complications |
DALK: Deep Anterior Lamellar Keratoplasty
DALK is now the procedure of choice for corneal stromal diseases with a healthy endothelium.
The most common indication to perform a DALK is Keratoconus, other indications are other corneal ectasia [18–21], corneal stromal dystrophies when the endothelium is not affected, corneal scarring [22, 23], corneal melting [24], Descemetoceles [24], penetrating corneal wound without loss of substance [25]. In very experienced hands of surgeons with a low conversion rate to PK, DALK should also be considered in case of dangerous infectious stromal keratitis unresponsive to medical treatment (fungi or Acanthamoeba infections) [26, 27].
DALK surgical techniques
Needle Big Bubble Technique
This is the most used DALK procedure. A suction trephine is used to perform a partial thickness corneal trephination at a depth of about 60–80%. A 27- or 30-gauge needle attached to an air-filled syringe is inserted deep into the paracentral stroma through the bottom of the trephination groove and is advanced so that the bevel remains parallel to Descemet membrane (DM) and faces down. At this point, air is injected, forming a large air bubble between DM and the corneal stroma in most cases (60–70%). The stromectomy must be completed then the donor can be sutured [28, 29].
Cannula Big Bubble
Cannula Big Bubble. Tunnel formation in the deep stroma using a 27 G spatula (a), air insufflation using a 27 G cannula achieving the Big Bubble formation (b)
It is common opinion that the deeper the air is injected, the higher the chances of generating a BB. Sarnicola and Toro described the surgical steps for achieving a Big Bubble (BB) using a blunt cannula [30]. After a partial corneal trephination, a smooth spatula is inserted as deep as possible into the peripheral trephination groove. The spatula is moved forward in the attempt to reach the predescemetic plane, deeper and deeper toward the center of the cornea. Once the predescemetic plane is reached, two important signs are frequently observed: reduced resistance of the advancement of the spatula and the appearance of DM folds. The spatula can then be removed, leaving a corneal tunnel into which a 27-gauge cannula attached to a 5 cc air-filled syringe is inserted. The cannula has a port that faces down so that air can push DM posteriorly. After advancing the cannula to the center of the cornea, air can be injected. The literature shows that using a cannula to inject air provides the highest rate of successful BB accomplishment [29, 31].
Air-Viscobubble Dissection
AVB is a technique designed to manage those cases in which BB formation has failed.
When air dissection does not result in big-bubble formation, superficial keratectomy is performed with a Golf knife. A new deeper tunnel is created into the stroma using the same spatula. The same cannula used for the air injection is then attached to a viscoelastic material-filled syringe, and viscodissection is tried as a second approach to separate DM from the corneal stroma. Sarnicola et al. reported the percentage of DALK obtained with this combined technique: AVB helped to attain DM separation from the stroma in 7% of cases that together with the 86% of cases in which DM separation from the stroma had been achieved with the Big Bubble technique using a cannula, resulted in a total achievement of DALK in 93% of cases [29, 32].
Results and Complications
The visual outcome after a DALK is similar to PK if the residual stromal bed thickness is less then 100 microns. Compare to PK, DALK provides tremendous advantages in terms of rejection rate, graft survival, and intraoperative and postoperative complications.
After a DALK procedure, rejection is extremely rare and is easily treatable because it does not involve the endothelium. Epithelial rejection is usually very mild, always reversible with steroid drops, and occurring within the initial postoperative weeks. Subepithelial rejection is a belated complication that generally happens within the first postoperative year; this complication is successfully reversible with topical steroids most of the time. Stromal rejection is a more dangerous complication because it can lead to the necrosis of the stroma. It is usually very rare [33, 34].
The endothelium cells count becomes stable after 2 years post-op, this allow a long term graft survival, probably lifetime [34]. Moreover DALK is not an open sky surgery and there are less intraoperative complications.
The most frequent complications of DALK are DM ruptures and double anterior chamber formation. The ability to solve these complications generally improves when surgeons gradually become more expert.
Endothelial Keratoplasty (EK)
Endothelial keratoplasty is the procedure of choice for endothelium disfunction treatment, including endothelial dystrophy (such as Fuchs endothelial dystrophy, posterior polymorphous dystrophy and congenital hereditary endothelial dystrophy), iridocorneal endothelial (ICE) syndrome, iatrogenic or post-traumatic bullous keratopathy and endothelial failure of a prior corneal transplant [35].
Compare to PK, EK provides tremendous advantages in terms of rejection rate, graft survival, visual outcome and intraoperative and postoperative complications [36].
Advantages and disadvantages of DMEK over DSAEK
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