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Various subtypes of primary open-angle glaucoma might exist. Continued research is needed to identify the characteristics of each subtype for better management.
Reviewed by Louis R. Pasquale, MD
Different forms of glaucoma have unique features, and lumping them together represents a disservice to patients along with a missed opportunity for physicians to learn about the various glaucoma subtypes, said Louis R. Pasquale, MD.
New drug targets for primary open-angle glaucoma (POAG) that are precision-medicine based are needed and will be developed by studying various candidate mechanisms for the disease, explained Dr. Pasquale, director, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston.
He provided an overview of a few subtypes of POAG he believes exist-i.e., paracentral OAG, African-derived OAG, and glaucoma associated with estrogen deficiency-to determine their differences and facilitate their diagnosis and management.
He described the case of a patient who presented with an apoplectic inferior altitudinal visual field loss in the left eye. However, IOP was relatively normal. The referring physician inquired if the patient had sustained a sudden ischemia or retinal embolic event, had newly discovered normal-tension glaucoma, or non-arteritic ischemic optic neuropathy.
This case illustrates the quandary in which ophthalmologists find themselves.
“How long have we been confused about POAG?” Dr. Pasquale asked. “The answer is: A really long time."
“The term is a misnomer,” he added. “The definition in the dictionary is pale blue or grayish green. The Latin root means ‘waterfall,’ which probably referred to patients who were functionally blind from a mature cataract.”
It was not until the invention of the ophthalmoscope that patients with clear media also were found to have excavated totally cupped optic nerves, which explained the blindness, Dr. Pasquale noted.
However, confusion about the disease persisted, and the terminology used might have actually confounded the confusion about the etiology of POAG, he said.
Redefinition of the disease is the easy part, according to Dr. Pasquale.
When measuring IOP, the value is elevated in most patients, although notably 90% of Japanese patients have normal values.
However, the slit lamp examination does not show the secondary cause of elevated IOP. Importantly, there is progressive excavation of the neural retinal rim with associated visual field loss.
Dr. Pasquale pointed to the importance of IOP in POAG. Compared with individuals with IOP less than 17 mm Hg, those with IOP of 35 mm Hg or higher have a 39-fold increased risk of POAG.
Similarly, when the body mass index (BMI) is 33 or higher (indicating obesity), the risk of type 2 diabetes also is 39-fold compared with someone with a BMI below 22.
“This very high effect on size suggests IOP is in the causal pathway of the disease,” he said.
Ophthalmologists must stop equating high IOP and optic nerve damage with POAG, Dr. Pasquale suggested. In addition, the term “low-pressure glaucoma” is confusing and should be abandoned. The situation seems to be much more complicated.
While POAG equals high-tension glaucoma and normal-tension glaucoma, his discomfort lies in the fact that suggests the two conditions are separate entities.
“They are not,” he said. “There is clear overlap between the two.”
Recognizing puzzle pieces
Dr. Pasquale reported two patients, a father and daughter, who had advanced high-tension glaucoma with untreated IOP of 24 mm Hg upon referral and normal-tension glaucoma with IOP of 18 mm Hg and a hemorrhage on the left optic nerve, respectively. Dr. Pasquale suggested the situation with these related patients has more to do with the genetics of the underlying disease process than with IOP itself.
Over a 17-year period, the daughter’s glaucoma progressed. A paracentral scotoma in the left eye had advanced. A disc hemorrhage developed later in the right eye, as did a paracentral scotoma despite maximal medical therapy and laser trabeculoplasties.
“We have to recognize this scenario as a separate entity that is attacking the central vision,” he said. “This is paracentral OAG (PCOAG) and it should be treated as a separate entity.”
This disease variation is characterized by an optic nerve biomarker in many patients, i.e., a triangular defect in the prelaminar nerve fiber layer.
In addition, the maximal IOP values in these patients are lower (21 ± 4.5 mm Hg) than in isolated nasal step patients (Park et al. Ophthalmology. 2011;118:1782-1789), according to Dr. Pasquale. The standard deviation indicates that a substantial number of patients had normal IOP, considered as normal-tension glaucoma, and a subset with higher IOP, i.e., high-tension glaucoma.
“This demonstrates that the stratification by IOP is not serving us well,” he said.
A second structural biomarker of PCOAG is frequent disc hemorrhages, as well as more hypotension, Raynaud’s phenomenon, and sleep apnea. Another genetic finding in patients with PCOAG is that the caveolin 1/caveolin 2 region contains genome-wide markers for elevated IOP and POAG.
“When POAG patients are stratified by paracentral loss versus isolated peripheral loss, a stronger association is seen for the top genetic markers with the paracentral cases than with the peripheral loss cases,” he said.
The caveolin region is important in PCOAG because it is adjacent to endothelial nitric oxide synthase (eNOS) in the membranes, and both regulate nitric oxide production.
Interestingly, if eNOS is knocked out in a murine model, elevated IOP and reduced outflow facility ensue, according to Dr. Pasquale.
“Nitric oxide signaling is important for regulating IOP,” he said.
Recognition of this mechanism is resulting in development of drugs that are nitric oxide donators and those that are rho-kinase inhibitors. These drugs improve endothelial cell signaling by enhancing smooth muscle cell relaxation and might hold promise for PCOAG, he noted.
Changes in diet--specifically, the addition of vegetable nitrates, a source of nitric oxide-also might help patients with PCOAG by modifying the disease risk (Kang et al. JAMA Ophthalmol. 2016;134:294-303).
“We found that compared with people who were consuming the lowest quantities of nitrates from vegetables, those with the highest [vegetable consumption] had about a 44% reduction in the risk of PCOAG,” Dr. Pasquale said.
Clinically, he advised the target IOP in these patients should be low, perhaps less than 10 mm Hg, but certainly below 16 mm Hg.
In the case of a 32-year-old African man with a positive history for glaucoma, the patient had an 8-year history of untreated visual loss and ultimately lost all vision in the right eye.
IOP was 24 and 18 mm Hg, respectively, in the right and left eyes. Central corneal thicknesses were low, and slit lamp evaluation and gonioscopy were unremarkable. The right optic nerve was excavated completely and cupped. The left eye has a glaucomatous disc but no visual field loss, according to Dr. Pasquale.
IOP in this case was not markedly elevated and there was no secondary form of glaucoma apparent. In such a case, Dr. Pasquale underscored the importance of patient education about glaucoma and determination of the status of his children.
“The misconception is that patients in their 20s, 30s, and 40s are unlikely to have glaucoma, but in this population, glaucoma is likely and it is important to detect it,” he said.
Dr. Pasquale cited a study (Bokman et al. PLoS One. 2014; 9(12):e115942), conducted in a Haitian population in south Florida, in which 21% of the participants aged 20 to 40 years either had an IOP of 24 mm Hg or higher or a cup-to-disc ratio over 0.7-indicating that glaucoma is developing in this population one or two decades earlier than in their Caucasian counterparts.
He also described the case of a 12-year-old African-American girl with IOP of 12 mm Hg, normal central corneal thickness and visual fields, and physiologic cupping. Her 34-year-old mother had moderate stage POAG, IOP no higher than 21 mm Hg, and optic nerves similar to her daughter, except for erosion of the superior and inferior neural retinal rims bilaterally.
“With the strong genetic predisposition to glaucoma in this population, we need to find the involved genes,” Dr. Pasquale said.
He also hypothesized there are likely pathophysiologic differences in glaucomatous optic neuropathy between African-American and Caucasian patients.
A study (Skaat et al. Ophthalmology. 2016;123:1476-1483) that sought to determine those differences in patients with optic disc hemorrhages and peripapillary atrophy between the races postulated that because disc hemorrhage is an independent risk factor for OAG, it must be more common in African-Americans than in Caucasians.
The evaluation of about 10,000 disc photographs from both racial groups with and without glaucoma showed, ironically, that African race was associated with reduced risk of disc hemorrhage, and the reason was unclear.
However, Dr. Pasquale noted the importance of this observation because it suggested that the retinal hemodynamics differs in patients of African heritage compared with Caucasians.
A 61-year-old Caucasian woman, a glaucoma suspect, had a gynecologic history of pre-eclampsia and hysterectomy with bilateral oophorectomy at age 53. She presented with superior visual field loss in the right eye. IOP was 21 mm Hg that decreased to 15 mm Hg with maximal medical therapy. The inferior neural retinal rims are excavated and worse in the right eye. Visual fields were similar to those in the previously described case of PCOAG.
“Estrogen is a big driver of eNOS activity. Retinal ganglion cells have receptors for estrogen,” Dr. Pasquale explained. “Studies in normal menstruating women found that the optic nerve structure varies with the function of the menstrual cycle as does the retinal sensitivity. IOP decreases during pregnancy, despite that the central corneal thickness tends to increase in the third trimester.”
A randomized trial (part of the Women’s Health Initiative study) indicated that postmenopausal hormone use was associated with lower IOP (Vajaranant et al. Am J Ophthalmol. 2016;165:115-124).
While estrogen is important in glaucoma-related traits (Figure 1), studies have shown there is an increased risk of POAG in women with decreased estrogen exposure during their life and conversely, there is a decreased risk for women with increased estrogen exposure.
An animal model of POAG bore that out, i.e., estrogen is neuroprotective and preserved visual function and structure (Prokai-Tatrai et al. Mol Pharm. 2013;1:3253-3261).
The challenge is how to use this information and perform a randomized clinical trial to determine how to stop glaucoma progression, Dr. Pasquale said.
In patients who present with very high IOP, he advised that ophthalmologists seek out secondary causes of glaucoma, such as steroid use or exfoliation.
Dr. Pasquale also alerted physicians to a careful annual follow-up of patients with physiologic cupping for development of POAG. Genome-wide association studies of the cup-to-disc ratio have found many genes associated with physiologic cupping, and several of those genes are associated with POAG.
The hope is that the future will see the development of a risk calculator with all genes that determine the optic nerve cupping and shape and predict who will develop POAG, he noted.
Returning to the initial case of the patient with apoplectic inferior altitudinal visual field loss in the left eye, Dr. Pasquale said the loss developed as the result of a 6-decibel loss annually.
“This rapid progression is a cause for great concern,” he said. “The ophthalmologist should seek alternative explanations for this loss, such as steroid use, eye rubbing, or some practice that might cause this degree of visual loss.”
Dr. Pasquale advised performing a diurnal curve to identify an IOP spike and possibly neuroimaging.
Louis R. Pasquale, MD
This article was adapted from Dr. Pasquale’s presentation of the American Glaucoma Society Subspecialty Day Lecture at the 2016 meeting of the American Academy of Ophthalmology. Dr. Pasquale is a consultant and advisor to Bausch + Lomb.