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Correspondence to:
J P Whitcher
University of California San Francisco, 95 Kirkham Street, San Francisco, CA 94143-0944, USA; Nepal@itsa.ucsf.edu
To know it is still not to love it
Keywords: autologous serum; ocular surface disease; dry eye; keratoconjunctivitis sicca
The dry eye is often referred to as a condition, a syndrome, or a disease; and it is likewise known by a variety of terms. Keratoconjunctivitis sicca (KCS), or more commonly keratitis sicca, refers to any eye with some degree of dryness either by history or by objective clinical findings. The literature is confusing on this subject and often blurs the difference between the symptoms of dryness and clinical findings based on objective criteria.1 In similar fashion, the term dry eye syndrome is sometimes used interchangeably with dry eye symptoms, a lapse in descriptive terminology that unfortunately clouds the issue. Other descriptive terms for ocular dryness include xerophthalmia, which is used almost exclusively to describe the eye findings associated with vitamin A deficiency in children, and xerosis, which connotes the extreme ocular dryness and keratinisation that sometimes occurs after Stevens-Johnson syndrome, trachoma, and other causes of severe conjunctival cicatrisation. And then there is Sj?gren’s syndrome, a generalised inflammatory disease that stands alone in its own category. Patients with Sj?gren’s syndrome usually have dry eyes or KCS but they also have or may not have an associated rheumatological disease depending on whether they have primary Sj?gren’s syndrome (without associated rheumatological findings) or secondary Sj?gren’s syndrome (with an associated rheumatological disease).2 Having KCS does not necessarily imply that a patient has Sj?gren’s syndrome, but the reverse with few exceptions is usually true.
The truth of the matter is that dry eyes, for which we can interchangeably use the term KCS, is a neglected orphan. Even though it has been recognised for 70 years, since Sj?gren first described the syndrome that bears his name in 1933,3 progress has been frustratingly slow in agreement on the diagnostic criteria for Sj?gren’s syndrome as well as on treatment for all forms of KCS. This situation exists because KCS is in reality a condition that occurs in a family of orphan diseases. To be sure, Sj?gren’s syndrome sits at the head of the table, but the other orphans in the KCS family have a way of frequently showing up quite unexpectedly. After Sjogren’s syndrome, there is a second group of diseases that has already been mentioned that can also produce severe KCS. These are the conjunctival cicatrisation syndromes: Stevens-Johnson syndrome, trachoma, ocular pemphigoid, drug induced pseudopemphigoid, graft versus host disease, chemical burns, and conjunctival cicatrisation that occurs after severe membranous conjunctivitis. A third group consists of those individuals who have signs of KCS because of a specific ocular disease: dacryoadenitis, congenital absence of the lacrimal gland, Riley-Day syndrome, cholinergic blockade due to drugs such as atropine, chronic blepharoconjunctivitis, senile atrophy of the lacrimal gland, and even the current epidemic of presumed KCS that occurs after refractive surgery. And the fourth group includes those atypical dry eye "orphans" that appear to have clinical KCS but who in reality have adequate tear production: trigeminal nerve paralysis with loss of corneal sensation, facial sensory nerve paralysis, exposure keratitis, and vitamin A deficiency resulting in xerophthalmia.4
The ultimate goal is to find curative solutions for this disparate family of diseases; keratoconjunctivitis sicca, in some forms, will always require ameliorative therapy
So we are presented with a family of orphan diseases, all complicated, many posing as diagnostic dilemmas,5 and none that is easily treatable. Treatment is, indeed, the issue here. If we look at Sj?gren’s syndrome alone, there have been 70 frustrating years of having to rely on partially successful ameliorative therapy for both the xerostomia and the KCS components of the syndrome. We still cannot "cure" Sj?gren’s syndrome. We can only make patients more comfortable and, fortunately in the case of the eye component, we can usually prevent the complications related to microbial keratitis that led to blindness in some cases of KCS in the past. And yet our treatment is still ameliorative, not curative, and until we find a way to reverse the inflammatory component of Sj?gren’s syndrome, just to name one of the orphans, millions of individuals, mostly women, will suffer daily discomfort and disability.
There is no therapeutic panacea for dry eyes. As a clinician taking care of dry eye patients on a daily basis, I find the treatments often frustrating and unrewarding. There are no "quick fixes," and to know the various treatment options that are available for our patients is definitely not to love the choices. To be sure, we have learned a few important lessons in the supportive treatment of KCS over the past few years. For instance, we have become vigilant about recognising and controlling secondary infections. However, probably the most important lesson we have learned is that dry eye patients usually do not tolerate artificial tears on a long term basis, especially those that have preservatives in them. The dryer the patient’s eyes and the more frequently they need eye drops, the more important becomes the issue of preservatives. Before the current preservative free artificial tears became commercially available, many of us used 1.25% or 0.625% preservative free gum cellulose as a drop of last resort. The solution frequently became contaminated with opportunistic pathogens and some patients developed microbial keratitis. Dry eye patients with chronic epithelial keratitis were particularly susceptible to corneal infections, so the development of commercial preservative free artificial tears in individually packaged disposable containers was a godsend. However, development of the ideal solution that mimics human tears with all of their complicated constituents has remained elusive. One has only to look at a short list of artificial tear preparations that have been tried in the recent past to realise that there is no ideal solution. Exotic tear substitutes, including human serum albumin, fibronectin, vitamin A drops, and sodium hyaluronase, to name but a few, all purport to contain certain factors and antiproteases that mimic human tears, but all have proved disappointing. They are either too difficult to manufacture on a commercial basis or they are too expensive. Other topical medications based on their anti-inflammatory effects, such as corticosteroids6 and cyclosporine,7 are of questionable benefit especially in cases of severe ocular dryness.
Those of us who take care of patients with severe KCS have known for several decades that there are some individuals who cannot use any artificial tears, even preservative free, on a sustained long term basis without developing an allergic reaction or toxicity to the drops. We have also found anecdotally that the one tear substitute these patients can almost always tolerate is their own serum. There has been renewed interest recently in the use of autologous serum for the treatment of KCS8 and persistent corneal epithelial defects,9 but the study in this issue of the BJO (p 647) by Noble et al, is the first to prove conclusively that 50% autologous serum is superior to conventional artificial tears for the treatment of KCS caused by a variety of conditions. The authors are to be congratulated for a beautifully designed and executed study. Even though the number of patients in this randomised, prospective, crossover clinical trial is small, the authors were scrupulous in the objective criteria they used to document improvement in the patients, and their statistical analysis of the data was flawless. I look forward to further studies of this quality involving even larger patient populations. Although the ultimate goal is to find curative solutions for this disparate family of orphan diseases, KCS in some forms will always require ameliorative therapy. This aspect of treatment should not be neglected. With more information from studies like this one, we may one day be able to approach the clinical management of KCS with greater confidence, secure in the knowledge that our treatments are safe, effective, and predictable in their ultimate benefits for the individual patient.
REFERENCES
Whitcher JP. Too dry or not too dry—is that really the question or do eye symptoms lie? Br J Ophthalmol 2003;87:665–6.
Patel SJ, Lundy DC. Ocular manifestations of autoimmune disease. Am Fam Physician 2002;66:991–8.
Sj?gren H. Zur Kenntnis dur keratoconjunctivitis sicca (keratitis filiformis bei hypofunktion der Tranendrüsen). Acta Ophthalmol Suppl 1933;2:1–151.
Whitcher JP. Clinical diagnosis of the dry eye. Int Ophthal Clin 1987;27:7–24.
Whitcher JP, Gritz DC, Daniels TE. The dry eye: a diagnostic dilemma. Int Ophthal Clin 1998;33:23–37.
Avunduk AM, Avunduk MC, Varnell ED, et al. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye patients: a clinical and immunocytochemical study. Am J Ophthalmol 2003;136:593–602.
Kunert KS, Tisdale AS, Gilpson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporin. Arch Ophthalmol 2002;120:330–7.
Tananuvat N, Daniell M, Sullivan LJ, et al. Controlled study of the use of autologous serum in dry eye patients. Cornea 2001;20:802–6.
Poon AC, Geerling G, Dart JK, et al. Autologous serum eye drops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol 2002;86:832.