February 21, 2011 at 5:47 pm #2992HarrisonKeymaster2 pts
Catastrophic Ocular Surface Failure in the Horse (AAEP 2010)
by: Nancy S. Loving, DVM
February 14 2011 Article # 17771
The soft, expressive equine eye holds a great fascination for horse lovers. And although it’s normally a resilient structure, it’s not immune from injury. At the 2010 American Association of Equine Practitioners Convention, held Dec. 4-8 in Baltimore, Md., Dennis Brooks, DVM, PhD, Dipl. ACVO, a professor of ophthalmology at of the University of Florida’s College of Veterinary Medicine gave this year’s Frank J. Milne State-of-the-Art Lecture on catastrophic ocular surface failure (OSF) in the horse, a condition that is most commonly caused by corneal ulcerations. He began by describing how decades ago equine eye injuries were hopeless cases, but that this is no longer true. He proclaimed, “The horse’s eye heals incredibly well, although not quickly, and our objective as veterinarians is to learn how to help it heal.”
Brooks noted that disease pathogens attacking the equine eye are some of the strongest and most complicated in all of ophthalmology, comparatively with other species. These diseases aren’t necessarily powerful because of the infections they cause, but they are enhanced because of the horse’s specific neutrophil (a type of white blood cell) response to them.
An understanding of how the eye works is instrumental in effectively treating and managing ocular injury. Brooks explained features of the ocular surface, which includes all parts of the front of the eye:
Conjunctiva lines the internal surface of the eyelids and contains lymphatic tissue.
The precorneal tear film smoothes the normally roughened corneal surface with an optical gel and tears that provide nutrition to the eye.
The limbus, which is the transition nutritive zone between the cornea and sclera, is an area of weakness.
Eyelids blink as many as 14 times per minute, and the upper lid moves the most.
The cornea is avascular (it has no blood supply), serves as a lens and a windshield, and bends light entering the eye.
Most sensory nerves in the equine cornea are superficial, so even a slight abrasion by wind causes discomfort. The mucin layer of tears attaches the tear film to the corneal surface to provide an optically smooth surface for light to pass through to the retina. This is visible as a shiny layer on the cornea. Normal replacement rate for tears is seven minutes, as compared to four minutes in humans–therefore, if medicine doesn’t stick to the cornea, it quickly flushes from the eye and (necessitating frequent treatment).
The innermost layer of the cornea, the endothelium, is one cell thick. Endothelium produces what’s called the Descemet’s basement membrane, which covers the inner surface of the cornea. This membrane is only as thick as six red blood cells. Endothelial disease interrupts “pumping” of “water” out of the normally dehydrated cornea, leading to blue discoloration from edema (fluid swelling)–the foremost part of the cornea is rich in chondroitin 6-sulphate, which absorbs water (water moves in but most be actively removed or pumped out). Topical hyperosmotic agents (5% sodium chloride) effectively draw out edema.
The horse is the only species for which it is known how fast corneal epithelial cells migrate for healing–0.6-1 mm/day. Healing begins at the corneal periphery and limbus, with healthy cells migrating across the ulcer site toward the center. Some drugs slow this down.
Brooks explained the limited ways an eye reacts to injury or disease with ocular surface failure:
Neutrophils migrate quickly into an ulcer to form an abscess or necrotic area (dead tissue) to create white cellular infiltrates;
Edema (fluid swelling) causes a blue hue; and
Superficial or deep blood vessels appear red as they migrate 1 mm/day–this is necessary for healing, but might impact the horse’s vision.
He reminded veterinarians in attendance that high-dose systemic NSAIDs (non-steroidal anti-inflammatory drugs given intravenously, intramuscularly, or orally) slow vascularization (blood supply) and, thus, can slow healing. Using topical plasma or serum hastens healing and can mean a shorter wait for blood vessel migration.
Treating OSF involves a multifold approach. Brooks stressed the importance of eliminating infection as well as reducing protease enzyme activity (indicative of ulcers) in the tear film–an ulcer won’t heal until protease activity returns to baseline. In addition, damaged or missing cornea must be replaced and the tear film rejuvenated–something the body does on its own. Another objective is to minimize inflammation of the cornea (keratitis) and iris.
As a corneal ulcer heals, epithelial cells at the ulcer edges push inward at a rate of 0.6 mm/day. It takes six weeks for epithelial cells to attach and adhere to corneal stroma (the connective tissue framework). Books said veterinarians should avoid irritating these healthy cells–some antibiotics such as ciprofloxacin are irritants. Brooks recommended waiting as long as possible to begin topical corticosteroid treatment.
A veterinarian can use fluorescein dye to detect defects in corneal epithelium, such as abrasions, erosions, or ulcers; cobalt blue filters in ophthalmoscopes aid visibility of fluorescein. Tear film (which is normally continuous; blinking maintains this continuity) normally breaks up in about 22 seconds if the eye is held open–this process is visualized by staining with nondiluted fluorescein, holding the eyelid open, and timing breakup of the tear film. If the break up occurs too quickly, this indicates the tear film is abnormal, which can slow healing. Rose Bengal dye stains for tear film instability, testing positive for virus, fungi, immune-mediated keratitis (a painful corneal disease), granulation or scar tissue, wind abrasion, or edema.
Seidel’s test screens for leaks of anterior chamber fluid through full thickness corneal ulcers or holes. The veterinarian stains an eye with fluoroscein and observes for leaking aqueous humor that dilutes the tear film. This is especially helpful when evaluating trauma or integrity of corneal sutures.
The equine cornea is constantly exposed to microbes. It was previously thought that cornea had to be damaged before bacteria or fungi could colonize, but in fact Brooks reported that microorganisms don’t require physical corneal damage to set up infection. Another suggested source of infection might be inoculation of microbes through a micropuncture (a traumatic injection of a microbe or foreign body).
Ocular surface barriers generally protect the eye from infection; however, Brooks noted that something in horse tears attracts neutrophils to sites of corneal injury, rendering these barriers ineffective. Neutrophils move in quickly, about 8 mm/day, and when these neutrophils die, they release enzymes that create adverse reactions in the eye (observable as an ulcer). An ulcerated equine eye has high tear protease levels, and it can be difficult to combat these enzymes in the face of infection. Bacteria and fungi also might repopulate during topical drug administration, complicating treatment.
Bacteria or fungi form around themselves a protective extracellular substance called biofilm, which makes them difficult to kill and culture, despite active infection in an injured eye. Once organisms rupture from the biofilm, Brooks said they seem more pathogenic (able to cause disease) than before. Debriding an ulcer interrupts the biofilm layer while removing necrotic tissue and is important to healing. Topical EDTA (ethylenediaminetetraacetate) is also useful to break up biofilm, so Brooks recommended combining EDTA and serum for treatment. Serum, usually taken from the eye-injured horse, might be more effective if obtained from a normal horse.
As mentioned before, neutrophils pose a major problem in equine corneal disease resolution by eliciting and releasing destructive enzymes. Metalloproteinase (MMP) enzymes are present in the cornea, specifically MMP-2; this particular MMP is important for growth and for repair related to wear and tear. Bacteria and microbes don’t produce MMPs; these enzymes are present in relatively inactive forms in the eye until an injury occurs. Corneal damage induces activity of MMP-9, which digests collagen. Neutrophil elastase (a serine protease, or proteinases) has active role in collagen destruction as well, but veterinarians aren’t sure what it is at this time; it might impede the inhibitors of MMP-9, creating a vicious cycle (i.e., the cornea is damaged, MMP-9 is released at higher levels than NE, but the inhibitor of MMP-9 makes the NE more active). Interestingly, Brooks noted that proteases increases are evident in tears of both eyes of a horse with an ulcer in only one eye.
A veterinarian can prescribe a single oral dose (10 mg/kg) of doxycyline (an antibiotic) to provide anti-protease activity for three days. Plasma, EDTA, and serum (blood plasma minus the clotting factor) also inhibit MMP activity. Another treatment Brooks prefers involves using amnion (placental membrane) to cover the cornea (via suture or bioadhesive) so that enzymes attack amnion rather than cornea as the ulcer heals. Amnion has strong anti-inflammatory properties that combat fibroblasts (connective tissue cells) that would otherwise scar. Brooks remarked that amnion gives Mother Nature time for the cornea to heal on its own. Other methods of corneal protection include contact lenses, collagen shields, third eyelid flaps, or temporary tarsorrhaphies (sewing the eyelids together).
Ulceration might progress in spite of effective antibiotic treatment. Veterinarians often use medication “cocktails” to treat difficult ulcers. Brooks described a combination of an antifungal drug (natamycin) and antibiotic (tobramycin and cefazolin) with serum. Diluting serum with these other drugs reduces anti-protease activity, but this cocktail is more effective against microbes than any of the drugs used alone. Indwelling lavage systems are an excellent way to infuse treatment, he said, noting that upper lid lavage treatment systems deliver greater concentration of medication to corneal lesions than lower lid lavage systems.
“It is rarely true that severe corneal disease results in anterior uveitis (inflammation of uvea including iris tissues),” he pointed out. Brooks stressed that horses are able to compartmentalize ocular inflammation, containing it to the front of the eye most of the time.
Medical treatment of ulcers includes attacking infectious microbes, decreasing tear protease activity, and treating concurrent anterior uveitis (inflammation of the iris and ciliary body–the circular muscle located behind the iris) when present. The latter could potentially lead to cataracts due to fibrin (a protein in the blood that forms an essential part of blood clots) adhesions (synechia) to the lens. Brooks noted that corneal ulcer disease severity cannot be equated directly with severe uveitis severity. Nonetheless, it is important to dilate the pupil promptly in a painful eye with uveitis because synechia can occur in seconds. One drop of atropine in a normal horse’s eye dilates the pupil (to prevent blindness) for two weeks. Brooks stressed that veterinarians exercise caution recommending topical atropine treatment since applying atropine to the eye four times a day for three days can decrease gastrointestinal motility. Combining atropine with phenylephrine achieves dilation that is safer to the GI tract. Often there is unnecessary concern that a horse with a dilated pupil will suffer retinal damage. This won’t occur unless the horse stares at the sun for an hour, which as Brooks pointed out, a horse isn’t likely to do.
In most cases, Brooks noted that mild fungal keratitis (corneal inflammation) resolves on its. However, in cases of trauma with plant material or subsequent to treatment with topical corticosteroids or antibiotics, fungi might take hold. Fungal plaques inhibit healing and destabilize the tear film. The corneal surface often appears dry in these horses, lacking its normal glistening luster. Brooks explained that fungi attacking the equine cornea produce an as yet unidentified chemical that inhibits blood vessel growth for ulcer repair. The more proteases present, the deeper fungi can invade.
Brooks described a stromal abscess as an infection within the corneal stroma beneath the eye surface. The more superficial the abscess, the more likely it’s bacterial rather than fungal. Deep abscesses cannot be drained because they usually contain solid material related to fungal infection, trauma, or ocular manifestation of systemic disease (OMSD, a disease in the body other than the eye that can cause illness in the eye.)
Treating Deep Eye Injury
A descemetocele (herniation of Descemet’s membrane) nearing rupture doesn’t stain with fluoroscein, and lack of nerves in that location might prevent the eye from appearing painful. For deep ulcers such as this, surgical treatment is often necessary. A third eyelid flap only provides physical support to such an ulcer while it’s healing, while a conjunctival pedicle flap (conjunctiva pulled across the ulcer and sutured in place) also provides continual plasma lavage as anti-protease treatment. Conjunctiva is only able to stick to ulcerated cornea, so this prevents any untoward adhesions elsewhere in the eye. Fibroblasts move in quickly and leave a significant scar that obscures a horse’s vision–Brooks said he finds this unacceptable so he looks to other methods of repair.
A prolapsed iris is an example of an eye trying to heal itself by plugging the hole with its own tissue and fibrin. Brooks said this isn’t a hopeless condition, yet only 40% of affected eyes retain vision following conjunctival flap treatment. A corneal transplant increases chance of vision to 68%. An iris that has prolapsed secondary to a corneal ulcer has a poorer prognosis –only 30% retain vision. To determine if a horse has the potential for sight in a seriously damaged eye, Brooks said to aim a bright light at the eye to see if the horse squints.
Penetrating keratoplasty (PK) and lamellar keratoplasty (LK) are corneal transplant techniques: PK is a full-thickness transplant of ocular structures; LK uses split-thickness tissues. Veterinarians remove the diseased tissue of an iris prolapse or deep corneal stromal abscess and replace it with a PK or LK graft. With these surgeries the veterinarian attempts to prevent enucleation (eye removal), but full vision might not be restored because many equine ocular disease processes deteriorate vision. Brooks achieves 80-92% success in retaining the eye when treating catastrophic eye injuries with these methods.
Brooks suggested that targeted corneal tissue replacement might be a more logical surgical approach, using only epithelium, epithelial stem cells, stroma, or Descement’s membrane, depending on which tissue requires replacement. He appealed to horse owners to help save sight in horses by donating corneal tissue from a horse that is dying from a condition other than ocular disease.
He emphasized throughout his presentation that the horse eye wants to heal and that current knowledge, techniques, and expertise are available to help equine eyes achieve this goal.
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