Eleven commandments for teaching ophthalmic surgery.
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Clinical Competence↗
Biomedical subjects
E B Dreyer
Publications and source records attributed to E B Dreyer.
Thy-1 is critical for normal retinal development.
In the mammalian retina, Thy-1, the most abundant mammalian neuronal surface glycoprotein, is found predominantly if not exclusively on retinal ganglion cells. We hypothesized that Thy-1 plays a significant role in retinal development. Neurite outgrowth of retinal ganglion cells from Thy-1(-) mice over multiple substrates was compared to that seen with wild-type controls. Adult mouse retinas were histologically compared between Thy-1(-) and three strains of Thy-1 positive mice. Thy-1(-) retinal ganglion cells had significantly less neurite outgrowth than controls. The inner nuclear, inner plexiform, ganglion cell and outer segment/pigment epithelium layers were thinner in Thy-1(-) retinae than in controls. Thy-1 appears to be critical for normal retinal development.
Animals↗
Infection with adeno-associated virus may protect against excitotoxicity.
Gene therapy has developed as a promising approach for therapy in a broad variety of conditions. Viral vectors have been developed that may replace a defective gene, prevent expression of a mutant gene, or deliver a protective gene and thereby delay cellular loss. Using adeno-associated virus containing green fluorescent protein (AAV-GFP) we were able to specifically transduce cells located in the inner retina and induce over-expression of GFP in adult rat retinae. The delivery and expression of GFP had no influence themselves on retinal ganglion cell survival. Administration of the reporter vector AAV-GFP provided retinal ganglion cells with slight but significant protection from intravitreal NMDA. This was a locally mediated phenomenon; greater protection was seen in regions with more transduced cells. Any evaluation of the efficacy of a putative viral vector should consider the possible protective or toxic effect of the native virus.
Animals↗
bcl-2 gene therapy exacerbates excitotoxicity.
The protooncogene bcl-2 can block neuronal death from both naturally occurring apoptosis and exogenous insults. bcl-2 is therefore a promising candidate for the prevention of excitotoxic neuronal death. Using an adeno-associated viral vector, we delivered the bcl-2 gene to the ganglion cell layer of the rat eye. We hypothesized that infection with bcl-2 would protect ganglion cells against excitotoxic cell death. However, retinal infection with bcl-2 increased ganglion cell susceptibility to both axonal injury and intravitreal NMDA. Our study--intended to explore the possibility of bcl-2 transduction as an in vivo therapeutic approach--revealed a deleterious effect of bcl-2 transduction.
Animals↗
Cation channel control of neurite morphology.
The development of neuronal polarity and morphology is essential for a functioning nervous system. The present study was undertaken to explore whether blockade of specific channels alter neuronal morphology. Retinal ganglion cells were cultured in the presence of antagonists to NMDA, AMPA/kainate, L-, N-, P-, and Q-type voltage-dependent calcium channels (VDCCs). Five parameters were measured under these conditions: the number of neurites at the cell body, total neurite length, the length of the longest neurite, the number of branch points per neurite, and the diameter of the cell soma. Antagonists to NMDA and L-type VDCCs reduce the number of neurites at the cell body; antagonists to P- and Q-type VDCCs increase the number of neurites. Antagonists to the N-type VDCCs increase total neurite outgrowth, while antagonists to the NMDA and P-type channels reduce total neurite length. Antagonists to the NMDA and L-type channels increase the length of a single neurite, while decreasing the number of branch points; antagonists to the P- and Q-type VDCCs do essentially the opposite-increase the number of neurites, while decreasing the length of each. Blockade of one or more cation channels in developing retinal ganglion cells significantly perturbs neurite morphology. This study may help elucidate part of the role that cation channel signaling plays in neuritic development.
2-Amino-5-phosphonovalerate↗
New perspectives on glaucoma.
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Glaucoma↗
Methanol-induced optic nerve cupping.
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Adult↗
An experimental basis for implicating excitotoxicity in glaucomatous optic neuropathy.
Most therapy for glaucoma is directed at the management of the intraocular pressure (IOP). Conventional wisdom holds that excessive pressure within the eye leads to the ganglion cell loss/optic nerve damage seen in this disease. Both glutamate and elevated IOP can selectively damage the retinal ganglion cells in the mammalian eye. We have identified an elevated level of glutamate in the vitreous humor of glaucoma patients (27 microM as compared to 11 microM in the control population). This concentration of glutamate suffices--on its own--to kill retinal ganglion cells. It is plausible that the IOP may represent an initial insult that precipitates the production of excessive glutamate. Therefore, even if glutamate elevation is an epiphenomenon associated with the course of the disease, it may contribute to ganglion cell loss in humans. Lowering the IOP may slow down glutamate production, but if nothing is done to block the toxic effects of glutamate as well, visual loss may result despite excellent IOP control. If interventions can be found to retard the production or toxic effects of glutamate, it may be possible to slow glaucomatous visual loss.
Animals↗
[The excitotoxicity theory of glaucoma].
Glaucoma can be defined as a disease in which one of the pathophysiological consequences of raised intra-ocular pressure is damage of the optic nerve, and subsequently the loss of retinal ganglion cells (RGCs). One of the main aims of modern glaucoma therapy is to alter the intraocular pressure, either surgically or pharmacologically. Recently it was shown that the vitreous of glaucoma patients contains increased levels of glutamate (27 microM as compared to 11 microM in controls). This concentration of glutamate is sufficient to induce retinal ganglion cell death. The rise in intraocular pressure is probably the initial insult, which enhances the increase or release of glutamate. Although the increase in intravitreal glutamate levels is an accompanying feature of glaucoma, it could contribute to the loss of retinal ganglion cells in humans itself. Therefore, despite efficient control of intra-ocular pressure, RGC's loss will continue resulting in further visual impairment, if the toxic effect of glutamate is not blocked. If it would be possible to understand the mechanism leading to excessive vitreous levels of glutamate in glaucoma or to block its toxic effects, then the resulting visual loss could be retarded. This review discusses various proposed mechanisms leading to intraocular glutamate toxicity and the role of neuroprotection in this disease. (Literature search by Medline).
Animals↗
Lidocaine toxicity to rat retinal ganglion cells.
PURPOSE: To examine the effects of the local anesthetic, lidocaine, on rat retinal ganglion cells (RGC) in vitro and in a modified in vivo assay. METHODS: For in vitro experiments, RGC were dissociated from freshly harvested Long Evan's rat pup retinas. The RGC were incubated overnight with varying concentrations of lidocaine (0.5-12.0 mM). Surviving cells were assayed at 24 hours. In an in vivo assay, 7-day-old Long-Evans rat pups were anesthetized and 2 microl of lidocaine (final intraocular concentration: 0.03-15 mM) or vehicle was injected intravitreally. Intravitreal coinjection of nimodipine or MK801 (dizocilpine) were also performed in a subset of animals. A week after injection, rat pups were sacrificed and each retina removed, dissociated and plated separately. RGC survival was immediately assessed. Living RGC were identified on the basis of morphology and counted in a masked fashion. RESULTS: Lidocaine is toxic in a dose dependent fashion to RGC in vitro. Lower concentrations (0.5 mM and 1.0 mM) were non-toxic; 2.0, 6.0 and 12.0 mM lidocaine killed 25%, 88% and 99% of the RGC respectively. Intravitreal lidocaine was also toxic to RGC in a dose dependent fashion. Lidocaine concentrations of 3.0 mM, 7.5 mM and 15 mM killed 25%, 38% and 44% of the RGC. This effect was blocked by the simultaneous administration of either nimodipine or MK801. CONCLUSIONS: Lidocaine is toxic to RGC both in vitro and in vivo. This effect is blocked in vivo by the simultaneous administration of agents known to block glutamate mediated neuronal death, suggesting that excitotoxicity may be involved in this process.
Animals↗
Susceptibility of retinal ganglion cells to excitotoxicity depends on soma size and retinal eccentricity.
PURPOSE: This study was undertaken to determine if retinal ganglion cell sensitivity to intraocular N-methyl-D-aspartate or kainate injections varied as a function of retinal location (eccentricity) or cell soma size. METHODS: Rat retinal ganglion cells surviving intraocular N-methyl-D-aspartate or intraocular kainate induced lesions were retrogradely labeled with horseradish peroxidase and analyzed using an image analysis system. Control animals were retrogradely labeled after vehicle injection only. Cell counting was performed at 48 sampling points over the entire retina and represented a total area of 1.92 mm2 per retina. RESULTS: Larger cells were more sensitive to kainate than to N-methyl-D-aspartate excitotoxicity; smaller cells more vulnerable to N-methyl-D-aspartate excitotoxicity. Further from the optic nerve, more smaller cells survived kainate administration. After N-methyl-D-aspartate administration, larger cells survived most, noticeably in the central retina. CONCLUSIONS: Our results suggest that loss of retinal ganglion cells after N-methyl-D-aspartate or kainate administration affects distinct populations of retinal ganglion cells, dependent upon soma size and retinal location. The mechanism by which certain classes of cells survive or succumb to such insults has yet to be determined.
Animals↗
Pilocarpine toxicity in retinal ganglion cells.
PURPOSE: Muscarinic agents reduce intraocular pressure by enhancing aqueous outflow, probably by stimulating ciliary muscle contraction. However, pilocarpine is a well characterized neurotoxin and is widely used to generate animal seizure models. It was therefore investigated whether pilocarpine was also toxic to retinal ganglion cells. METHODS: Dissociated whole retinal preparations were prepared from postnatal day 16 to 19 rats. Retinal ganglion cells had been previously back-labeled with a fluorescent tracer. Retinal cells were incubated with pilocarpine, lithium, and inositol derivatives, and viability of the retrogradely labeled retinal ganglion cells was assayed after 24 hours. RESULTS: Pilocarpine was toxic to retinal ganglion cells in a dose-dependent fashion. This toxicity was potentiated by lithium and blocked by epi- and myo-inositol. CONCLUSIONS: Pilocarpine is toxic to retinal ganglion cells in a mixed culture assay. This toxicity appears to depend on the inositol pathway and is similar to its mode of action in other neurons. However, 0.4 mM pilocarpine (the lowest concentration that did not affect ganglion cell survival) is roughly 1000-fold higher than the vitreal concentration and 20-fold higher than the scleral concentration that can be obtained with topical administration of 2% pilocarpine in the rabbit eye.
Animals↗
The contribution of various NOS gene products to HIV-1 coat protein (gp120)-mediated retinal ganglion cell injury.
PURPOSE: There is growing evidence that the neuronal pathology seen with HIV-1 is mediated, at least in part, through an excitotoxic/free radical pathway. Nitric oxide (NO) plays a critical role in the nervous system, in both normal and pathologic states, and appears to be involved in a variety of excitotoxic pathways. Whether isoforms of nitric oxide synthase (NOS) are involved in gp120-mediated neuronal loss in the retina was therefore explored. METHODS: To determine which (if any) of the various isoforms of NOS are critical in gp120-mediated damage in the retina, neuronal NOS-deficient [nNOS(-/-)], endothelial NOS-deficient [eNOS(-/ -)], and immunologic NOS-deficient [iNOS(-/-)] mice were subjected to intravitreal injections of gp120. RESULTS: Retinal ganglion cells in the nNOS(-/-) mouse were relatively resistant to gp120, manifesting attenuation of gp120-induced injury compared with wild-type mice. The iNOS(-/-) and eNOS(-/-) mice were as susceptible to gp120 toxicity as control animals. NOS inhibitors were protective against this toxicity. CONCLUSIONS: The presence of nNOS is a prerequisite for the full expression of gp120-mediated loss in the retina; eNOS and iNOS do not appear to play a significant role.
Animals↗
Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway.
PURPOSE: Ethambutol is an essential medication in the management of tuberculosis. However, it can cause an optic neuropathy of uncertain etiology. Ethambutol toxicity was therefore studied in rodent retinal cells, and agents that might block its toxicity were considered. METHODS: The toxicity of ethambutol and related agents was evaluated in rodent retinal dissociated cell preparations and whole eyes. Calcium fluxes and mitochondrial function were evaluated by fluorescent and staining techniques. For in vivo assays, adult rats were administered oral ethambutol over a 3-month period. Cell survival was assessed by stereology. RESULTS: Ethambutol is specifically toxic to retinal ganglion cells in vitro and in vivo. Endogenous glutamate is necessary for the full expression of ethambutol toxicity, and glutamate antagonists prevent ethambutol-mediated cell loss. Ethambutol causes a decrease in cytosolic calcium, an increase in mitochondrial calcium, and an increase in the mitochondrial membrane potential. CONCLUSIONS: The visual loss associated with ethambutol may be mediated through an excitotoxic pathway, inasmuch as ganglion cells are rendered sensitive to normally tolerated levels of extracellular glutamate. Ethambutol perturbs mitochondrial function. Its toxicity may depend on decreased ATPase activity and mitochondrial energy homeostasis. Glutamate antagonists may be useful in limiting the side effects seen with ethambutol.
Animals↗
Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors.
Nitrates have been a major part of the internist's pharmacopoeia for more than 100 years, predominantly for the relief of anginal symptoms. The effects of nitroglycerin on the eye and specifically on intraocular pressure has been investigated with diverse results. However, nitroglycerin may also serve to protect retinal ganglion cells against glutamate mediated toxicity--a form of cell death that may be critical in glaucomatous blindness. Consequently, we therefore sought to evaluate whether nitroglycerin preparations, taken for non-ophthalmic reasons, had an effect on glaucomatous damage.
Aged↗
Comparison of mitomycin C trabeculectomy, glaucoma drainage device implantation, and laser neodymium:YAG cyclophotocoagulation in the management of intractable glaucoma after penetrating keratoplasty.
PURPOSE: This study aimed to compare the surgical outcomes of mitomycin C trabeculectomy glaucoma drainage device (GDD) surgery and laser neodymium:YAG (Nd:YAG) cyclophotocoagulation (CPC) in the management of intractable glaucoma after penetrating keratoplasty (PKP) in a retrospective study. DESIGN: Interventional case series. PARTICIPANTS/METHODS: The medical charts of consecutive patients who had pre-existing glaucoma or who developed glaucoma after PKP and underwent a surgical procedure to control the glaucoma at the University Eye Associates of Boston University Medical Center, New England Eye Center, and Massachusetts Eye and Ear Infirmary between January 1991 and July 1995 were reviewed. Follow-up ranged from 6 months to 4 years after the glaucoma procedure. A total of 38 patients were included consisting of 17 patients who underwent mitomycin C, 10 patients who underwent GDD surgery, and 11 patients who had CPC. INTERVENTION: Mitomycin C trabeculectomy, GDDs, or Nd:YAG CPC to control glaucoma after PKP was performed, MAIN OUTCOME MEASURES: Graft status, postoperative intraocular pressure (IOP), and visual acuity were the main outcome measures. RESULTS: There were no differences among the three groups with respect to the follow-up time after the corneal graft operation (P = 0.15) or after the glaucoma operation (P = 0.98). At the final follow-up, the average decrease in the IOP was 17 mmHg (P < 0.001) after mitomycin C, 15 mmHg (P = 0.003) after GDD surgery, and 14.4 mmHg (P = 0.001) after CPC. There were no differences in the proportion of patients who developed postoperative IOP above 20 mmHg (P = 0.50) and in the proportion who developed hypotony (P = 0.10) among the three groups. Two grafts failed after mitomycin C and one failed after CPC. Among the three procedures, there were no differences in the proportion of patients who experienced either an improvement (P = 0.14) or a decrease (P = 0.22) in the visual acuity by more than one line after the glaucoma procedure. One patient each in the GDD group and the CPC group lost light perception after the procedure. The risk of graft failure was almost three times higher for each additional PKP (odds ratio = 2.80, P = 0.02). CONCLUSIONS: No differences were found among the three glaucoma procedures with respect to controlling IOP and graft failure. There was a trend for patients treated with CPC to have a higher incidence of graft failure, glaucoma failure, hypotony, and visual loss by more than one line, although this was not statistically significant. The number of PKPs was associated with graft failure, independent of the surgical procedure.
Adolescent↗
A proposed role for excitotoxicity in glaucoma.
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Animals↗
Effect of chronic nitrate treatment on retinal vessel caliber in open-angle glaucoma.
PURPOSE: A recent report has suggested that nitrate therapy may delay the progression of glaucomatous damage. To investigate the mechanism that may mediate this effect, we sought to determine whether nitrate therapy is associated with retinal vasodilatation in patients with glaucoma. METHODS: Retinal venous and arterial diameters were determined from color fundus photographs of the optic nerve head obtained during a retrospective study designed to investigate any potential effects of chronic nitrate treatment on the progression of glaucomatous pathology. Fourteen eyes of 14 patients who were receiving chronic nitrate therapy for systemic diseases unrelated to glaucoma were randomly selected. Vascular measurements were compared with those of 15 eyes of 15 control patients with glaucoma who did not receive any nitrate therapy. RESULTS: In comparison with control patients, nitrate-treated patients showed significant average vasodilatation of 17% (P = .008) and 13% (P = .01) in the superior and inferior temporal retinal veins, respectively. A 5% increase in average retinal arterial diameter was also detected, but this was not statistically significant. CONCLUSION: Chronic nitrate treatment is associated with retinal venous dilatation in patients with glaucoma. Although not assessed in this study, it is possible that a protective effect of nitrates may be mediated by a vasoactive effect leading to improved perfusion of the retina and perhaps the optic nerve head, in a similar fashion to what has been observed in the circulation of the heart. Additional studies of the effect of nitrates on the ocular circulation are needed, however, to support this speculation.
Aged↗