Ocular Manifestations of Ehlers-Danlos Syndrome
There is an amazing amount of collagen in the eye (80% of the ocular structures), but relatively, a surprising lack of vision-threatening Ehlers-Danlos Syndrome (EDS) related effects. Ehlers Danlos Syndrome patients often manifest numerous ocular symptoms. It is important to understand which symptoms may be indicative of an urgent condition and which are merely annoying. Additionally, it can be difficult to know when a symptom is Ehlers Danlos Syndrome related or is an indication of a non-EDS condition.
This summary should help to guide both patient and doctor with many pieces of the ocular puzzle, guiding both toward conservative, but not unnecessary treatment and testing.1
An incredible 27 different genes are responsible for making the collagen in the structures of the eye.2 The category of EDS that most greatly affects the eye is the rare Type VI- Kyphoscoliosis Type. In this type, there is a lack of Lysyl Hydroxylase, making the eye structure weak.3 Thus, the eye can perforate with very little trauma. Fortunately, there are only about 60 reported cases of the Kyphoscoliosis Type VI worldwide.4
The following are common ocular signs, characteristics, and symptoms for Ehlers Danlos Syndrome patients. Some patients will show many of these signs and symptoms and some will show few if any.
Also known as near-sightedness, myopia causes the patient to have more difficulty seeing objects at a distance than objects up close. Myopia is common in EDS and non-EDS patients. Myopia is typically due to a slightly elongated eye or a very steep cornea, or both.5 In Ehlers Danlos Syndrome, however, the corneas are often found to be fairly flat, meaning that the near-sightedness is due primarily to elongation of the eye.6
Ehlers Danlos Syndrome patients are prone to myopia and elongated eyes due to the stretching of the collagenous sclera. The retina (neural tissue) doesn’t stretch with the sclera but rather gets “pulled along for the ride” and can become thin resulting in retinal holes, tears, staphylomas, retinal degenerations, and detachments. Dilation of the eyes is recommended annually, or any time the patient notices a sudden increase in floaters, flashes of light (usually out to the side of the vision), or immediately if it seems as if a curtain is coming up over one eye. These can be symptoms of a retinal detachment and may need to be treated on an urgent basis.7
In this condition, the cornea (the front part of the eye) bulges outward in a cone shape, and gravity pulls the cone downward, blurring the vision and making it difficult to see well with glasses or soft contact lenses. Rigid contact lenses are usually tolerable for many years, approximately 5% of keratoconic patients will need a corneal transplant as their rigid contact lenses become less comfortable with the progression of their keratoconus. Some new research (discussed below) may radically reduce this percentage soon. Most patients with keratoconus are best treated with scleral contact lenses.
Early symptoms of keratoconus include vision that just doesn’t seem as clear to the patient as it should be – even with use of new glasses or soft contact lenses. It is usually worse in one eye than the other.
Diagnosis of Keratoconus
Corneal topography will indicate steepened corneal curvature, especially on the inferior cornea. If topography indicates keratoconus this is a prime opportunity to screen the patient for Ehlers Danlos Syndrome. This screening need not be extensive, but a quick Beighton scale, understanding that hypermobility is more common in the metacarpo-phalngeal and wrist joints with keratoconic patients, is a great place to start.8
In keratoconic patients, one eye is usually able to “cover for the other eye” for months to years, thus no treatment beyond glasses or contacts may be necessary during this time. When both eyes are involved to the point that the patient is unable to see what he/she needs to see, then other options are explored. This usually begins with gas permeable lenses, which may remain comfortable for the patient for many years.
Treatment of Keratoconus
If the gas permeable lenses designed for keratoconus are not comfortable, one of the new generations of contact lenses with a soft skirt and a rigid center are becoming increasingly popular as manufacturers are learning how to avoid the previously common splitting of the contact lens between the rigid portion and the soft portion. SynergEyes™ lenses are one of the most popular brands. Scleral lenses (rigid lenses that cover the entire cornea and overlap onto the sclera) are making an impressive comeback with increased comfort for the patient. Scleral contact lenses are now the keratoconus treatment of choice by keratoconus specialists.
Surgical Keratoconus Treatment
If these lenses are not tolerable, or if their comfort is unacceptable at any time, other options can be considered, including:
- Corneal transplantation (or grafting): This may involve a penetrating keratoplasty (a full thickness transplantation or graft) or a lamellar keratoplasty (a partial thickness transplantation or graft). These transplants are generally successful (over 90%) primarily because the cornea does not have a vascular system which would normally transport the cells to reject a transplant. It is possible to see a graft begin to develop keratoconus, but this generally doesn’t begin to occur until at least 18 years after surgery.9
- There is an exciting new discovery that could change the prognosis and lives of keratoconic patients everywhere. Researchers have learned that by rinsing the cornea with riboflavin drops for about 30 minutes, then shining UV-A rays on the cornea for about 30 minutes (CR3) the collagen fibrils of the cornea develop stronger cross-links, strengthening the cornea. This corneal strengthening is resulting in the halt and even the reversal of keratoconic progression. The implications for the treatment of Type VI EDS, and the use of riboflavin and UV-A on the skin is also enticing for most researchers, and we eagerly await testing.10
- Please be aware that patients with EDS, and especially those with signs of keratoconus, are not candidates for refractive surgery. Because of the abnormal structure of the collagen in the cornea, the patients are more prone to poor healing, corneal ectasias (bulging of the corneas after surgery), and a disappointing result. Orbscan and pachymetry results usually indicate areas of corneal thinning (prior to surgery).
Although previous studies have indicated that the population of Ehlers Danlos Syndrome patients rarely shows keratoconus, the corollary indicates the opposite – up to approximately 40% of keratoconus patients have been shown to have EDS.
This is a fairly subjective finding, but Ehlers Danlos patients tend to have thin scleras (the underlying “white part” of the eye). Thus, the darker underlying layer, the choroid, shines through with a blue-grey tinge. Most children normally have bluish scleras, but as we age the sclera thickens. This is easiest to see in a very dim room with a bright light shining on the temporal cornea (while the patient looks nasally).12
This is most commonly seen in Marfan’s syndrome or in Ehlers Danlos Syndrome patients with marfanoid phenotype (appearance), or those with EDS Type VI. The intraocular lens of the eye is held in place by thin zonules that can break easily in Marfan’s and cause the lens to subluxate. If this happens, the patient may notice double vision out of that eye. The lens is surgically removed with as little trauma to the eye as possible.13
Angioid streaks can be seen during ophthalmoscopy (best seen with the binocular indirect ophthalmoscope), and are seen in some EDS patients and patients with other conditions such as thalassemia, sickle cell anemia, Paget disease of bone, tumoral calcinosis, hyperphosphatemia, lead poisoning and PXE – pseudoxanthoma elasticum).14
Angioid streaks can be easily overlooked if the eye is examined with too much magnification. Angioid streaks appear as mud cracks in the fundus. These are actually breaks in one of the layers of connective tissue in the eye (Bruch’s membrane). If angioid streaks are seen on examination, the search should begin for a systemic cause.15 Generally, the streaks themselves are harmless. They should be monitored on an annual basis to check for abnormal blood vessel formation in the cracks which may need to be treated with a laser. Otherwise, they are mainly an indication of a systemic irregularity such as Ehlers Danlos Syndrome, causing the condition.16
Epicanthal folds are often recorded in the literature as a frequent sign of Ehlers Danlos Syndrome; however, a study of the literature reveals that “epicanthal folds” are often misdiagnosed, and true epicanthal folds are actually fairly rare in Ehlers-Danlos Syndrome.
An epicanthal fold is a fold of skin that comes down across the inner angle (canthus) of the eye. The epicanthal fold is fairly common in children with Down’s Syndrome, and many healthy babies and toddlers have epicanthal folds that they typically outgrow by the age of 3-5 years. True epicanthal folds sometimes make it appear as if the child has “crossed eyes”. This is easily differentiated from esotropia by gently pinching back the skin near the nose, and verifying that the child’s eyes are tracking properly.
What is common in the eyes and lids of Ehlers-Danlos Syndrome patients, however, is redundant skin on the upper lids, easy eversion of the upper lids and downward slanting eyes (the temporal portion of the eyelids slant down a bit). Again, perfectly harmless, but this appearance can be another piece of the puzzle for the doctor.17
Dry eyes are a common finding in EDS patients (and not uncommon in non-EDS patients). There are numerous effective treatments and medications for this symptom, which can become debilitating in some patients if left untreated.
First, the eye doctor will need to determine why the eyes are dry (and ironically, the patient’s main complaint may be watery eyes – due to reflex tearing from the corneal dryness. Unfortunately, reflex tears do not contain all three layers of tears and thus provide no therapeutic benefit to the patient).
Normal tears that cover the corneal surface are comprised of three basic components:
- The lipid, or oil component, which is the outer layer of the tear film and helps prevent the lacrimal layer beneath it from evaporating or overflowing onto the lower eyelid.
- The lacrimal, or watery component, provides the bulk of the tears and contains salts, proteins, and an enzyme called lysozyme that protects and nourishes the eye.
- The mucoid, or mucus component – the bottom (base) layer of tears. This component tends to cause the tears to adhere to the eye and prevents evaporation.
All three components of the tears in proper balance, are necessary for effective lubrication.
Diagnosing Dry Eye Syndrome
A complete dry-eye work-up is needed to determine the cause of the dryness, and thus the effective treatment. Fluorescein, together with other dyes (lysamine green or rose bengal) will indicate the extent of cell dryness and damage. A Schirmer Test can measure the lacrimal (“watery”) tear production, usually performed with anesthetic over 5 minutes.
Treatment of Dry Eye Syndrome
Treatment of dry eye syndrome primarily consists of one or more of the following; medications, nutritional supplements, artificial tears and punctal occlusion. Dry eye therapy must be tailored to the specific cause of the patient’s symptoms. Often a stepwise approach for dry eye treatment is beneficial.
The prescription medication Restasis can help eyes increase tear production, and a topical steroid drop can reduce the inflammation that often results from a chronic dry eye (this is usually used initially, then tapered and discontinued as symptoms improve). Equally important is the avoidance of medications that can cause or exacerbate dry eyes – antihistamines and diuretics, for example.
Another treatment option is the use of Lacriserts® – tiny discs made of hydroxypropyl cellulose that are inserted by the patient into the inferior cul-de-sac of the lower lid. These small discs “melt” throughout the day, providing a continuous source of moisture for the patient.
Ointments at night-time can be used (unpreserved ointments are preferred), and are especially helpful if the patient does not sleep with their eyes completely closed (“nocturnal lagophthalmus”, a fairly common condition). It is also recommended that the patient sleep without their ceiling fans.
Essential Omega 3 Fatty Acids
A critical aspect of dry eye treatment involves the use of the essential fatty acids also known as the Omega 3 fatty acids. Eicosapentaenoic acid and docosahexaenoic acid, more commonly known as EPA and DHA are the essential fatty acids that are known to improve the tear break up time by making the tears oily, thus decreasing their evaporation rate.
Punctal plugs are effective in retaining the patient’s own tears. These silicone plugs are (painlessly) inserted into the lower, and sometimes the upper and lower puncta (the opening of the tear drain, if you will). It is similar to putting a cork in the drain. These plugs are also removable, should they cause the retention of too many tears. It is generally not advisable for EDS patients to have their puncta surgically closed because of the risk of poor healing, and the common reopening of the surgically closed puncta.
There is no evidence in the literature that indicates a loss of reflex tearing with EDS.18
In glaucoma the drainage of aqueous humor (the liquid in the front part of the eye) is inefficient, or the eye produces fluid too quickly to drain effectively. This causes pressure on many structures of the eye, including the optic nerve. The damaged optic nerve can result in blindness if not treated. The most common type of glaucoma is called “primary open-angle glaucoma” or “POAG”. In cases of POAG, the drainage canal for ocular fluid appears to be open.
A highly nearsighted individual has a greater risk associated with POAG, and nearsightedness is more common with EDS. The elongated eyeball, characteristic of nearsightedness, allows a larger optic channel with the optic nerve fiber becoming more susceptible to pressure and injury.19
Glaucoma can be congenital, for example, when the trabecular meshwork, responsible for fluid drainage, fail to form completely. Some infants are born with defects in the angle of the eye that slow the normal drainage of aqueous humor, a condition most often correctable with surgery if discovered early enough. This is often seen in Type VI EDS, in conjunction with an abnormally small cornea (“microcornea”) and the thin, blue sclera.
Individuals who have either Ehlers-Danlos syndrome or Marfan’s syndrome, a condition characterized by elongation of the bones, appear to have a higher association with glaucoma.
Treatment for glaucoma (POAG) begins with eye drops and/or pills to lower the pressure. If the glaucoma is due to a defect in the drainage canal, argon laser surgery is usually indicated to open a few areas for the fluid to drain. As in any surgical treatment for Ehlers Danlos Syndrome patients, special care is taken to traumatize the eye as little as possible.20
Symptoms of POAG don’t appear until it may be too late to save the vision in that eye. Annual eye exams including routine checks of intraocular pressure (with pachymetry or Orbscan for accuracy of diagnosis) and early treatment when warranted are the best ways to thwart glaucoma and its damaging ocular effects.21
Crossed eyes or strabismus can also be found in Ehlers Danlos Syndrome patients and non-EDS patients alike.
Strabismus occurs when the six extraocular muscles that control eye movement are not in balance. Not dissimilar to the loose joints in the Ehlers Danlos Syndrome patient, one or more of the extraocular muscles is looser than the others, resulting in the eye drifting or crossing.
Extra effort may be needed to keep proper alignment of the eyes, causing eye fatigue. Multifocal lenses (bifocals or trifocals) can help to balance the muscle activity associated with changing focus from far away to close up and back to distance. Prism in prescription glasses can be helpful in directing light to the correct spot on the retina so that the eyes do not need to work so hard to do so.
Surgical repair of a strabismus may be complicated because sutures may be difficult to place in the thinned sclera of Ehlers Danlos patients, especially in Type VI. As in any muscle or ligament surgery on the EDS patient, some surgical results may not have lasting effects.22
The macula is the part of the retina that is used for central vision. In macular degeneration, loss of proper functioning of the macula results in blindness of the central vision (peripheral vision is usually left intact). It is the leading cause of blindness in those Americans over the age of 55 years, and it affects over 10 million Americans.
The cause of macular degeneration is not yet fully understood, but it does appear that Ehlers Danlos Syndrome patients are more prone to developing this condition. Macular degeneration can be divided into two types – atrophic (or the “dry” form) and the more damaging “exudative” (or “wet” form). Because the macula is physically supported by the collagen of the eye and receives nutrients through the network of blood vessels in the area, it is easy to hypothesize how a collagen and/or vessel abnormality could contribute to macular degeneration. More research will need to be done, however, to effectively treat or prevent this condition
Prevention of Macular Degeneration
A major National Eye Institute study, Age Related Eye Disease Study (AREDS), has produced strong evidence that certain nutrients such as beta carotene (vitamin A) and vitamins C and E in conjunction with zinc and Omega – 3 fatty acids may help prevent or slow progression of dry macular degeneration.23
Macular Degeneration Treatment
Until recently the only available treatment to seal leaking vessels in the exudative form of macular degeneration was with laser photocoagulation.24 This was followed by Photodynamic Therapy (PDT) with Visudyne® (a drug injected intravenously and used to help direct the laser to the affected area) and is not suitable for all types of lesions.25
Recently, it was discovered that there is a protein in the eye which encourages the development of blood vessels. Given the name “vascular endothelial growth factor” (VEGF), researchers have been working to develop treatments to inhibit VEGF by trapping it or preventing it from binding with elements which will stimulate growth. Chemically synthesized short strands of RNA (nucleic acid) called “aptamers” prevent the binding of VEGF to its receptor. Presently three types of VEGF inhibitors are in use: Lucentis, Macugen and Avastin. All are given by intraocular injection.26
Because of the inherent weakness of the sclera in EDS, these patients are more susceptible to developing posterior staphylomas. This is usually seen in conjunction with high myopia. Binocular indirect ophthalmoscopy or fundus photography are both good screening tools for staphylomas.27
Carotid-Cavernous Sinus Fistulas
A carotid-cavernous sinus fistula is the rupture of a blood vessel that subsequently bleeds into a sinus cavity and/or some part of the eye. The blood flow can cause serious structural damage to the eye and is considered a true emergency. Individuals often report hearing their pulse in their temple and having a frontal headache on one side or the other. Sometimes the eye on that side is proptotic (it seems to be more prominent than the other eye) and it can become very red. 28
Check for carotid-cavernous sinus fistula by placing a stethoscope over the patient’s temple and listen for a ‘whooshing’ sound. Carotid-cavernous sinus fistulas are more commonly found in the vascular form of Ehlers Danlos Syndrome, (Type IV), but all types and the normal population are susceptible as well. 29
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