New research characterizes glaucoma as neurologic disorder rather than eye disease

A new paradigm to explain glaucoma is rapidly emerging, and it is generating brain-based treatment advances that may ultimately vanquish the disease known as the "sneak thief of sight." A review now available in Ophthalmology, the journal of the American Academy of Ophthalmology, reports that some top researchers no longer think of glaucoma solely as an eye disease. Instead, they view it as a neurologic disorder that causes nerve cells in the brain to degenerate and die, similar to what occurs in Parkinson disease and in Alzheimer's. The review, led by Jeffrey L Goldberg, M.D., Ph.D., assistant professor of ophthalmology at the Bascom Palmer Eye Institute and Interdisciplinary Stem Cell Institute, describes treatment advances that are either being tested in patients or are scheduled to begin clinical trials soon.

28 march 2012--Glaucoma is the most common cause of irreversible blindness worldwide. For many years, the prevailing theory was that vision damage in glaucoma patients was caused by abnormally high pressure inside the eye, known as intraocular pressure (IOP). As a result, lowering IOP was the only goal of those who developed surgical techniques and medications to treat glaucoma. Creating tests and instruments to measure and track IOP was crucial to that effort. Today, a patient's IOP is no longer the only measurement an ophthalmologist uses to diagnose glaucoma, although it is still a key part of deciding how to care for the patient. IOP-lowering medications and surgical techniques continue to be effective ways to protect glaucoma patients' eyes and vision. Tracking changes in IOP over time informs the doctor whether the treatment plan is working.

But even when surgery or medication successfully lowers IOP, vision loss continues in some glaucoma patients. Also, some patients find it difficult to use eye drop medications as prescribed by their physicians. These significant shortcomings spurred researchers to look beyond IOP as a cause of glaucoma and focus of treatment.

The new research paradigm focuses on the damage that occurs in a type of nerve cell called retinal ganglion cells (RGCs), which are vital to the ability to see. These cells connect the eye to the brain through the optic nerve.

RGC-targeted glaucoma treatments now in clinical trials include: medications injected into the eye that deliver survival and growth factors to RGCs; medications known to be useful for stroke and Alzheimer's, such as cytidine-5-diphosphocholine; and electrical stimulation of RGCs, delivered via tiny electrodes implanted in contact lenses or other external devices. Human trials of stem cell therapies are in the planning stages.

"As researchers turn their attention to the mechanisms that cause retinal ganglion cells to degenerate and die, they are discovering ways to protect, enhance and even regenerate these vital cells," said Dr. Goldberg. "Understanding how to prevent damage and improve healthy function in these neurons may ultimately lead to sight-saving treatments for glaucoma and other degenerative eye diseases."

If this neurologically-based research succeeds, future glaucoma treatments may not only prevent glaucoma from stealing patients' eyesight, but may actually restore vision. Scientists also hope that their in-depth exploration of RGCs will help them determine what factors, such as genetics, make some people more vulnerable to glaucoma.

Provided by American Academy of Ophthalmology

Glaucoma Linked to Slower Reading, Reading Impairment

Effect of disease on reading speed is significant with advanced bilateral field loss

19 jan 2009-- In elderly adults with advanced bilateral field loss, glaucoma is associated with slower reading and increased reading impairment, according to research published in the January issue of the Archives of Ophthalmology.

Pradeep Y. Ramulu, M.D., of Johns Hopkins University in Baltimore, and colleagues used data from the Salisbury Eye Evaluation study to assess spoken reading speed and glaucoma status in 1,154 elderly subjects.

The researchers found that reading impairment rates were significantly higher among subjects with either unilateral or bilateral glaucoma (21.1 percent and 28.4 percent, respectively) than in subjects without glaucoma (16 percent). But their regression analyses showed no significant impact of glaucoma on spoken reading speed until the disease was bilateral with severe visual field loss.

"These data from a population-based, elderly sample demonstrate high overall rates of reading impairment, with one in eight white subjects and one in three African American subjects having impaired reading," the authors conclude. "Future work should evaluate reading in subjects with glaucoma under more realistic conditions to further explore if reading impairment is more prevalent than reported herein."

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Steady, Low Intraocular Pressure Best to Preserve Visual Field in Glaucoma

SEOUL, South Korea, Aug. 13 -- Fluctuations in intraocular pressure may increase the risk of visual field deterioration in glaucoma patients even if they are able to maintain pressures below 18 mm/Hg, researchers found.
In patients who achieved intraocular pressure below that level, progressive visual field deterioration was significantly more common among those whose pressures fluctuated by more than two standard deviations without crossing the 18 mm/Hg threshold (P<0.001), wrote Samin Hong, M.D., of Yonsei University College of Medicine here, in the August issue of Archives of Ophthalmology.
"Our results suggest that glaucomatous visual field damage cannot be stabilized by only lowering the postoperative IOP but also requires reducing the long-term fluctuation of the post-operative IOP," he said.
Dr. Hong and colleagues studied 408 patients who had undergone phacoemulsifcation, posterior chamber intraocular lens implantation, and trabeculectomy to lower intraocular pressure.
Measurements of intraocular pressure and visual field were taken at three months, six months, and yearly after surgery for 13 years. Patients were divided into two groups -- those whose intraocular pressure fluctuated by less than two standard deviations (group 1) and those whose pressures fluctuated by more than two standard deviations (group 2).
The study included 246 patients with primary open-angle glaucoma and 162 with chronic primary angle-closure glaucoma. The mean follow-up was 9.2 years. All patients maintained intraocular pressure at less than 18 mm/Hg throughout follow-up.
Sixty of the primary open-angle glaucoma patients and 42 of the chronic primary angle-closure glaucoma patients had fluctuations of more than two standard deviations during follow-up.
There was no significant difference in visual field defect scores among patients whose pressure was stable during follow-up, but "the number of patients with progressive [visual field] loss was significantly higher in group 2 (30.0% for [primary open-angle glaucoma]; 28.6% for [chronic primary angle-closure glaucoma]) than in group 1" (9.7% and 10.0%, respectively), they wrote.
In an accompanying editorial Joseph Caprioli, M.D., of the Jules Stein Eye Institute, UCLA, theorized that long-term fluctuation in intraocular pressure might disrupt homeostatic mechanisms.
"Irregular and large [intraocular pressure] fluctuations may cause a loading and unloading of stresses, and as opposed to conditions of static stress, the tissue is unable to compensate and damage occurs," Dr. Caprioli wrote.
The study by Hong and colleagues, suggests that modulation of pressure rather than its reduction might be an appropriate treatment for glaucoma, he wrote.
He pointed out that "the main disadvantage of the study is its retrospective nature with all the typical attendant biases."
Specific guidelines for intraocular pressure modulation "must await a better understanding of the pathophysiologic consequences of [pressure] fluctuation in glaucoma," Dr. Caprioli concluded.
No funding source was disclosed for the study and neither Dr. Hong nor Dr. Caprioli disclosed competing interests. Primary source: Archives of OphthalmologySource reference: Hong, S et al "Long-term Intraocular Pressure Fluctuation and Progressive Visual Field Deterioration in Patients With Glaucoma and Low Intraocular Pressures After a Triple Procedure" Arch Ophthalmol. 2007; 125:1010-1013. Additional source: Archives of OphthalmologySource reference: Caprioli,J "Intraocular Pressure Fluctuation: An Independent risk Factor for Glaucoma" Arch Ophthalmol. 2007; 125:1124-1125.

Glaucoma and Alzheimer's May Have Common Origins and Treatment

LONDON, Aug. 6 -- A combination of drugs that target the amyloid-beta pathway implicated in Alzheimer's disease appear to be highly effective against glaucoma as well, at least in animal models, investigators here reported.
Amyloid-b peptide, found to accumulate in the brains of people with Alzheimer's disease, accelerated the programmed death of retinal ganglion cells in rat models of glaucoma, but its action was prevented by three drugs that inhibit Ab formation and aggregation, wrote M. Francesca Cordeiro, M.D., of University College London, and colleagues.
The findings, published online in Proceedings of the National Academy of Sciences, suggest that blocking the action of amyloid-b peptide may offer a new method for slowing or preventing glaucoma progression.
"Perhaps the most exciting finding of the work has been that combination therapy, targeting three different aspects of the amyloid-b pathway, produced the maximal reduction of retinal ganglion cell apoptosis (>80%)," one of the earliest signs of glaucomatous neural damage, they wrote.
Although conventional glaucoma therapy -- both medication and surgery -- is aimed at lowering intraocular pressure, glaucoma can progress even when intraocular pressure is normal, indicating that other mechanisms may be at work, the authors noted.
"The principal step leading to irreversible loss of vision in glaucoma isretinal ganglion cell apoptosis, and the question is what mechanisms precede this cell death," they wrote.
Because amyloid-b has recently been implicated in the death of retinal ganglion cells, the authors conducted a series of four experiments to assess the relationship between the peptide and glaucomatous damage to ocular nerves.
They first looked at the association of amyloid-b with retinal ganglion cell apoptosis in rat models of glaucoma, in which elevated intraocular pressure is induced in one eye, with the other eye serving as a control.
They found that there was significant overlap of amyloid-b and apoptotic retinal ganglion cells, suggesting that the known neurotoxic effects of the peptide might also damage neurons in the optic pathway.
The researchers then injected two forms of amyloid-b into the vitreous humor of the eyes, and saw that the effect of the protein increased over time and higher doses of the most potently neurotoxic amyloid-b oligomer produced the highest degree of retinal ganglion cell die-off.
In the final two stages of their experiment, they looked at the effects of monotherapy and a combination of three drugs on the retinal ganglion cells.
The drugs include an inhibitor of b-secretase, an enzyme that cleaves the amyloid-precursor protein in the first step of abnormal amyloid-b deposition, Congo red, a dye that has been shown to completely block amyloid-b aggregation and neurotoxicity in hippocampal neurons of rats, and a monoclonal antibody directed against amyloid-b.
They found that overall, the anti-amyloid-b antibody appeared to be the most effective at preventing retinal ganglion cell apoptosis, with effects lasting up to 16 weeks, which may be because of a combined effect of the drug to both block amyloid-b action and prevent its aggregation.
"In comparison, Congo red dramatically reduced retinal ganglion cell apoptosis at three weeks and resulted in a delayed peak of retinal ganglion cell apoptosis at eight weeks after raised intraocular pressure," they wrote. "However, compared with the [antibody], Congo red appeared to have a shorter window of protection against retinal ganglion cell apoptosis."
The beta-secretase inhibitor did not significantly prevent, but did appear to at least delay the peak. This may have been related to the low dose used, the authors said, noting that there is evidence to suggest that beta-secretase inhibition may be an effective intervention in this setting.
When the authors tried the agents in combination, however, they hit the jackpot, observing a significantly improved neuroprotective effect after three weeks of increased intraocular pressure compared with the anti-amyloid-b antibody alone.
The triple therapy resulted in an 84% mean reduction of retinal ganglion cell apoptosis compared with a 74% reduction for the monoclonal antibody alone (P<0.05).
There was also a significant protective effect of the combination of the b-secretase inhibitor plus antibody compared with the b-secretase inhibitor alone (P<0.05).
All of the other combinations were significantly better than saline placebo, but not better than monotherapy with the anti-amyloid-b antibody, they noted.
"Our results suggest that combination therapy targeted at different points of the amyloid-b pathway may provide the most promising approach to prevent glaucomatous retinal ganglion cell apoptosis," they wrote. "Thus, the amyloid-b antibody and its use in combination therapy may have great potential in glaucoma treatment."
Dr. Cordeiro said that the findings also suggest possible methods for testing Alzheimer's disease therapies.
"Since we have shown that drugs for Alzheimer's disease can tackle glaucoma, then potentially we could use a damaged retina to screen Alzheimer's drugs that target beta-amyloid build up," she said.
The study was funded by the Wellcome Trust. The authors declared that they have no conflicts of interest.Primary source: Proceedings of the National Academy of SciencesSource reference: Guo L et al. "Targeting amyloid-b in glaucoma treatment" PNAS doi: 10.1073/pnas.0703707104