Erythropoietin: Timing Is Everything
Until recently, erythropoietin’s (EPO) claim to fame was as a hormone that stimulates erythrocyte production in bone marrow. The pleiotropic growth factor is widely used to treat anemia in patients, many of whom are at risk for vascular disease.
It had been suggested that EPO was highly upregulated during hypoxia in the mouse model and elevated in the vitreous of patients with diabetic retinopathy, but how EPO affected angiogenesis or normal vascular survival was largely unknown.
A recent report has shed new light on a Dr. Jekyll and Mr. Hyde phenomenon of EPO. In a mouse model, production of EPO was found to be three to 10 times below normal in early-stage diabetic retinopathy and 12 to 33 times above normal in late-stage retinopathy.1 The investigators also showed that early administration of exogenous EPO not only cut healthy vessel loss by half and reduced formation of deformed vessels by 30 percent, but that EPO given at later stages had just the opposite effect—promoting detrimental neovascularization.
In addition to its vascular benefits, EPO’s early use protected against hypoxia-induced retinal neuronal apoptosis. One way EPO may help is by inhibiting caspase, a proapoptotic enzyme. “EPO appears to cause normalization of the neurovascular network,” said senior author Lois E. H. Smith, MD, PhD, professor of ophthalmology, Harvard Medical School in Boston.
According to the study’s authors, EPO likely protects retinal vessels and neurons through both local and systemic mechanisms. They suggested that EPO acts not only locally by preventing apoptosis of retinal vessels and neurons but also systemically by mobilizing bone marrow-derived cells to populate injured retinal vessels. Which is more prominent—prevention of neuronal loss or prevention of vascular loss—may never be fully understood, said Dr. Smith. “It’s hard to separate out the two because the nerves and vessels go hand in hand.”
Dr. Smith suggested that physicians view EPO the way they do other hormones, such as insulin. “We don’t want it too high, and we don’t want it too low. If it is viewed in that way, normalization of EPO—in either the first stage or the second stage—might be a way to prevent retinopathy as well as to help treat it at the end stage.” This might represent a major advance given that there are no successful treatments for prevention of vessel loss.
These findings have ramifications not only for retinopathy but also for patients with diseases affected by other types of abnormal blood vessel growth, such as cancer. A recent meta-analysis showed that high doses of EPO given to treat anemia in cancer patients increased their risk of tumor growth by 10 percent.2 “This might well reflect that it’s increasing vascular development at a time when you don’t want it,” said Dr. Smith, emphasizing that clinical trials are required to confirm this. She underscored the importance of evaluating each individual medical problem and scrutinizing timing. “It might be important at certain times to actually give EPO, and at other times to suppress it,” she said. Given at the wrong time, EPO could accelerate full-blown retinopathy, for example.
It is critical to know the levels of erythropoietin in patients at risk for abnormal blood-vessel growth, said Dr. Smith, especially because all tissues, including the eye, produce EPO. For this reason, further studies are needed in humans to determine normal baseline levels of EPO as well as levels at different stages of diabetes and other diseases, where pathological angiogenesis plays a significant role.
1 Chen, J. et al. J Clin Invest
2 Bennett, C. L. et al. JAMA
Endogenous Cells May Be Able to Mend the Retina
What if cells in the eye could be stimulated to undergo neuroregeneration and repair the retina? According to one study, the once unfathomable may be possible. In the lab of Dong Feng Chen, MD, PhD, assistant professor of ophthalmology at Harvard University and associate scientist at Schepens Eye Research Institute in Boston, certain non-neuronal cells in mouse eyes were manipulated to transform into progenitor cells—stemlike cells that can induce photoreceptor regeneration in the retina.1
Dr. Chen said the study came about because of evidence that suggested stem cells exist in the adult retina and brain. “After injury, we could see progenitor cells, which are normally dormant in adults, become awakened and start to divide,” she said. “We were interested to learn what activated them and how they may be involved in neuroregeneration.”
To study this possibility, the scientists focused on the retinal Müller glia, which in higher vertebrates appear to possess progenitor cell properties and the ability to generate new neurons after injury. They injected different concentrations of glutamate and its analog, alpha-aminoadipate, subretinally into mice.
“Interestingly,” Dr. Chen noted, “high levels of glutamate can injure neurons and cause retinal damage. However, we found that a low concentration—50 times lower than the concentration that causes neural death—actually stimulates the Müller glia to turn into progenitor cells.”
When the glutamate or alpha-aminoadipate was injected into the back of the eye, it prompted the progenitor cells to migrate to the outer nuclear layer where the photoreceptor cells are located, and the progenitor cells turned into photoreceptor cells. And, she said, “We found the analog, alpha-aminoadipate, caused fewer side effects, such as cell damage, as compared with glutamate.
“This is very exciting and promising,” said Dr. Chen, “because when exogenous embryonic stem cells are used in transplantation, they don’t necessarily know what types of cells to become. However, this approach shows more potential because the Müller cells residing in the retina, after turning into progenitors, know what to become: retinal-specific neurons, such as photoreceptor cells. They are more responsive to the local positional cues than exogenous stem cells.” She said that one of the most surprising findings of this study was the fact that the neurotransmitter itself—in this case glutamate—can be the signal that turns on these progenitor cells.
Of course, more research needs to be done. “Our next step is to see if we can activate enough photoreceptor cells in animals carrying inherited retinal degeneration to restore vision,” Dr. Chen said, “and we are hoping that there are similar types of endogenous stem cells in the brain and in the central nervous system, as well. This could open up a whole new set of possibilities.”
—Lori Baker Schena
1 Takeda, X. et al. Invest Ophthalmol Vis Sci
Idiopathic Intracranial Hypertension
Race Is a Risk Factor in Vision Loss From IIH
Researchers at Emory University have reported that when it comes to vision loss among patients with idiopathic intracranial hypertension (IIH), race matters.1 The disease, a rare but important cause of insidious vision loss in young people, is more aggressive in African-Americans, who may need closer follow-up and lower thresholds for early interventions.
The study wasn’t designed to answer whether race is a risk factor for IIH, a disease characterized by a high cerebrospinal fluid pressure. Rather, it asked whether race is a risk factor for the vision loss that arises in patients with IIH. The findings: Black patients with IIH were 3.5 times more likely than nonblacks to have severe vision loss in at least one eye. The risk of vision loss in both eyes was 4.8 times greater in blacks than nonblacks.
There have been earlier discussions of race as a risk factor in vision loss resulting from IIH, but the Emory researchers had data to address the question with adequate power. They had access to records of 450 consecutive patients with IIH seen at the university’s neuro-ophthalmology clinic between 1989 and 2006. Nearly 200 of the patients were black, and 253 were nonblack, said lead author Beau B. Bruce, MD, a neuro-ophthalmology fellow at Emory.
In addition to the findings on race, the study suggested that a higher frequency of anemia, higher body mass index and higher cerebrospinal fluid pressure on average among blacks may partially account for the more frequent vision loss that group experienced. With regard to potential risk factors, patients who were black, male and more obese, or who had anemia, hypertension or sleep apnea were more likely to have severe vision loss.
The researchers considered, but discredited, socioeconomic and other factors that might account for differences between races. For example, the time to diagnosis was actually longer in nonblack patients than in black patients. And medical conditions such as sleep apnea, anemia and systemic hypertension were more common in black patients, suggesting they had adequate access to primary and specialty care. There was no difference between the races in application of diagnostic modalities such as MRI.
Care of IIH patients requires collaboration between ophthalmologists and neurologists, Dr. Bruce said, but he stressed that ophthalmologists are on the front line for diagnosing, managing and protecting these patients’ vision. “This disorder is one of the reasons that all patients with headache need a careful examination of the ocular fundus to exclude optic nerve head edema.”
1 Bruce, B. B. et al. Neurology
On Watertight Wounds
Watertight wounds are the standard of care for preventing endophthalmitis after cataract procedures, and when wound construction alone is not self-sealing, many surgeons have depended on stromal hydration to do the job. That may be a mistake, according to James P. McCulley, MD, professor and chairman of ophthalmology at the University of Texas Southwestern Medical Center in Dallas.
At the annual meeting of the American Society of Cataract and Refractive Surgery in Chicago, Dr. McCulley presented data from a review of cataract surgeries at his institution and compared them with historical averages as well with the results of a recent study by the European Society of Cataract and Refractive Surgeons. “The ESCRS study had an incidence of endophthalmitis of 0.38 percent, which is really quite high when compared with the historical gold standard of 7 in 10,000, or 0.07 percent, and especially when compared with the incidence at the University of Texas, which was 0.008 percent.”
Dr. McCulley said that it’s his opinion that there’s upward trending of endophthalmitis because surgeons have stopped ensuring truly watertight wound closure at the conclusion of surgery. With intracameral cefuroxime, European ophthalmologists were able to bring the rate back down to 0.07 percent. “The use of antibiotics forgave or perhaps compensated for the fact that surgeons had increasingly tried to save time and a few dollars by not suturing their wounds. Many fooled themselves into thinking they had a watertight wound by stromally hydrating, which lasts for only a short period of time,” he said.
Dr. McCully’s secret for such an impressive control of endophthalmitis at the University of Texas is hardly revolutionary: “My contention is that maintenance of a sterile environment, antisepsis of the lids and ocular surface, thoughtful prophylactic antibiotic use and good surgical technique with a watertight wound closure should make endophthalmitis a rare occurrence. The safest thing, if wound construction does not result in a watertight wound, is to secure it with a suture, and not with stromal hydration.”
—Denny Smith, Senior Editor