Finding clues for unsolved mysteries in glaucoma

Orlando, FL-The glaucomas continue to intrigue us with unsolved mysteries.

Paul Palmberg, MD, PhD, enumerated several examples during Glaucoma Subspecialty Day at the annual meeting of the American Academy of Ophthalmology. He challenged investigators to find the answers.

● What causes the unilateral transformation of the corneal endothelium in the iridocorneal endothelial (ICE) syndrome?

An exciting development, according to Dr. Palmberg, was a report (Arch Ophthalmol. 1995;113:1226-1228) by Jorge Alvarado, MD, that showed that about 60% of patients with the ICE syndrome who had undergone corneal transplantation had herpes simplex virus genome present in the endothelium. More studies are needed to confirm this finding and to determine if it is possible to treat this condition early to prevent progression.

● Why do synechiae not form in Fuchs’ heterochromic iridocyclitis?

In contrast to most types of uveitis, Dr. Palmberg noted that steroids do not seem to be of benefit in suppressing the inflammation in Fuchs’ heterochromic iridocyclitis. They are not needed since neither peripheral anterior synechiae nor posterior synechiae form in this condition. Furthermore, steroid use risks steroid cataract and steroid glaucoma. However, the question remains why no adhesions form between the iris and the lens and the iris and the angle.

● Other questions surrounding Fuchs’ heterochromic iridocyclitis.

Part of the mystery regarding causation probably has been solved, as two recent studies have reported evidence of rubella virus antibodies in a large percentage of patients with Fuchs’ heterochromic iridocyclitis (Quentin CD, Reiber H. Am J Ophthalmol. 2004;138:46-54, and de Groot-Mijnes JD, et al. Am J Ophthalmol. 2006;141:212-214). Moreover, since the last large outbreak of rubella in 1963-1964 and introduction of a rubella vaccine in 1969, the incidence of Fuchs’ heterochromic iridocyclitis does appear to have been reduced (Birnbaum AD, et al. Am J Ophthalmol. 2007;144:424-428).

However, why does angle neovascularization occur in Fuchs’ heterochromic iridocyclitis and why does it not result in angle closure as neovascularization does in other conditions? Because angle closure does not occur or occurs very rarely, panretinal photocoagulation (PRP) is not needed to suppress this angle neovascularization.

“Uveitis normally is treated with steroids, and neovascularization is normally treated with PRP. Neither treatment applies in Fuchs’ heterochromic iridocyclitis. Why?” Dr. Palmberg asked.

● Why are isolated serous choroidal detachments almost always present nasally or temporally but not inferiorly or superiorly?  What is it about the anatomy and vascular connections of the choroid that accounts for this?

● Why is there a forward rotation of the ciliary body processes in plateau iris syndrome?

“Plateau iris syndrome is certainly a rare form of angle closure. We found it in 2.7% of 1,742 cases subsequent to a laser iridotomy done at Bascom Palmer Eye Institute (AAO presentation, “Peripheral Iridoplasty,” 1988). After a laser iridotomy is performed one must repeat indentation gonioscopy with a Zeiss type lens (Forbes M. Arch Ophthalmol. 1966;76:488-492) to determine whether any residual angle closure is present, and if so, to determine whether the closure is due to synechiae or is due to only a reversible appositional closure in a plateau configuration (forward rolled ciliary processes) (Pavlin CJ, et al. Am J Ophthalmol. 1992;113:390-395). That appositional closure may be present right after the iridotomy is performed, or may develop years later. Some cases with forward rolled ciliary processes may be secondary to the uveal congestion of an acute attack of angle closure and might resolve with conservative treatment, but the majority of cases are present in a quiet eye and in the opposite eye as well. When appositional angle closure is still present in a quiet or quieted eye, Dr. Robert Ritch’s laser iridoplasty is the definitive treatment and is highly successful in opening angles and reducing the IOP (Ritch R, et al. Ophthalmology. 2004;111:104-108). This may have to be repeated in 5 to 10 years, but it almost cures plateau iris syndrome,” he explained.

Curiously, in young patients with angle closure who are not hyperopic, plateau iris syndrome accounts for a fairly high percentage of the cases. Why is that so?

Before that treatment, the ciliary body is forward, which changes after iridoplasty.

● Why does ganglion cell loss respect the raphe?

Despite the fact that the ganglion cell bodies are exposed to the same IOP, they have very different sensitivity to injury. One often sees total loss of field above or below the raphe and in the immediately adjacent retina on the other side of the raphe there can be total preservation. Why does that happen?

Questions he posed about this curiosity are: What organizes the course of the optic nerve fibers to respect the raphe as they grow out from the ganglion cells during development? What organizes the course of the retinal arteries and veins to respect the raphe as they develop? And, would a better understanding of the embryology of raphe formation lead to a better understanding of this great difference in sensitivity of adjacent ganglion cells in the retina?

“I would love to learn the answers to these questions,” he said.

● Why do the trabecular meshwork cells become senescent in primary open-angle glaucoma (POAG)?

Dr. Palmberg recounted, human trabecular endothelial cells are grown easily from donated eyes of aging normal adults (Polansky JR, et al. Invest Ophthalmol Vis Sci. 1979;18:1043-1049).  However, these cells never or rarely grew from donated eyes of patients with POAG in his studies or those of other investigators.

“The cells were present and metabolically active but would not divide,” he said.

Normal human trabecular meshwork cells can be grown in culture and they can be aged faster by passaging the cells.

“When that happens, Tony Hajek, PhD, in our lab showed that these cells become senescent and produce very little hyaluronic acid but continue to produce chondroitin sulfate, which is similar to other bodily tissues with aging,” he said.

Paul Knepper and colleagues studied coded samples of trabecular meshwork that we sent to him (five normal and five from patients with POAG). Quantitative histochemistry studies showed the same effects of senescence in these samples (Knepper PA, et al. Invest Ophthalmol Vis Sci. 1996;37:1360-1367).

“Dr. Knepper identified the same findings in these eyes present naturally as we found in cells with accelerated aging. As senescence progresses in vivo, there is a decrease in hyaluronic acid and an increase in chrondroitin sulfate in the trabecular meshwork. Dr. Knepper showed that that is what is present in eyes in which the cells could not be grown. What is making the cells in the trabecular meshwork senescent in glaucoma?” Dr. Palmberg queried.

“The glaucoma detectives still have a lot of work to do. David Campbell, MD, PhD, determined what is happening in pigmentary glaucoma, ghost cell glaucoma, ICE syndrome, and modern goniosynechiolysis. There are more glaucoma detectives out there who are going to answer some of these questions,” Dr. Palmberg concluded.

Dr. Palmberg has no financial interest in the subject matter.

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