Medicinal nomenclature is a curious thing: The systematic logic of Latin-based anatomical identification contrasts with the haphazard terminology used in the naming of diseases. So we call conditions “primary” or “essential” if their underlying cause is unknown, even though “idiopathic” would seem a more appropriate descriptor. Other diseases take on the names of those who first described them, such as Paget’s disease or Cushing’s syndrome, labels that say more about the condition’s history than its etiology. Then there is the wholesale use of the prefix “pseudo,” telling us it “looks like this disease, but it’s not.” Ultimately, we end up with names like pseudopseudohypoparathyroidism, a bone disorder far simpler than its name would imply. These pseudo-portmanteaus provide vague clues to the underlying condition, but still leave us wishing for a more descriptive, less verbose designation.
In ophthalmology, all of these elements contribute to pseudoexfoliative syndrome, a condition whose name is at the same time descriptive, historical and yet still a bit misleading. PXS is a systemic condition that first appears in the anterior chamber and can lead to cataract, glaucoma and complications with intraocular surgery. Here, we take a wide-ranging look at what the latest research reveals about PXS diagnosis, etiology, and genetics. We also compare PXS with related disorders and discuss ideas for treatment strategies.
Fibrillar material on the patient’s anterior lens capsule is a hallmark sign of pseudoexfoliation syndrome. ( All images courtesy Ike Ahmed, MD.)
What’s in a Name
The exfoliation syndrome associated with glaucoma that was first described in 1917 was later referred to as pseudoexfoliation to distinguish it from an occupational condition of “true exfoliation,” a delamination of the lens capsule common in glassblowers.
Fibrillar material on the patient’s anterior lens capsule is a hallmark sign of pseudoexfoliation syndrome. ( All images courtesy Ike Ahmed, MD.) Unlike the black box of primary open-angle glaucoma, it was clear from earliest studies that patients developed glaucoma from PXS as the exfoliative material built up in and around the trabecular meshwork, slowed aqueous humor outflow and caused an elevation in intraocular pressure.
Diagnosis of PXS
The central finding in a diagnosis of PXS is the presence of white or light flakes in the anterior chamber of the eye, whose resemblance to epithelial debris gave rise to the description as exfoliation. Studies on the nature of the material suggest that it consists of connective tissues (elastin, collagen) together with adhered enzymes.
Exfoliation syndrome goes beyond the build up of anterior segment debris. Changes in the lens capsule and iris are also seen in PXS.
Collectively, PXS effects in the anterior segment lead to ocular hypertension and open-angle glaucoma. PXS is also associated with increases in angle closure, cataract and lens subluxation. Lens capsule atrophy in combination with poor mydriasis can make for challenging cataract surgery in PXS patients.
PXS: A Systemic Disease
The association of PXS with connective tissue dysregulation is naturally more readily identifiable in the setting of the anterior segment. However, systemic manifestations of PXS have been investigated in both small-scale, retrospective studies and large-cohort, population-based research.
Focal membrane disruption of melanin-containing cells can give the iris a moth-eaten look in pseudoexfoliation.
Several other conditions have been associated with PXS. An association with sensorineural hearing loss was shown in a study that compared auditory function in PXS patients with age-matched controls.
The association of PXS with connective tissue dysregulation in the eye suggests that it may exert similar effects in other tissues, but for obvious reasons these effects are more readily identifiable in the setting of the anterior segment. Case studies have suggested associations between PXS and skin disorders, pulmonary disease and additional renal conditions. Progress in identifying the genetic loci for PXS is likely to advance investigations into these and other systemic diseases.
Genetics of PXS and Glaucoma
Most of the genes linked to PXS have been identified with genome-wide association studies.
GWAS have identified the LOXL1 locus as a PXS-associated gene in subjects from diverse genetic backgrounds, further strengthening the case for the gene as a key factor in PXS disease. Despite this, other loci including genes for the extracellular matrix protein, clusterin, the enzyme glutathione transferase and the signaling peptide TNF-α have also been implicated in PXS disease.
Genetics of POAG are complex, and identification of glaucoma-associated genes such as myocilin or optineurin has provided some insight without yielding breakthroughs in either the etiology or treatment of the disease.
Research has found that the common denominator in all glaucoma-linked genes is an association with extracellular matrix and trabecular function, but these same genes may also be participants in homeostasis of the lamina cribrosa matrix. A unifying link, then, is a common effect on the extracellular matrix at both the front and the back of the eye.
Changes in the signaling pathway regulated by TGFβ is another aspect of glaucoma pathophysiology seen in pseudoexfoliation and in all other forms of the disease. Patients with glaucoma of any etiology exhibit elevated aqueous humor TGFβ, a cytokine that both regulates matrix formation and causes increases in IOP.
Putting PXS Pieces Together
Another intriguing piece of this puzzle is the phenomenon of normal-tension glaucoma, patients who exhibit the optic nerve head degeneration of glaucoma without an elevation in IOP. A growing body of evidence implicates a mismatch in trans-lamina cribrosa pressures in NTG.
One explanation for these observations is that factors such as elevated TGFβ are responses to the pressure differentials sensed at the level of the LC, the trabecular meshwork or both. Elevation of matrix regulatory stimuli may initiate a positive feedback cycle in which remodeling could promote or facilitate cupping, nerve damage and further remodeling. While speculative, this idea is consistent with current therapeutic standards that primarily slow the process down. An interesting idea might be to test a dual therapy of IOP-lowering agents in combination with antagonists of matrix remodeling factors such as TGFβ or connective tissue growth factor.
This allows us to return to one of those inappropriately named diseases that we touched on earlier in this discussion, Marfan syndrome. Marfan is an autosomal dominant disorder caused by dysregulation of the gene for fibrillin 1, a connective tissue protein. Although it is still in the investigational stage, early clinical data suggest that a family of drugs called sartans (such as losartan) that are classified as angiotensin antagonists may be effective in reducing risk of aortic aneurysm, the major risk in patients with this syndrome.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Dr. McLaughlin is a medical writer at Ora Inc. in Andover.