Steven B. Koevary

Comprehensive review of the effects of diabetes on ocular health

In light of the potentially devastating effects of diabetes on ocular health, it behooves the eyecare professional to pay close attention to ocular changes in their diabetic patients so that they can be treated early and effectively. In this article, anterior and posterior segment changes and disease are reviewed in depth, including extraocular, neurological and optic nerve changes. This article intends to provide a useful resource to clinicians regarding the full range of ocular complications associated with diabetes.

Accumulation of Porcine Insulin in the Rat Brain and Cerebrospinal Fluid Following Ocular Application

We previously reported that insulin accumulated in the retina and optic nerve following ocular application. Since the optic nerve is surrounded by meninges and cerebrospinal fluid (CSF) and since it extends back to the thalamus, we examined whether the topical application of insulin eye drops also resulted in the accumulation of insulin in the CSF and brain. The data presented in this paper show that this is in fact the case. Following the ocular application of a 0.75% solution of porcine insulin, significant concentrations of insulin were demonstrable in the CSF extracted from the cisterna magnum, as well as in three brain regions. While it is not yet clear how insulin got into these target tissues, our data argue against a mechanism involving uptake from the blood (a fraction of topically applied compounds normally enters the vasculature through the conjunctiva and nasal mucosa). It is theorized that insulin may enter the CSF surrounding the optic nerve and by so doing, not only disseminate throughout the CSF space but also throughout the brain. The implications of these findings for central nervous system drug delivery are discussed.

Pharmacokinetics of insulin uptake by ocular tissues and the role of cerebrospinal fluid in optic nerve insulin accumulation following topical insulin application

BACKGROUND As part of our ongoing studies concerning the efficacy of using topically applied medications to treat retinal and optic nerve diseases, we previously showed that insulin accumulated in the retina, optic nerve, and cerebrospinal fluid (CSF) following topical application. The purpose of this study was to investigate which route insulin takes to get to the posterior segment of the eye, and to specifically assess the role of the CSF in optic nerve insulin accumulation. METHODS Lewis rats that received 125I-insulin eye drops were killed at different time points and their ocular tissues counted in a gamma counter. In order to determine whether elevated levels of CSF insulin could lead to optic nerve insulin accumulation, a separate cohort of animals was injected in their lumbar cistern with unlabeled insulin and their optic nerves later assessed for the presence of insulin by enzyme-linked immunosorbent assay. RESULTS All ocular tissues (except the lens) showed at least one significant time point elevation in 125I-insulin compared to baseline. Both the combined cornea/iris/ciliary body and the sclera showed a notable, overall increase in counts over baseline, with values at 20 and 30 minutes being significantly elevated. The highest numbers of counts were seen in the aqueous humor. Animals injected intralumbar cisternally with insulin showed elevated insulin concentrations in their optic nerves and cisterna magna-derived CSF that did not appear to be due to uptake of insulin from the circulation. CONCLUSIONS These results support the hypothesis that the insulin that accumulates in the retina and optic nerve following topical application arrives there after diffusing through the sclera, though an intraocular route--while unlikely--cannot be ruled out.

Prevention of experimental autoimmune uveoretinitis by intrathymic S-antigen injection

The objective of this paper was to determine whether intrathymic injection of retinal S-antigen (S-Ag) can prevent experimental autoimmune uveoretinitis (EAU) in Lewis rats. Lewis rats were injected intrathymically with 25-100 micrograms of S-Ag in 100 microliters split between thymic lobes. Controls received vehicle alone (PBS) or 100 micrograms of BSA. Animals were immunized two weeks later with 100 micrograms of S-Ag in CFA with or without pertussis toxin (0.5 micrograms/rat). Clinical ocular disease was confirmed by histopathology. Splenocytes and lymph node cells were assayed, in vitro, for their ability to proliferate in response to various concentrations of S-Ag. Furthermore, attempts were made to adoptively transfer protection to naive rats using spleen cells from intrathymically injected animals and to adoptively transfer EAU to protected rats using Con A activated cells from affected animals. Intrathymic injection of S-Ag reduced the incidence of EAU in animals subsequently immunized with S-Ag and pertussis, and prevented it entirely in rats immunized in the absence of pertussis. Splenic and lymph node cells from intrathymically injected animals showed reduced reactivity to S-Ag compared to controls, suggesting that intrathymic S-Ag injection may have rendered them tolerant to this antigen. We were unable to adoptively transfer protection to naive rats, nor were intrathymically injected rats protected from EAU induced by the adoptive transfer of primed lymph node cells. These data demonstrate that intrathymic S-Ag injection can be an effective method for protection from EAU, apparently through the induction of immunological tolerance and not active suppression. The tolerance was not absolute and could be overcome by increasing the intensity of the antigenic challenge.

Systemic and ophthalmic manifestations of West Nile virus infection

The first cases in the USA of infection with the mosquito vector-borne West Nile virus (WNV) – an enveloped, single-stranded RNA – occurred in 1999 in New York. Since then, it has moved westward and now affects people in nearly every state, with most annual cases appearing in late summer. Suspected infection can be confirmed by ELISA and reverse transcriptase PCR. The incubation period of WNV prior to the onset of symptoms can be as long as 2 weeks. Three clinical categories of infection have been defined: asymptomatic, West Nile fever (WNF) and West Nile meningoencephalitis. The most common symptoms of WNF are flu-like and include fever, headache, myalgia, malaise, diarrhea, vomiting and fatigue. In less than 1% of cases, individuals develop severe, potentially fatal neurologic disease that has been variously classified as West Nile meningitis, West Nile encephalitis and West Nile poliomyelitis (acute flaccid paralysis). The most commonly reported ocular features of WNV infection are multifocal, bilateral chorioretinal lesions characteristically found in either a scattered or linear pattern. Other features include anterior uveitis, retinal vasculitis, optic neuritis and vitritis; less commonly, nystagmus, abducens nerve palsy, optic disc edema and absence of corneal reflex have been reported. Patients were also reported to present with blurred vision, floaters, redness, visual field defects and diplopia. Ocular symptoms of WNV are generally self limited; however, in some notable cases, reduced visual acuity and field loss may persist. Many of the ocular symptoms of WNV infection are associated with numerous viral, bacterial and parasitic diseases, highlighting the importance of differential diagnosis in confirming WNV infection. The fact that ophthalmic manifestations associated with WNV have only been recognized relatively recently makes the long-term prognosis in patients difficult to predict. However, most patients presenting with chorioretinitis show improvement over time, with visual acuity returning to baseline after a few months. There are currently no approved treatments for WNV, although recombinant vaccines are under development.

Effect of anterior chamber-associated immune deviation (ACAID) on rat islet allograft rejection

Anterior chamber-associated immune deviation (ACAID) is characterized by the systemic inhibition of delayed type hypersensitivity (DTH) reactions to antigens which have previously been placed into the anterior chamber of the eye. Since its initial characterization, ACAID has been elicited to a wide variety of antigens, including alloantigens, and has been shown to be due to the immune deviating effects of factors such as transforming growth factor beta (TGF-ß) in the aqueous humor on ocular antigen-presenting cells (APCs). ACAID can also be induced by injecting animals with nonocular APCs, such as peritoneal exudate cells (PECs), which have been precultured with TGF-ß and antigen in vitro. The objective of this study was to determine whether alloantigenic ACAID can be effective in preventing the rejection of rat islet allografts. The notion that islet allograft rejection can be inhibited by ACAID stems from an early study showing an ACAID-induced delay in the rejection of skin grafts. Furthermore, the immune cells mediating a DTH reaction are similar to those implicated in islet allograft rejection, suggesting that they, too, may be subject to inhibition by ACAID. Our results showed that in spite of successful ACAID induction to islet allografts, recipient rats consistently rejected their grafts. Cytotoxic T cell activity (which is not inhibited by ACAID) directed against donor alloantigens was high in these animals and may have accounted, in part, for graft failure.