AIDS and the Eye

AIDS and the Eye
C. Stephen Foster, MD, FACS, FACR

The ocular manifestations of AIDS revolve primarily around infectious and malignant disease. Prior to the advent of multi-drug “cocktail” therapy for HIV infection, opportunistic infectious disease of the eye was extremely common, and, in fact was a sentinel “marker” for a marked reduction in CD4 cell counts and entry into the final, lethal stages of AIDS.

With the advent of multi-drug anti-HIV therapy, the prevalence of opportunistic AIDS-related eye infectious disease and malignancy has been dramatically reduced. Still, we will occasionally see a patient in whom the onset of an ocular infectious disease is, in fact, the first clinical manifestation of the presence of occult HIV infection. For example, we recently cared for a young man who had had an outbreak of shingles (herpes zoster infection) affecting one eye, and unlike the situation in immunocompetent individuals who sustain such an infection, this patient’s problem persisted, resisted all efforts, both medical and surgical to bring an end to the problem, and eventually resulted in a search for an occult explanation for why this person’s ocular infectious problem should be so persistent. It was discovered that his CD4 T cell count was quite low, and a recommendation was made to him that HIV antibody and antigen testing be performed. Both tests were positive, enabling the clear establishment of the diagnosis and thereby referral to the appropriate physicians to institute multi-drug therapy for this patient’s HIV infection.

Other microbes are also notable “sentinel markers” of HIV infection. These include toxoplasmosis, Candida (fungus), herpes simplex virus, Pneumocystis carinii, cytomegalovirus. It is the latter microbe which used to produce the most profound ocular morbidity in patients with AIDS, producing a bilateral necrotizing retinitis which ultimately blinded many patients prior to their demise. Other microbes, including syphilis and tuberculosis and Cryptococcus and Cryptosporidium and microsporidium are also potential opportunistic pathogens which can express themselves as an eye infection in patients who are immunocompromised secondary to AIDS. The most common malignant problem which may occur in the eye as a consequence of such immunocompromise is kaposi’s sarcoma, usually affecting the conjunctiva. Lymphoma and various types of carcinoma may also develop in the eye.

Major advances have occurred in the past decade and a half in both the diagnosis and treatment of patients with HIV infection. The HIV epidemic is still with us, however, and will remain so for the indeterminate future. The most effective strategy for avoiding HIV infection remains celibacy and avoidance of high risk behaviors such as drug abuse, for those individuals who are not sexually active and monogamy with an known, uninfected partner for those who are sexually active. The hope for all of us, of course, is that the quest for development of an effective vaccine, which can be highly protective, will be successful.

Association of Ocular Inflammatory Disease with Inflammatory Bowel Disease

Association of Ocular Inflammatory Disease with Inflammatory Bowel Disease
C. Stephen Foster, M.D., F.A.C.S, F.A.C.R.

Even more surprising than the association between arthritis and eye inflammation, at least to some people, is the association between bowel inflammation and eye inflammation. But history tells us that such an association exists. This may be true not only in infectious inflammatory bowel disease, as in the case of Whipple’s disease, but also in inflammatory bowel disease(IBD) generally considered to be autoimmune. For example, approximately 5% of patients who develop ulcerative colitis will experience episodes of recurrent uveitis; some patients with ulcerative colitis will develop other ocular inflammation such as scleritis or episcleritis. And an even greater association exists between Crohn’s disease (regional ileitis) and ocular inflammation. Interestingly, the “activity” of the inflammation in the eye and the inflammation in the gut rarely are concurrent, i.e., the inflammatory bowel disease may be under excellent control, but uveitis may be extremely troublesome, and vice versa, the eye may not have any difficulty at all, while the patient is having major flare-ups of inflammatory bowel disease. Additionally, one of the more effective medications for control of the inflammatory bowel disease activity, Sulfasalazine, has proven to be, in our hands and in those of others, particularly disappointing in controlling the recurrent episodes of uveitis in patients with inflammatory bowel disease-associated uveitis. Patients with IBD associated uveitis generally required one of the immunomodulatory medications, such as Methotrexate, Azathioprine,or Cyclosporin and in some cases may need to have biologic therapy, such as Remicade or Humira.

In contrast, patients with “irritable bowel syndrome” associated uveitis can often be managed with topical therapy or with sulfasalazine or an oral non-steroidal anti-inflammatory agent without the need of a immunosuppressant/immunomodulatory agent. The exact connection between “irritable bowel syndrome” (as opposed to inflammatory bowel disease), and uveitis is not well proven, but it has been the strong clinical impression of many experts of uveitis that such an association exists.

Birdshot Retinochoroidopathy

Birdshot Retinochoroidopathy
C. Stephen Foster, M.D., F.A.C.S, F.A.C.R.

What is Birdshot Retinochoroidopathy?

Birdshot retinochoroidopathy, commonly referred to simply as “birdshot”, is a rare form of posterior uveitis which mainly affects the retina and choroid. The disease occurs in women more often than men, typically Caucasian, and most often between the ages of 30 and 60. “Birdshot” can be a severe and blinding disease if unrecognized or undertreated.

What causes “birdshot”?

The etiology of the disease is, as yet, unknown. There is a class of genes known as human leukocyte antigens (HLA), and specifically one called HLA-A29 (also HLA-A29.2 or HLA-A*2902), that is present in the overwhelming majority of “birdshot” patients, and is thought to be involved in the development of the disease. Infection, by virus or bacteria, in susceptible individuals is thought to act as a trigger, with the disease then being self-propagated by an autoimmune mechanism.

What are the symptoms of “birdshot”?

It is normally a chronic problem, with symptoms that develop and progressively worsen over several months to years. The most common complaints are:

  • Floaters and flashes
  • Blurry or hazy vision, sometimes described as looking through murky water
  • Decreased color and/or night vision

Patients usually do not complain of pain or redness, though it can be present. There are not any systemic diseases that are typically associated with “birdshot”.

How do you diagnose “birdshot”?

Clinical examination is the most important tool in the diagnosis of “birdshot”, though a full history and review of systems must be performed to help evaluate for other potential infectious or autoimmune causes. Examination often shows little to no inflammation in the “front” of the eye, however dilated exam can reveal a dense collection of inflammatory cells and debris in the vitreous, pallor of the optic nerve, attenuation of retinal vessels, retinal vasculitis, macular edema, and the presence of “birdshot lesions” or creamy yellow-white spots involving the retina and choroid. Cataract formation can also occur as a result of long-standing inflammation or chronic use of corticosteroid eye drops. Rarely, new blood vessels can sometimes grow between choroid and retina which can cause severe vision loss even after inflammation is treated.

What testing is performed to help diagnose “birdshot”?

A large array of clinical testing can be very helpful, starting with checking blood work, especially for the presence of the HLA-A29 gene when “birdshot” is suspected. Color vision testing can show mild to severe deficit. Fundus autofluorescence may reveal abnormal areas of hypopigmentation that correspond to “birdshot lesions” or overlap areas or normal appearing retina. Fluorescein angiography may show window defects in areas of “birdshot lesions” or evidence of macular edema, retinal vasculitis, optic nerve inflammation, or choroidal neovascularization. Indocyanine green (ICG) angiography is used to evaluate the choroid, and can show hypolucent lesions that may not be visible on dilated exam. Visual field testing with a blue-on-yellow protocol (shortwave automated perimetry, or SWAP) is more sensitive than normal white-on-white visual field testing, and may show more advanced field defects. Optical coherence tomography (OCT) can reveal macular edema or epiretinal membranes. Lastly, and perhaps most importantly, standard electroretinogram (ERG) can be a very useful tool in both the diagnosis of “birdshot”, and in assessing response to therapy, particularly the 30-Hertz photopic protocol, which will often show delayed implicit times and decreased signal amplitudes that may improve with treatment.

Can “birdshot” be treated?

Yes, this disease is very treatable, and after proper treatment, it is even possible to achieve long-term remission of active inflammation while off all medications. Unfortunately, damage done to retina and choroid, and to most other parts of the eye affected, is irreversible, which makes timely recognition and initiation of therapy the key to a good outcome and preserving vision.

How do you treat inflammation from “birdshot”?

“Birdshot” is a severe and stubborn form of uveitis, and as with all types of uveitis, inflammation must be quieted by whatever means necessary or blindness will ensue.

Corticosteroids
Coritosteroids are usually the way to treat most non-infectious uveitis quickly, but for “birdshot”, the way in which they are given may have an effect on the disease course. Our research at MERSI has found that patients who have received oral corticosteroids have shown a higher rate of disease recurrence, even after achieving long-term remission on immunomodulatory therapy. Injection into the eye (intravitreal injection) was not shown to have this risk. Topical eye drops are not effective in treating inflammation in the back of the eye.

Immunomodulatory Therapy
Immunomodulatory therapyis the standard of care for treating birdshot retinochoroidopathy. Our years of experience at MERSI treating patients with “birdshot” have shown the most effective initial treatment strategy involves starting combination therapy with mycophenolate mofetil (CellCept®), an antimetabolite, and modified cyclosporine A, a calcineurin-inhibitor. In cases of intolerance or poor efficacy, mycophenolate is sometimes replaced with another antimetabolite, or the patient is transitioned to intravenous therapy with a TNF-α inhibitor such as infliximab (Remicade®). Stubborn and poorly controlled disease on these medications may require use of an alkylating agent such as cyclophosphamide (Cytoxan®).

Corticosteroid Implant
A corticosteroid implant surgically placed within the eye, fluocinolone (Retisert®), can be used for patients who are not able to achieve remission on or tolerate immunodulatory therapy, or in cases where this option presents less of a burden on life than long-term medical therapy.

What other problems are associated with “birdshot” and how are they treated?

Cataracts and Glaucoma
Cataracts and glaucoma can both occur as a result of active inflammation or long-term treatment with corticosteroids.

  • Cataracts can be removed, ideally when inflammation has been treated and the eye is quiet, but may need to be removed to see and treat problems inside the eye.
  • Glaucoma is initially treated with eye drops, followed by laser therapy, and lastly surgery if necessary.

 

Retina
Problems with the central retina, especially macular edema and epiretinal membranes, are frequently seen.

  • Macular edema may resolve when inflammation is treated, however if it persists, it can also be treated with topical NSAIDs or oral acetazolamide.
  • Epiretinal membranes can be surgically removed if they are felt to cause progressively worsening vision. Intraocular injection of either corticosteroid or a VEG-F inhibitor, such as bevacizumab (Avastin®), is extremely effective in treating macular edema. These can also be used to treat choroidal neovascularization, new blood vessels that grow between retina and choroid as a result of a break in the barrier that lies between them.

Cataract Surgery and Uveitis

Cataract Surgery and Uveitis
C. Stephen Foster, M.D., F.A.C.S, F.A.C.R.

Cataract develops in patients with uveitis because of the uveitis itself and also because of the steroids which is the cornerstone of treating uveitis. Cataract developing in an eye with a history of chronic or recurrent uveitis has historically been called cataracta complicata, and, indeed, the uveitic cataract is complicated cataract. It is complicated both from the standpoint of technical aspects of the surgery itself (limited access secondary to posterior synechiae, pupillary membrane, and pupillary sphincter sclerosis, iris delicacy and vascular abnormalities, and pre-existing glaucoma), and also because of the high likelihood of an exuberant postoperative inflammatory response which can ruin the desired surgical outcome. But the increasing availability of more delicate microsurgical techniques, through the use of pupil expanders, visco elastic material, small incision phacoemulsification techniques, etc. has dramatically reduced the misadventures that use to be so common.

Yet, despite these advances surgeons are frequently still disappointed with the visual outcome of cataract surgery in the patient with a history of uveitis. This typically occurs as a result of two things: damage done to the macula or optic nerve long before the time for cataract surgery has arrived, through the consequences of recurrent or chronic, even “low grade” inflammation; and significant ongoing chronic or recurrent inflammation which sabotages an initially good visual result from cataract surgery. Both these problems are avoidable, but avoidance of structural damage to areas of the eye critical for good vision requires a philosophy, on the ophthalmologists’ part, of total intolerance to chronic or recurrent inflammation, achieving the goal of complete freedom of inflammation through a stepladder algorithm approach in aggressiveness of therapy. Indeed, prevention of cataract development in the first place often derives from such a philosophy. And postoperative inflammatory damage which sabotages an initially good visual outcome occurs, generally, if the patient is prepared ahead of surgery with treatment techniques that prevent exuberant inflammation postoperatively, and prevent a recurrence of inflammation or a continued low grade chronic inflammation longitudinally following surgery.

The exact details of surgical technique, above and beyond the routine required for adequate access to the lens and control of inflammation is very much patient and disease-specific. For example, many (indeed, perhaps even most) patients with a history of uveitis can have, as part of the surgical plan, implantation of a posterior chamber intraocular lens implant; exceptions to this generalization exist, for example, in most patients with uveitis on the basis of juvenile idiopathic arthritis, and in patients for whom recurrent inflammation episodically through time is unpredictable and generally not preventable (i.e., patients with sarcoidosis, or even with patients with a history of multiple recurrences of toxoplasma retino-choroiditis.) Also, the exact details of which glaucoma procedure to perform, in the patient who needs glaucoma surgery in conjunction with cataract surgery, is also somewhat disease-specific and patient-dependent. And, finally the issue of simultaneous pars plana vitrectomy is very much disease-dependent. We believe, for example, that most patients with JIA-associated iridocyclitis and patients with pars planitis or uveitis that has been characterized by great “vitritis” or multiple recurrences affecting the posterior segment very much benefit from primary pars plana vitrectomy at the time of the cataract surgery.

For further reading on this subject may I suggest the following references:

REFERENCES:

  1. Foster CS, Barrett F: Cataract Development and Cataract Surgery in Patients with Juvenile Rheumatoid Arthritis-associated Iridocyclitis. Ophthalmology 1993; 100:809-817.
  2. Foster CS, Fong LP, Singh G: Cataract Surgery and Intraocular Lens Implantation in Patients with Uveitis. Ophthalmology 1989; 96:281-288.
  3. Foster RE, Lauder CY, Meisler DM, et al: Extracapsular cataract extraction with posterior chamber intraocular lens implantation in uveitis patients. Ophthalmology 1992; 99:1234-1241.
  4. Gee SS, Tabbara KF: Extracapsular cataract extraction in Fuchs’ heterochromic iridocyclitis. Am J Ophthalmol 1989; 108:310-314.
  5. Kaufman AH, Foster CS: Cataract extraction in pars planitis patients. Ophthalmology1993; 100:1210-1217.
  6. Seamone CD, Deschenes J, Jackson WB: Cataract extraction in uveitis: comparison of aphakia and posterior chamber lens implantation. Can J Ophthalmol 1992; 273:1231-124.

Cataract Surgery in Ocular Cicatricial Pemphigoid

Cataract Surgery in Ocular Cicatricial Pemphigoid
C. Stephen Foster, M.D., F.A.C.S, F.A.C.R.

We reported the results of our experience with cataract surgery in 20 patients (26 eyes) with biopsy-proven cicatricial pemphigoid. All patients were on systemic immunosuppression at the time of surgery (dapsone, azathioprine, cyclophsophamide, or combinations) and were treated with peri-operative oral corticosteroids. Patients were evaluated pre- and postoperatively for conjunctival inflammation, conjunctival cicatrization, degree of keratopathy, and disease stage. No patient progressed in disease stage. Vison improved an average of 3.5 Snellen lines (-3 to +8). Worse outcome was associated with chemotherapy intolerance or the presence of any preoperative conjunctival inflammation. Thirteen patients remained on immunosuppressives for the entire study. Corneal ulcers developed postoperatively in three patients in whom continued immunosuppression was not tolerated. Results indicate that after successful abolition of all conjunctival inflammation through chemotherapy, cataract surgery may be safely performed in patients with cicatricial pemphigoid.

Connection Between Arthritis and Ocular Disease

Connection Between Arthritis and Ocular Disease
C. Stephen Foster, M.D., F.A.C.S, F.A.C.R.

The eye is made up primarily of collagen, as are ligaments, tendons, and tissue within joint spaces. It is, perhaps, primarily because of this similarity in composition that the eye is often affected by many of the same diseases which affect joints. Some of these disorders include Juvenile Rheumatoid Arthritis, Adult Rheumatoid Arthritis, Systemic Lupus Erythematosus, Relapsing Polycondritis, Behcet’s Disease, Granulomatosis with Polyangiitis (formerly called Wegener’s), Polyarteritis Nodosa, and Scleroderma or systemic sclerosis. Additionally, the type of vasculature that is present in the eye has special characteristics that produce an extraordinarily sensitive “barometer” or “sentinel canary” in the eye for potentially lethal vasculitis that can be associated with the aforementioned collagen vascular diseases. Specifically, we know from considerable experience that, despite the fact that a patient’s rheumatoid arthritis may be “burned out” as far as active inflammation of the joints in concerned, nonetheless, the patient may well have subclinical rheumatoid vasculitis affecting various internal organ systems. The eye is a very potent indicator of such subclinical potentially lethal vasculitis, and if the eye becomes involved with retinal vasculitis, uveitis, scleritis, or peripheral ulcerative keratitis in such a patient, we take that as a very strong signal that the patient must be evaluated extremely carefully for potentially underlying vasculitis affecting viscera and we also take such a potentially blinding ocular lesion very seriously from the standpoint of the need for aggressive systemic immunomodulatory therapy in order to prevent permanent damage to the eye from such lesions.

For example, we have seen many instances in which patients with systemic lupus erythematosus appear, systemically, to be doing quite well (indeed, the patient’s Rheumatologist has told her that she is doing very well) despite the fact that new-onset uveitis, scleritis, or retinal vasculitis has developed in one eye. We have seen this story evolve to life-threatening central nervous system vasculitis and/or lupus renal disease when the onset of the ocular inflammation was not taken as an indication for increasing the vigor of systemic therapy. We have tried diligently, therefore, over the past 15 years to raise the consciousness, not only of ophthalmologists worldwide, but also of rheumatologists and other internists of the valuable indicator that the eye can be with respect to seriousness of associated arthritic/collagen vascular disease.

Connection Between Skin Disorders and Ocular Disease

Connection Between Skin Disorders and Ocular Disease
C. Stephen Foster, M.D., F.A.C.S, F.A.C.R.

Most individuals do not realize the extraordinary connection between skin and eye, much less the fact that many skin diseases have concomitant ocular manifestations. These may range from the relatively trivial, nuisance consequences of acne rosacea, with its associated chronic eye lid and conjunctival inflammation, to the profoundly vision-threatening ocular consequences of ichthyosis, pemphigoid, Stevens Johnson Syndrome, and, even in some cases, allergic diseases like eczema.

Patients with inflammatory eye disease (as opposed to cataract or macula degeneration or glaucoma) would be well advised to alert their ophthalmologist to the fact that they have a skin disorder, if they have one. By being alerted to the existence of a dermatologic condition, the ophthalmologist may very well discover that the patient’s inflammatory eye problem is, in fact, closely related to the dermatologic problem, and this may well guide therapy to a more systemic approach, rather than through the simple expedient of local topical drop therapy.

Corneal Transplantation and Immunologic Tolerance

Corneal Transplantation and Immunologic Tolerance
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Corneal transplants, more often than not, are “tolerated (i.e., not rejected), unlike solid organ transplants such as heart, lung, kidney and skin. For 40 years it was imagined that this phenomenon occurred because of the lack of blood vessels and lymphatics in the cornea, resulting in antigen “invisibility” of the foreign material (i.e., piece of cornea from an unrelated donor), from the recipient patient immune system, and therefore the lack of an immune response against the corneal transplant. Indeed, a British immunologist was awarded the Nobel Prize in Medicine in the early 1950’s for his experiments on this topic, and his description of the phenomenon of immunologic tolerance.

It turns out, however, that the high success rate enjoyed by most corneal transplants is more complex than imagined 40 years ago. The foreign corneal antigens or proteins on the transplanted cornea are not invisible for the recipient’s immune system, but rather are recognized very rapidly by the recipient’s immune system. The thing is, however, rather than an “attack-and-destroy” immune response, a curious (and lucky for us) immune response develops in which regulatory cells which actively discourage the development of “attack-and-destroy” cells in the immune system are rapidly developed, and it is the continued activity of these regulatory cells which accounts for the tolerance of most corneal transplants. Tolerance can be interrupted or broken if the immune system is perturbed, particularly if it is “reved up” through an upper respiratory infection or immunization, with the result that “attack-and-destroy” types of immunologic cells suddenly do begin to attack the corneal transplant. In most instances, the patient and ophthalmologist will recognize this quickly, will treat the eye with frequent application of steroid eye drops, and will eventually be able to stop those eye drops, despite the fact that it is quite clear that the recipient immune system has now unquestionably recognized that foreign corneal transplant, and has made an immune response against it. But the temporary use of the steroid drops has allowed the brief perturbation in the immune system to subside and has enabled the patient’s regulatory cells to once again gain the upper hand, mediating the continued freedom from transplant rejection.

The take home lessons most important from this story for patients are:

  1. Corneal transplants have an extraordinarily high degree of success today;
  2. Even if the patient develops an episode of corneal transplant rejection, recognition of the earliest signs and symptoms of that by the patient (discomfort, light sensitivity, redness, decrease in vision,) with prompt presentation to the ophthalmologist and recognition by that ophthalmologist that the earliest phases of a transplant rejection exist, will result in aggressive treatment of the transplant with steroid drops, and salvage of the transplant 90% of the time.

Diabetes and Diabetic Retinopathy

Diabetes and Diabetic Retinopathy
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Diabetic retinopathy is a leading cause of blindness in the United States, and, indeed, in all developed countries. Sixteen million Americans have diabetes; only about half are aware that they have it. One type, Type 1, has its onset in childhood or young adulthood, and it typically requires insulin therapy nearly from the beginning of its onset. Type 2, adult onset diabetes, often can be treated with diet or diet plus oral medications, but a significant number of people with Type 2 diabetes also evolve into the need for insulin therapy.

Diabetic retinopathy is characterized by blood vessel damage and poor delivery of oxygen and nutrients to areas previously supplied by the damaged blood vessels. Almost everyone who has diabetes for 20 or more years will develop some degree of diabetic retinopathy. Typically the type of retinopathy which develops in most patients, at least in the beginning, is called “background” retinopathy, with the development of small aneurysms in blood vessels, and the development of hemorrhages and exudates and edema in the retina. As areas of the retina become more and more starved for oxygen, these changes in the retina increase, and eventually new blood vessel formation develops, the phase of diabetic retinopathy known as “proliferative” diabetic retinopathy. Ordinarily, one might imagine that such new blood vessels would be good, given the fact that perhaps they could supply more blood and oxygen to the oxygen-starved areas of retina. However, these blood vessels are not normal, are incredibly delicate, typically leak, and frequently rupture and hemorrhage, producing pronounced degrees of vision loss as a result of these consequences.

This form of advanced, proliferative diabetic retinopathy occurs in about 25% of patients with insulin dependence for 15 years or more. Additionally, even in those patients with Type 2 diabetes not taking insulin, a quarter will develop proliferative diabetic retinopathy at about the 25-year anniversary of their diabetes.

In addition to the duration of diabetes, the “tightness” of blood sugar control is a clear additional factor related to the likelihood of onset of diabetic retinopathy; the better and more faithful the blood sugar control, the less likely proliferative diabetic retinopathy is to occur.

Prevention, therefore, may be possible through very vigorous blood sugar control each day. Additional risk factors for retinal and blood vessel disease (high blood pressure, high blood fat levels, smoking, etc.) may also be influential and are worthy of attention.

Treatment of diabetic retinopathy, once it develops, revolves around laser photocoagulation treatments (in addition, of course, to proper blood sugar control). Patients who develop mild to moderate “background” retinopathy with clinically significant edema of the retina may require simple “spot” treatment with laser, while those who develop more severe “background” retinopathy, with or without clinically significant macula edema, will probably require much more extensive (so called “pan retinal”) laser treatment. Patients with proliferative diabetic retinopathy will usually require pan retinal photocoagulation and sometimes will require additional, spot treatments near the macula. Finally, vitrectomy surgery will be required for those patients who develop proliferative retinopathy with hemorrhage into the vitreous.

Dry Eye

Dry Eye
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Dry Eye or Keratoconjunctivitis sicca syndrome (KCS or dry eye) is a problem of major epidemiologic importance. It affects literally millions of people around the globe, with women dramatically over represented, particularly those women who have entered menopause. The problem may accompany dry mouth, and may be found in association with a systemic disease such as rheumatoid arthritis or systemic lupus erythematosus. It is, in many instances, far more than a simple “nuisance” problem. It has the potential for serious ocular consequences, beginning with the formation of dry spots on the cornea, progressing to epithelial defects or “abrasions” which resist healing, and then in some instances eventuating to ulceration of the cornea, sometimes even with frank perforation.

The mainstay of treatment for dry eye syndrome through the years has been replacement of fluid through the use of artificial tears. And while this is an important approach to the treatment of dry eye, it is by no means the only (or perhaps even the most important) approach. Conservation measures are also extremely important: the use of punctum plugs to reduce the lose of fluid from the eye through the nasolacrimal duct into the lacrimal sac and then down the throat, the use of side shield panels to spectacles to reduce the amount of air flow across the cornea and hence reduce evaporation, and the use of humidification techniques at home, again, in an effort to reduce the rate of loss of fluid from the surface of the eyes through evaporation. Additionally, we strongly believe that increasing the flow of oil from the oil ducts in the eyelids that supply a thin film of oil to the preocular tear film is extremely useful and important in the care of patients with KCS. Almost every patient whom I see with dry eye has a significant contribution from the oil component of the tear film being deficient. The use of warm compresses twice daily with gentle lid massage to dilate the oil ductules in the lids, further liquefy the oil, which sometimes “sets up” like toothpaste inside the oil ducts, promotes continual flow of oil to the tear film, producing a much more stable tear film and a tear film which is much more efficient at keeping the surface of the eye lubricated, retarding evaporation of the liquid from the surface of the eye, and promoting more uniform spreading of the tear film across the entire extent of the ocular surface.

The use of anti-inflammatory and immunomodulatory agents by topical application also play a role in many patients’ dry eye care, since inflammation of the lacrimal gland has been shown to be present and to be hindering the normal function of that tear-producing gland in a significant proportion of patients with dry eye disease. Hence, topical Alrex (a weak corticorsteroid) and topical Restasis (containing cyclosporin) have been shown to be beneficial in such patients. Xiidra (Lifitegrast) is a new immune mediator dropfor management of dry eye shown to be effective as well.

Additionally, dietary supplementation with foods rich in omega 3 free fatty acids, such as cold water fish (eg, salmon) can also help in the restoration of the normal health and functioning of the dysfunctional lacrimal and Meibomian glands. Lipiflow procedure is another option for treatment of Meibomian gland dysfunction and Blepharitis.

Finally, the use of specially constructed scleral lenses can additionally be helpful in retaining a layer of liquid against the cornea in patients who have profound lack of adequate tears.

Episcleritis

Episcleritis
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

What is episcleritis?

Episcleritis is inflammation of the episclera, which is the thin vascular outer coating of the eye wall, the sclera. Episclera lies underneath the more superficial layers of conjunctiva and other connective tissues. Unlike the more severe disease scleritis, episcleritis is a benign condition and is usually not associated with other systemic inflammatory diseases. The vessels that appear inflamed in either episcleritis or scleritis actually run through the episclera. It can appear in one section of or diffusely over the eye, or as a nodule of inflammation on the eye. It can occur in both eyes simultaneously, but more often occurs just in one, and almost never causes any permanent damage. Most often it is seen and treated by general ophthalmologists or even primary care physicians, unless the problem becomes more frequent or severe.

What are the symptoms of episcleritis?

Redness is the main symptom of episcleritis. Patients will sometimes also complain of irritation or even burning. Symptoms can start and stop abruptly, and can recur often. Frank pain is not present and the eye should not be tender to the touch nor be significantly sensitive to light. Any of these symptoms suggest another disease process is taking place.

Do I have episcleritis or scleritis?

This is the most common point of confusion for most patients who have been afflicted by inflammation of the eye wall, and unfortunately, also for many eye care specialists who see these patients when their disease presents for the first time. Redness is common to both, but in episcleritis it involves the more superficial blood vessels in the conjunctiva and episclera, where as in scleritis it involves the deeper episcleral vessels. In episcleritis, this redness will mostly disappear when your ophthalmologist puts certain kinds of dilating eye drops in your eyes, but in scleritis, the deeper vessels will still appear red and inflamed despite use of these drops. Episcleritis is typically painless, or at best annoying. Pain and tenderness, however, are hallmarks of scleritis, especially pain that worsens with eye movement or radiates to different parts of the head, mimicking headache, sinus disease, or tooth ache. Bottom line: if the eye is significantly painful and red, it is probably something other than episcleritis.

What causes episcleritis?

Unfortunately, this is not known. It is thought to involve inflammation of the small vessels that run along the eye wall, a disease process known as microangiopathy, similar to scleritis. The level of inflammation present in episcleritis and the immunologic driving-force behind it are much less severe than in scleritis.

What other medical conditions are associated with episcleritis?

Episcleritis is usually not associated with any systemic disease. Only about 3 out of 10 people with episcleritis have an associated systemic disease. It can, however, present in a wide variety of conditions causing ocular surface inflammation, including connective tissue or vascular disease (such as lupus or rheumatoid arthritis), infection, rosacea, gout, or allergy. A work up is not always done for episcleritis unless it is more stubborn or severe.

What are complications from episcleritis?

Thankfully, episcleritis does not cause permanent damage to the eye. Rarely, it can be accompanied by mild inflammation of the peripheral cornea or inflammatory cells inside the eye. There are times, however, when a patient may later develop scleritis after first having episcleritis, and at that point vision threatening complications become a concern. Sadly, complications from episcleritis sometimes occur from treatment of episcleritis because of long term use of steroid eye drops.

How do you treat episcleritis?

Treatment of episcleritis is most often conservative. Observation without treatment may be all that is necessary for episcleritis that does not cause significant redness or irritation. Lubricating drops can help both soothe irritation as well as surface inflammation. More often a topical non-steroidal anti-inflammatory drug (NSAID) is used on a daily basis, either until symptoms resolve, or can be used safely long term in cases of recurrent episcleritis. Corticosteroid eye drops may help to relieve episcleritis but should never be relied on long term due to inevitable complications of cataracts and glaucoma. If episcleritis is particularly stubborn or severe, oral NSAID therapy can be used. Eye redness, irritation, or pain requiring treatment more aggressive than this should be reevaluated by a specialist for the presence of a more serious disease process, like scleritis.

Herpes and the Eye

Herpes and the Eye
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Herpes! The first thought in most people’s mind is venereal disease, sexual transmitted disease (STD). But, in fact most instances of herpes, at least those affecting the eye, are not sexually transmitted, and are not even the type of herpes that is usually associated with sexually transmitted disease. The vast majority of instances of herpes infection of the eye are from type 1 herpes simplex virus, the type of herpes virus that causes fever blisters and cold sores. The primary infection is usually acquired during childhood, and there may be no signs or indication of that contraction of the microbe. But the microbe establishes a saprophytic relationship in nerve tissue (ganglion), and lies dormant or latent, in a state similar to hibernation, until provoked to “wake-up,” multiply, migrate down nerves and establish clinically obvious infection in the area supplied by that nerve, for example, lip, tongue, or, in some rare instances, the eye.

Ocular manifestations of herpes simplex infections can be in the conjunctiva (conjunctivitis), in the sclera (scleritis), in the cornea (keratitis), inside the eyeball itself (uveitis), or in the retina (retinitis). It is a potentially dangerous process even when it affects just conjunctiva, since infection in this area can in some instances result in spreading or inoculation into the cornea. When the infection involves cornea or the intraocular parts of the eye or the retina, the potential for substantial loss of vision is enormous.

Therefore, proper diagnosis and treatment is critical if one is to preserve good vision and, more importantly, be free of repeated episodes of reactivation of the virus from its latent state and reestablishment of active infection again, and again, and again. Proper therapy during an episode of active, (productive) infection, with rapidly multiplying virus is with the use of antiviral medication, sometimes used just topically, but also sometimes used systemically (by mouth). And just as in the case of the debilitating effects of recurrent episodes of active infection in patients with frequently recurrent genital herpes, so too with herpes infections of the eye the person’s life can be literally transformed through the long-term use of prophylactic oral antiviral medication (for example, acyclovir). We first showed this in our care of patients who needed to have corneal transplantation as a result of scarring secondary to recurrent episodes of inflammation in the cornea secondary to herpes simplex virus. We showed that long-term treatment with oral acyclovir resulted in a much higher success rate of the corneal transplants, a much lower rate of recurrence of herpes keratitis, and a much lower rate of irretrievable rejection of the cornea transplant. We have now also shown that this strategy is effective for patients with uveitis secondary to herpes.

Juvenile Idiopathic Arthritis and Uveitis: What is it and what is its effect on the eye?

Juvenile Idiopathic Arthritis and Uveitis
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Uveitis is a serious complication of juvenile idiopathic arthritis (JIA). Approximately 6% of all cases of uveitis occur in children, and up to 80% of all cases of anterior uveitis in childhood are associated with JIA. Although remarkable progress has been made in the care of patients with JIA-associated uveitis since the development of corticosteroids for systemic and ophthalmic use in the 1950’s, up to 12% of children with uveitis associated with pauciarticular JIA still develop permanent blindness as a result of low-grade chronic intraocular inflammation. Ironically, these children are often under careful observation by ophthalmologists who may opt to tolerate low-grade ocular inflammation, hoping to avoid the development of corticosteroid-induced ocular adverse effects such as cataracts and glaucoma. The vision-robbing consequences of low-grade uveitis occur extremely slowly, typically over a period of 4 to 8 years, and the end result is clear: even low-grade uveitis may lead eventually to ocular damage, including band keratopathy, maculopathy (macular edema, macular cysts, epiretinal membrane), glaucomatous optic neuropathy, and cataract formation from chronic inflammation and corticosteroid therapy. Although surgical treatment of cataract and glaucoma is remarkably successful in the general population, it is consistently less so in patients with JIA-associated uveitis.

Epidemiology

The prevalence of JIA in the United States has been estimated recently at 30,000 to 50,000 cases. JIA is more common in girls, with a female-to-male ratio of 3:2. There are 3 types of JIA onset: systemic, which constitutes 11% to 20% of cases; polyarticular (5 or more joints), 17% to 40%; and pauciarticular, 40% to 72%. The peak age at onset of JIA is between 2 and 4 years. The incidence of iridocyclitis in patients with JIA ranges from 8% to 24% and varies among sub-groups of JIA. Uveitis occurs both in children with JIA who are antinuclear antibody (ANA) positive and in those who are ANA negative. Approximately 78% to 90% of patients with JIA-associated iridocyclitis have pauciarticular arthritis; 90% of these patients are ANA positive. Between 7% and 14% of JIA patients with uveitis have polyarticular arthritis; 2% to 6% have systemic arthritis. Uveitis precedes the onset of arthritis in approximately 6% of cases and may be detected at the time of initial diagnosis of arthritis. The majority of patients develop iridocyclitis within 4 to 7 years after JIA onset; the average age at the time of diagnosis of JIA-associated iridocyclitis is 6 to 8 years. The highest risk of iridocyclitis is within 2 years after the onset of arthritis and declines considerably after 8 years have elapsed from the onset of JIA. In some patients, however, the interval between onset of arthritis and uveitis may exceed 20 years. In general, little or no correlation exists between arthritis activity and the presence of uveitis. The uveitis associated with JIA is typically anterior, involving the iris and ciliary body, and generally affects both eyes.

Diagnosis and Course

The eyes of patients with JIA-associated uveitis commonly appear normal (not red or inflamed) on external examination and routine ophthalmoscopy. Because patients with JIA are young, they may not notice or report small visual changes that are slowly developing as a result of active inflammation. Therefore, current guidelines recommend that children whose age at onset of JIA is less than 7 years and who do not have known iridocyclitis should have a complete ophthalmologic examination including slitlamp evaluation, every 3 to 4 months if they have pauciarticular or polyarticular JIA and ANA positivity, every 6 months if they have pauciarticular or polyarticular JIA but ANA negativity, and every 12 months if they have systemic JIA. However, Candell, Chalom and colleagues recently reported that, in a retrospective study, although the prevalence of uveitis was lower in ANA-negative patients compared with ANA-positive patients, ocular complications were more common in children with uveitis who were ANA negative. These authors speculated that perhaps ANA-negative children were screened less intensively and thus fared worse. Patients with JIA are considered at low risk for developing iridocyclitis 7 years after the onset of their arthritis but should have yearly ophthalmologic examinations indefinitely thereafter. Once iridocyclitis is diagnosed, the managing ophthalmologist can determine the frequency of visits, depending on the severity of uveitis, its response to therapy, and the treatment used.

A recent retrospective study on predictors of visual outcomes in JIA-associated uveitis reported the characteristics of JIA-associated iridocyclitis in 43 patients with JIA-associated uveitis who were followed for at least 6 months at a tertiary care center. Forty-seven parameters were analyzed to determine the relative odds of visual rehabilitation associated with each characteristic. Thirty-seven patients (86%) were girls. The mean known age of uveitis onset was 13 years; disease onset was 4 years earlier, on average, in girls than in boys. Ninety-three percent of patients with uveitis had chronic inflammation, 5% had recurrent inflammation, and 2% had an acute monophasic disease course. The mean overall duration of uveitis was 146 months, and girls had a significantly longer duration of active disease than boys. After considering all potential confounders, male sex, shorter duration of uveitis, older ages at uveitis onset, and a shorter delay in presentation to a uveitis subspecialist were associated significantly with improvement in visual acuity. Visual acuity at presentation, older age at uveitis onset, use of systemic nonsteroid anti-inflammatory drugs such as methotrexate and/or immunomodulatory drugs, absence of glaucomatous optic neuropathy, and male sex were correlated significantly with a final visual acuity outcome of 20/40 or better.

Therapy

There are no randomized controlled trails evaluating treatment strategies for JIA-associated uveitis. Observational studies and clinical experience have led us to advocate a treatment philosophy of tolerating no active inflammation at any time in the eyes of children with JIA-associated iridocyclitis. We use a “stepladder” algorithmic approach of progressive aggressiveness of treatment to achieve that goal. The cornerstone of initial management is topical steroid therapy (prednisolone 1%). Regional injection steroids (triamcinolone acetonide) and systemic steroids (prednisone) are often used simultaneously in the initial care of a patient with JIA-associated iridocyclitis. If the inflammation persists after 90 days of treatment and attempted withdrawal of oral and topical steroids, chronic use of an oral NSAID is indicated. Naproxen (available in suspension), 10 to 15 mg/kg per day in 2 divided doses, is a common first choice; tolmetin, 20 to 30 mg/kg per day in 4 divided doses is another choice. These 2 agents have the longest safety record in childhood use. However, pediatricians and pediatric rheumatologists may choose from a wide range of other NSAIDs and dosages for their patients. We usually prescribe a histamine H2-receptor antagonist (ranitidine or famotidine) or the synthetic prostaglandin E1analog misoprostol as prophylaxis for gastritis or ulcerative symptoms for patients who receive NSAIDs, especially if an NSAID is given with a systemic steroid. The Cox-2 specific NSAIDs, such as Celebrex, may become especially appealing for long-term care.
In approximately 30% of cases, JIA-associated iridocyclitis is not satisfactorily controlled by conventional anti-inflammatory treatments, and iridocyclitis recurs whenever steroids are withdrawn despite the longterm use of an oral NSAID. We believe that at this stage advancing to low-dose, once-a-week methotrexate therapy (o.3-o.5 mg/kg per week; typically, 7.5-25 mg per week) should be considered. The dosage of methotrexate can usually be increased to a maximum of 40 mg weekly to control the iridocyclitis if the standard starting dose is not adequate. Therapy with methotrexate, a folic acid antagonist, has had an exceptional safety and efficacy record as used by rheumatologists to care for children with the joint manifestations of JIA. Published data and clinical experience indicate that immunomodulatory agents have considerably fewer adverse effects than systemic corticosteroids when used as single agents in relatively low doses for the treatment of JIA-associated uveitis. The mechanisms of action of methotrexate in JIA are not well understood. However, methotrexate seems to have both antiinflammatory and immunosuppressive actions. The potential for drug-induced adverse effects, such as bone marrow suppression, hepatic toxicity, pneumonitis, and oral ulcerations exists. Clinical studies have shown that the concurrent administration of folic acid or folinic acid with methotrexate does not reduce the efficacy of the drug but might alleviate some of its potential toxicities. The concurrent use of folic acid, 1 mg/d, the close involvement of the physician in longitudinal care, and the appropriate monitoring of hematologic parameters and hepatic enzyme levels minimize the risk of adverse effects. We believe that such careful management accounts for the safety record of low-dose, once-weekly methotrexate. There is no known risk of sterility with low-dose methotrexate therapy. The risk of increased susceptibility to a malignancy later in life also is probably not significant in children with JIA treated with methotrexate. There have been reports of Epstein-Barr virus associated lymphoma and lymphoproliferative disorders occurring in patients with adult RA receiving low-dose methotrexate therapy; discontinuation of methotrexate therapy often leads to complete remission. The authors of these studies acknowledge that methotrexate probably has no direct oncogenic effect itself, but may promote or enhance malignancies associated with Epstein Barr Virus infection in individuals with disorders such as RA. We know of no such predisposition in JIA patients.

When methotrexate treatment fails or is not tolerated, other immunomodulators, such as azathioprine (1-2 mg/kg per day), cyclosporine (2-5 mg/kg per day), mycophenolate mofetil (mg/m2 body surface area bid), or chlorambucil (0.10-0.16 mg/kg per day) may replace methotrexate or be used adjunctively to achieve the goal of total quiescence of ocular inflammation. However, the frequency of failure of methotrexate treatment is quite small. Infliximab or Adalimumab may also be considered.

Further reduction in the occurrence of irreversible blindness secondary to uveitis in patients with JIA depends on early diagnosis of iridocyclitis, facilitated by mandatory vision screening programs in day care centers and schools, and on the use of therapeutic algorithms that include methotrexate and other immunomodulators to eradicate intraocular inflammation. Patients with JIA-associated uveitis should be promptly referred to colleagues experienced with such therapy before permanent ocular damage develops. Our hope is that cooperation among physicians of all specialties caring for patients with JIA will reduce the ocular morbidity and blindness secondary to JIA-associated iridocyclitis.

Systemic Treatment of Ocular Inflammatory Disease (OID)

Systemic Treatment of Ocular Inflammatory Disease (OID)
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R

Most eye diseases which are treatable are treated with eye drops. In fact, the number of instances in which patients attending a general ophthalmologist’s office might be prescribed a systemic medication (i.e., one which is taken, for example, by mouth) is vanishingly small. Perhaps because of this and other factors, most ophthalmologists eventually consider treating patients with an eye problem only rarely with systemic medication. And while this is usually perfectly appropriate, in some instances, such as in the care of patients with uveitis, we believe that to neglect strong consideration of systemic therapy for the condition is to ensure that no progress will be made in reducing the prevalence of blindness secondary to the disease. Indeed, the evidence on the subject of the uveitis is clear: the prevalence of blindness caused by this disease has not been reduced in the past thirty years; it remains the number three cause of preventable blindness in the United States.

Eye drops (steroids) remain the mainstay and cornerstone of treatment of patients with uveitis. But some patients with uveitis continue to have episodes of active inflammation each time the topical steroid drops are reduced and discontinued. All ophthalmologists realize that they cannot keep their patient with uveitis and other forms of OID on topical steroids indefinitely; cataract is a guaranteed side effect from the chronic use of steroid eye drops; glaucoma is a significant possibility from such use; and increased susceptibility to eye infections, including those from herpes simplex virus, is also a risk. The all-too-frequent scenario, therefore, is:

Treatment of the uveitis with steroid drops, resolution of the uveitis, tapering and discontinuation of the steroid drops, recurrence of the uveitis, reinstitution of steroid eye drop therapy, etc.

We believe that there is a better way, and, in fact, the “outcomes” study data show that this is so. Our philosophy, over the past few decades has been to not tolerate even low-grade chronic uveitis, but also not to tolerate endless amounts of steroid use. We achieve this goal through a “stepladder” approach in aggressiveness of therapy. The next “step” on this stepladder, after topical steroids, is oral nonsteroidal anti-inflammatory drug therapy. This class of drug, nonsteroidal anti-inflammatory drugs, is typified by aspirin, ibuprofen, naproxen, etc. Unless a patient has a contraindication to the use of such medications chronically by mouth (for example, history of peptic ulcer disease), we place the patient on prescription strength nonsteroidal anti-inflammatory drugs, and then attempt to taper the topical steroid drops, expecting the oral nonsteroidal medication to keep the uveitis from recurring. This strategy, in our hands, is effective in approximately 70% of selected patients. In those 30% who do not respond to this strategy, we then advance to systemic immunosuppressive/immunomodulatory therapy, sometimes referred to as “chemotherapy.” I place this word in quotation marks simply because it is not the kind of chemotherapy that most patients think of when they hear that word, i.e., cancer-type therapy. Rather, it is the type of chemotherapy typically used by rheumatologists in their care of patients with severe rheumatoid arthritis, and by dermatologists in their care of patients with severe psoriasis, or in their care of patients with certain blistering dermatitis diseases. This is the area in systemic drug therapy for ocular disease in which the vast majority of ophthalmologists are uncomfortable, primarily out of ignorance (and I do not mean that in a pejorative way, but rather in a factual way.) Ophthalmologists are not used to using these medications, and carry with them the “baggage” learned in Medical School about the risks of immunosuppressive chemotherapy drugs, typically as they are used in solid organ transplant patients and in patients with malignant disease. And those risks are simply not the same as the risks associated with the low-dose, single-agent immunosuppressive chemotherapeutic programs that rheumatologists, dermatologists, and ocular immunologists use in their care of patients with non-malignant inflammatory disease. The potential for drug-induced “mischief” exists; but, used correctly, the likelihood of a significant drug-induced problem is quite small. The drugs, of course, must be managed by an individual who is, by virtue of training and experience, an expert in their use, in a patient who is responsible, keeps his or her appointments, etc.

We believe that unless or until increasing numbers of ophthalmologists embrace the idea of systemic therapy for certain blinding ocular diseases, the prevalence of blindness from such diseases will go unchanged, as it has over the past 30 years.

Chemotherapy: Risks and Outcomes

Chemotherapy: Risks and Outcomes
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Inflammatory eye disease has blinded countless numbers of individuals during both ancient and modern times. And while most of such instances have occurred on the basis of infectious inflammation, not a trivial number of instances has occurred on the basis of autoimmune inflammation. A revolution in care of such patients occurred in 1950, with the introduction of corticosteroid therapy, both systemic and topical, for autoimmune inflammation, including ocular inflammation. Within a decade, however, it became clear that the chronic use of corticosteroids for patients with chronic autoimmune inflammatory eye disease resulted in unacceptable side effects, including cataract and glaucoma. Some pioneers, such as Frank Newell, Vernon Wong, James Gills, Richard O’Connor and others began to explore the risk/benefit ratio or equation of nonsteroidal immunomodulatory medication in the care of such individuals. Enormous progress has been made in this area since work of these early pioneers, and today ocular immunologists and other knowledgeable physicians acquainted with the proper use of immunosuppressive chemotherapeutic medications in the care of patients with progressive, blinding autoimmune inflammatory disease, routinely use this strategy to wonderful effect, preventing the blinding consequences that were occurring or would have otherwise obtained had such medications not been employed.

Regrettably, however, a substantial number of otherwise perfectly modern ophthalmologists are unaware of these advances, and, even worse, carry with them the “baggage” of “knowledge” of the terrible side effects of systemic immunosuppressive chemotherapy. They remember learning about secondary malignancy, secondary infection, bone marrow suppression, liver and kidney damage, and even death from their days in medical school, caring for patients or at least hearing about patients receiving chemotherapy for treatment of cancer, or receiving multiple immunomodulatory drugs following bone marrow transplantation or kidney or heart or lung transplantation.

What they do not realize is that dermatologists and rheumatologists have used low-dose, immunomodulatory therapy in their patients with severe psoriasis, with blistering dermatitis, and with rheumatoid arthritis for many years, with an excellent safety track record. The literature is replete with reports to this effect, and the reader of this addition to our Web Site is referred to such literature, referenced below. One example of the critical importance of increasing numbers of ophthalmologists approaching the idea of systemic immunomodulatory therapy of patients with chronic ocular inflammatory disease comes from the area of uveitis therapy.

Uveitis is the third leading cause of blindness in the United States. Further, and sadly, the prevalence of blindness secondary to uveitis has not been measurably reduced over the past 30 years. Those of us who deal with immunosuppressive chemotherapy of patients with ocular inflammatory disease at tertiary referral centers may enjoy an outstanding, successful track record in both ocular outcomes and systemic safety in these endeavors. But until increasing numbers of ophthalmologists come to the realization that this approach to treatment should be explored sooner rather than later in the care of patients with such diseases, the prevalence from blindness is not going to be measurably reduced beyond that which we see today.

REFERENCES

  1. 1. Tugwell P, Pincus T, Yocum D, et al: Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis. The New England Journal of Medicine.333(3):137, 1995.
  2. 2. Wallace CA, Bleyer A, Sherry DD, et al: Toxicity and Serum Levels of Methotrexate in Children with Juvenile Rheumatoid Arthritis. Arthritis and Rheumatism. 32(6):677, 1989.
  3. 3. Dana MR, Merayo-Lloves J, Schaumberg D, et al: Visual Outcomes Prognosticators in Juvenile Rheumatoid Arthritis-associated Uveitis. Ophthalmology. 104(2):236, 1997.
  4. 4. Graham LD, Myones BL, Rivas-Chacon RF, et al: Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. The Journal of Pediatrics. 120(3):468, 1992.
  5. 5. Hemady RK, Baer JC, Foster CS. Immunosuppressive Drugs in the Management of Progressive Corticosteroid-Resistant Uveitis Associated with Juvenile Rheumatoid Arthritis. Controversies in Ophthalmology In: International Ophthalmology Clinics (Ed. Frederick A. Jakobiec, M.D.) Little Brown and Company, Boston, Massachusetts 32(3): Summer 1992.
  6. Singh G, Fries JF, Spitz P, et al: Toxic Effects of Azathioprine in Rheumatoid Arthritis. A National Post-Marketing Perspective. Arthritis and Rheumatism. 32(7):837, 1989.
  7. 7. Weinblatt ME, Coblyn JS, Fraser PA, et al: Cyclosporin A Treatment of Refractory Rheumatoid Arthritis. Arthritis and Rheumatism. 30(1):11, 1987.
  8. 8. Sandoval DM, Alarcon GS, Morgan SL. Adverse events in methotrexate-treated rheumatoid arthritis patients. British Journal of Ophthalmology. 34 Suppl 2:49, 1995.
  9. 9. Salach RH, Cash JM: Methotrexate: the emerging drug of choice for serious rheumatoid arthritis. Clinical Therapeutics. 16(6):912, 1994.
  10. 10. Shiroky JB. Combination sulfasalazine and methotrexate in the management of rheumatoid arthritis. Journal of Rheumatology. Supplement 44:69, 1996.
  11. 11. Petrazzuoli M, Rothe NJ, Grin-Jorgensen C, et al: Monitoring patients taking methotrexate for hepatoxicity. Does the standard of care match published guidelines?Journal of American Academy of Dermatology. 31(6):969, 1994.

Cost of Care of Patients with Uveitis

C. Stephen Foster MD

Increasingly restrictive “gate keeping” policies of health maintenance organizations, insurance companies, and other medical insurance plans have created increasing pressure on ophthalmologists to be parsimonious in their use of medical services in both the diagnostic and therapeutic care of patients with a variety of medical disorders, including those with uveitis. These pressures are particularly prominent in the physician’s care of patients with chronic disorders, and ophthalmologists caring for patients with uveitis are increasingly experiencing this restrictive pressure. We wondered what the cost of diagnostic and therapeutic care of a patient with uveitis might be, given what we, as a uveitis referral center, see as appropriate yet fiscally prudent care. The cost of care obviously varies greatly, depending on the underlying cause and on the severity of the patient’s uveitis and associated complications. As a first step in estimating the total annual direct cost in the care of patients with uveitis we restricted our analysis to patients with HLA-B27 associated uveitis. We also restricted our analysis to the direct medical cost of caring for such patients, recognizing that direct non-medical costs, indirect morbidity costs, and other intangible economic loss costs, disability payments, absences from work, etc. are real but difficult to measure costs of the total cost of the patient’s illness. Direct medical costs are transactions and expenditures for medical products and services, including diagnostic studies, physician fees, hospitalization costs, surgical costs, rehabilitation and subsequent long-term care costs.

A cohort of 105 patients with HLA-B27 associated uveitis were studied in 2002. The diagnosis in each instance was established on our Service, and a minimum follow-up of two years existed for each patient. The medical records were reviewed for the diagnostic studies and costs of each performed, the physician and hospital fees associated with visits and/or surgery, in the cost of medical therapy. The average direct annual cost per patient per year was calculated. A stepladder approach to therapy was employed in an effort to eliminate recurrences of uveitis. The first step on the stepladder was the use of steroids, through any route required to achieve the goal of quieting the uveitis. Oral non-steroidal anti-inflammatory agents were added, if recurrence typically continued despite the use of steroids. Immunosuppressive chemotherapy was employed if patients continued to have recurrence of inflammation despite the use oral non-steroidals. Ten patients eventually required the use long-term oral immunosuppressive agents, and 30 patients were on chronic oral non-steroidal anti-inflammatory drugs. The average annual cost of care of the patients with HLA-B27 associated uveitis was $4,108.60 (range $433 to $9,683.18). These results reflect an average cost of caring for a cohort of patients with recurrent HLA-B27 associated uveitis of varying severity. The results may serve as an indicator, to health maintenance organizations and other pooled-risk insurers, of the cost of prudent care of patients with this form of uveitis. We would emphasize that we were very cautious and parsimonious in our use of laboratory tests and frequency of return visits, striving for the greatest degree of economy, while at the same time striving for the best possible outcomes (for outcomes analysis studies performed on these and other patients with uveitis, please refer to the Bibliography section of this Web Site). Clearly, patients with recurrent or chronic uveitis require significant expenditure of the health care dollar. It is, however, money well spent, since the preservation of sight from modern care of such patients profoundly reduces the prevalence of blindness secondary to uveitis, and hence reduces the economic burden on our society in total.

Did you know the Connection between Arthritis and Ocular Disease?

Connection Between Arthritis and Ocular Disease
C. Stephen Foster, M.D.

The eye is made up primarily of collagen, as are ligaments, tendons, and tissue within joint spaces. It is, perhaps, primarily because of this similarity in composition that the eye is often affected by many of the same diseases which affect joints. Some of these disorders include Juvenile Rheumatoid Arthritis, Adult Rheumatoid Arthritis, Systemic Lupus Erythematosus, Relapsing Polycondritis, Behcet’s Disease, Granulomatosis with Polyangiitis (formerly called Wegener’s), Polyarteritis Nodosa, and Scleroderma or systemic sclerosis. Additionally, the type of vasculature that is present in the eye has special characteristics that produce an extraordinarily sensitive “barometer” or “sentinel canary” in the eye for potentially lethal vasculitis that can be associated with the aforementioned collagen vascular diseases. Specifically, we know from considerable experience that, despite the fact that a patient’s rheumatoid arthritis may be “burned out” as far as active inflammation of the joints in concerned, nonetheless, the patient may well have subclinical rheumatoid vasculitis affecting various internal organ systems. The eye is a very potent indicator of such subclinical potentially lethal vasculitis, and if the eye becomes involved with retinal vasculitis, uveitis, scleritis, or peripheral ulcerative keratitis in such a patient, we take that as a very strong signal that the patient must be evaluated extremely carefully for potentially underlying vasculitis affecting viscera and we also take such a potentially blinding ocular lesion very seriously from the standpoint of the need for aggressive systemic immunomodulatory therapy in order to prevent permanent damage to the eye from such lesions.

For example, we have seen many instances in which patients with systemic lupus erythematosus appear, systemically, to be doing quite well (indeed, the patient’s Rheumatologist has told her that she is doing very well) despite the fact that new-onset uveitis, scleritis, or retinal vasculitis has developed in one eye. We have seen this story evolve to life-threatening central nervous system vasculitis and/or lupus renal disease when the onset of the ocular inflammation was not taken as an indication for increasing the vigor of systemic therapy. We have tried diligently, therefore, over the past 15 years to raise the consciousness, not only of ophthalmologists worldwide, but also of rheumatologists and other internists of the valuable indicator that the eye can be with respect to seriousness of associated arthritic/collagen vascular disease.

Pediatric Uveitis

Uveitis is the third leading cause of blindness in America, and 5% to 10% of the cases occur in children under the age of 16. But Uveitis in children blinds a larger percentage of those affected than in adults, since 40% of the cases occurring in children are posterior uveitis, compared to the 20% of posterior Uveitic cases in the adult Uveitis population.

There are, at any one time, approximately 115,000 cases of Pediatric Uveitis in the United States, with 2,250 new cases occurring each year. Spread across the entire U.S. population, therefore, and across all offices of Ophthalmic practitioners, the likelihood that any one individual practitioner will care for a patient with Pediatric Uveitis is relatively small, and the likelihood that any single individual will have significant experience in caring for large numbers of cases over a long period of time is vanishingly small. This accounts, we believe, at least in part for the sub-optimal care that many of our children with Uveitis appear to be receiving, even in these “modern” times. The stakes are incredibly high, for the child, for the parents who will be faced with (usually) many years of dealing with this health problem in their child, and for society at large because of the life-time of dependence which occurs in those who eventually reap substantial visual handicap as the result of sub-optimal treatment.

We believe that current epidemiologic data emphasize two critically important goals for all of us in Ophthalmology, acting together, in an effort to change the current prevalence of blindness caused by Pediatric Uveitis:

  1. Repeatedly emphasizing to parents, other medical colleagues, especially Pediatricians, and school personnel the critical importance of routine (annual) vision screening for all children.
  2. The critical importance of beating back the frontiers of general ignorance and mind sets, eliminating the all-too-common pronouncement by physicians to parents of a child with Pediatric Uveitis that:
  3. “He’ll (She’ll) out grow it.”
  4. “The drops will get him (her) through it.”
  5. “It’s just the eye; systemic therapy is not warranted.”

Statements (a) and (b) are true, but too often pull the doctor, and patient, and family into the seduction of nearly endless amounts of topical steroid therapy. It is generally true that the child will in fact “out grow” the Uveitis, i.e., that the Uveitis will no longer be a problem eventually. The pity is, however, that so often by the time the child “out grows it”, permanent structural damage to retina, optic nerve, or aqueous outflow pathways has already occurred, and the blinding consequences are now permanent. It is also true that for any individual episode of Uveitis, the steroid drops usually will get the patient through it. But the fact is that so many children with Pediatric Uveitis have recurrent episodes of Uveitis such that the cumulative damage caused by each episode of Uveitis and the steroid therapy for each episode eventually produces vision-robbing damage. And item (c) is simply the result of the common myopic viewpoint of Ophthalmologists: that it is just an eye problem, and therefore should simply be treated with eye medications. Nothing could be further from the truth! And unless and until large numbers of Ophthalmologists reframe this socially and epidemiologically important matter, the prevalence of blindness secondary to Pediatric Uveitis is not going to change.

The differential diagnosis of Pediatric Uveitis is relatively vast, and therefore the detective work required to properly pursue the underlying diagnosis is complex. The job can be slightly simplified by “playing the odds”, categorizing the case as carefully as possible into anterior non-granulomatous; anterior granulomatous; intermediate; posterior, with vasculitis; posterior, without vasculitis; and categorizing it into the general age groups of Infancy (0 to 2 years), Toddler-School Age (2 to 10 years), and Adolescence (10 to 20 years).

The most common etiologic groups in children segregated into these groups are shown in Tables 1-6

TABLE 1 (Anterior Non-Granulomatous)

Idiopathic

HLA-B27 associated

Juvenile Rheumatoid Arthritis

Ankylosing Spondylitis

Reactive Arthritis (formerly called Reiter’s syndrome) disease

Psoriasis

Inflammatory bowel disease

Nephritis

Systemic lupus erythematosus

Herpes Simplex virus

Lyme disease

Leukemia

Drug-induced

TABLE 2 (Anterior Granulomatous Uveitis)

Sarcoidosis

Inflammatory bowel disease

Syphilis

Herpes simplex virus

Tuberculosis

Bechet’s disease

Multiple Sclerosis

Fungal disease

Whipple’s disease

Leprosy

TABLE 3 (Intermediate Uveitis)

JRA

Pars Planitis

Multiple Sclerosis

Lyme disease

Sarcoidosis

TABLE 4 (Posterior Uveitis, without vasculitis)

Toxocariasis

Toxoplasmosis

Leukemia

Tuberculosis

Intraocular Foreign Body

Vogt-Koyanagi Harada Syndrome

TABLE 5 (POSTERIOR UVEITIS, with vasculitis)

Posterior Uveitis with vasculitis

Cytomegalovirus

HSV/VZV

Inflammatory bowel disease

Syphilis

Bechet’s disease

Systemic lupus erythematosus

Kowasaki’s disease

Sarcoidosis

Polyarteritis nodosa

Granulomatosis with Polyangiitis (formerly called Wegener’s)

TABLE 6 (most common causes of Uveitis in infants)

Herpes Simplex Virus

Toxocara

Congenital Loes

Retinoblastoma

TABLE 7 (most common causes of Uveitis in Toddlers/School Children)

Toxocariasis

Toxoplasmosis

Leukemia

Vogt-Koyanagi Harada Syndrome

Diffuse Unilateral Sclerosing Neuroretinitis

Juvenile Rheumatoid Arthritis

TABLE 8 (most common causes in Adolescents)

JRA

Pars Planitis

VKH

Toxoplasmosis

HLA-B27-associated sarcoidosis

Bechet’s disease

Intraocular Foreign Body

We believe that aggressive efforts should be made to uncover the underlying cause of Uveitis in any child. If the review of systems is negative and the patient has non-recurrent anterior granulomatous Uveitis, we would not do laboratory studies. However, if review of systems is positive, we would “follow the review of systems”.

For recurrent anterior non-granulomatous Uveitis we would obtain a complete blood count and urine analysis, ANA testing, HLA-B27 testing, and would “follow the review of systems”.

The diagnostic step ladder in a pediatric patient with anterior granulomatous Uveitis, recurrent or not, would include a CBC with urine analysis, and FTA-ABS testing, Lyme disease antibody and western block, PPD analysis, chest X-ray, ANA, and angiotensin converting enzyme determination. Chest CT, and Gallium scanning would be pursued if diagnosis of sarcoidosis was strongly suspected, and, of course as usual, we would “follow the review of systems positives”.

In a patient with intermediate Uveitis, all would deserve laboratory evaluation, including CBC, urine analysis, chest X-ray, FTA-ABS, ACE, PPD, Lyme, and ANA titers.

Any patients with posterior Uveitis would deserve an extensive vasculitis work-up, if vasculitis were present, and a search for “the usual suspects” with an eye to an infectious etiology, such as that producing a granuloma in the choroid in a patient with toxocariasis or Toxoplasmosis. An audiogram or lumbar puncture would be done if positive on the review of systems were found such as tinnitus and/or meningeal signs or symptoms. Finally, a diagnostic vitrectomy would be added to the step ladder in a patient with posterior Uveitis if all non-invasive studies were unrevealing and the case was difficult to treat successfully.

On the matter of treatment, here too we believe strongly in the step ladder approach, always beginning with steroids, in any route required to achieve the desired goal, i.e., abolition of all active inflammation. Topical steroids would be followed by an examination under anesthesia with regional steroid injection therapy in a patient with granulomatous or non-granulomatous anterior Uveitis. Systemic steroids would be employed in the event that this approach did not achieve the goal of abolition of all active cells. We are extremely reluctant to get involved with long term daily systemic steroid use in a youngster, because of the obvious growth-retarding properties of such therapy. But long term oral non-steroid anti-inflammatory drug therapy, managed by a Pediatrician, can be extremely successful, in our experience in approximately 70% of children with recurrent non-granulomatous anterior Uveitis. If this strategy is not successful, then consideration of once weekly, low-dose, Methotrexate or daily Cyclosporine or CellCept would be the next considerations.

In granulomatous disease topical steroids often are not sufficient, and systemic therapy, particularly with oral non-steroidal inflammatory drugs, may be utilized sooner rather than later.

With Intermediate Uveitis topical steroids are not effective in penetrating to the level of inflammatory focus. Regional steroid injections or systemic steroids are employed to treat that area, sometimes with adjunctive topical steroids for anterior chamber “spill over” reaction. Retinal Cyropexy can be effective in selected cases of recurrent Pars Planitis, as can therapeutic Pars Plana Vitrectomy. Systemic immunomodulatory therapy, as usual, represents the final step in the step ladder approach in the aggressiveness of care.

Patients with Posterior Uveitis of course do not respond to topical therapy and therefore require systemic steroids and/or immunomodulators right from the very beginning.

We hope that this will provide some help to those Ophthalmologists who have also concluded that the usual approach to Pediatric Uveitis, i.e., steroid drops, is not always sufficient, but who are hesitant to take the initiative to commit the patient to more aggressive treatment.