Russell N. Van Gelder

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells

Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate numerous nonvisual phenomena, including entrainment of the circadian clock to light-dark cycles, pupillary light responsiveness, and light-regulated hormone release. We have applied multielectrode array recording to characterize murine ipRGCs. We find that all ipRGC photosensitivity is melanopsin dependent. At least three populations of ipRGCs are present in the postnatal day 8 (P8) murine retina: slow onset, sensitive, fast off (type I); slow onset, insensitive, slow off (type II); and rapid onset, sensitive, very slow off (type III). Recordings from adult rd/rd retinas reveal cells comparable to postnatal types II and III. Recordings from early postnatal retinas demonstrate intrinsic light responses from P0. Early light responses are transient and insensitive but by P6 show increased photosensitivity and persistence. These results demonstrate that ipRGCs are the first light-sensitive cells in the retina and suggest previously unappreciated diversity in this cell population.

The imprinted gene Magel2 regulates normal circadian output

Mammalian circadian rhythms of activity are generated within the suprachiasmatic nucleus (SCN). Transcripts from the imprinted, paternally expressed Magel2 gene, which maps to the chromosomal region associated with Prader-Willi Syndrome (PWS), are highly enriched in the SCN. The Magel2 message is circadianly expressed and peaks during the subjective day. Mice deficient in Magel2 expression entrain to light cycles and express normal running-wheel rhythms, but with markedly reduced amplitude of activity and increased daytime activity. These changes are associated with reductions in food intake and male fertility. Orexin levels and orexin-positive neurons in the lateral hypothalamus are substantially reduced, suggesting that some of the consequences of Magel2 loss are mediated through changes in orexin signaling. The robust rhythmicity of Magel2 expression in the SCN and the altered behavioral rhythmicity of null mice reveal Magel2 to be a clock-controlled circadian output gene whose disruption results in some of the phenotypes characteristic of PWS.

Herpes simplex virus type 2 as a cause of acute retinal necrosis syndrome in young patients

PURPOSE To determine the causative virus in acute retinal necrosis (ARN) syndrome in a series of patients by calculation of modified Witmer coefficients. DESIGN Noncomparative case series. PARTICIPANTS Ten patients with ARN syndrome from four medical centers. METHODS Aqueous samples, vitreous samples, or both were collected prospectively during surgery from patients with a clinical diagnosis of ARN syndrome. Serologic measures of intraocular and serum antibodies to potentially causative viruses were measured by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES Modified Witmer coefficients (immunoglobulin G and immunoglobulin A) for herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV), and cytomegalovirus (CMV), as well as adenovirus type 2, were calculated from aqueous or vitreous samples, or both. RESULTS Intraocular antibody measurements were strongly suggestive of a single diagnosis in 9 of 10 patients tested. Modified Witmer coefficients demonstrated intraocular antibody production to HSV in five patients and antibodies to VZV in four patients, and the measurement was inconclusive in one patient. No patients were positive for adenovirus or CMV. Strain-specific antibody titers demonstrated that all HSV-positive patients were reactive only to HSV-2. Herpes simplex virus type 2 was found predominantly in younger patients with ARN syndrome (mean age, 21.2 +/- 10 years; range, 17-39 years), whereas VZV was more commonly seen in older patients (mean age, 40.8 +/- 12.2 years; range, 29-58 years; P = 0.033). Immunoglobulin A testing confirmed immunoglobulin G testing in all patients examined. CONCLUSIONS Although VZV is thought to be the most common cause of ARN syndrome, HSV-2 is an important cause of ARN syndrome, particularly in younger patients. Because infection with HSV-2 has important medical ramifications, these results suggest that determination of a causal agent should be considered in some cases of ARN syndrome.

Applications of the polymerase chain reaction to diagnosis of ophthalmic disease.

The polymerase chain reaction (PCR) is a powerful molecular biologic technique for the analysis of very small amounts of DNA. This technique has found increasing use in the past 10 years for the detection of pathogenic organisms associated with many forms of ocular inflammatory and infectious disease. PCR has shown utility in the diagnosis of viral uveitis, infectious endophthalmitis, and parasitic eye disease. The strengths and weaknesses of this diagnostic technique are discussed. Additionally, uses of PCR in linking known pathogens to disease, and to discovering novel pathogens, are addressed.

Preservation of light signaling to the suprachiasmatic nucleus in vitamin A-deficient mice

To investigate the role of retinal-based pigments (opsins) in circadian photoreception in mice, animals mutated in plasma retinol binding protein were placed on a vitamin A-free diet and tested for photic induction of gene expression in the suprachiasmatic nucleus. After 10 months on the vitamin A-free diet, the majority of mice contained no detectable retinal in their eyes. These mice demonstrated fully intact photic signaling to the suprachiasmatic nucleus as measured by acute mPer mRNA induction in the suprachiasmatic nucleus in response to bright or dim light. The data suggest that a non-opsin pigment is the primary circadian photoreceptor in the mouse.

Inner retinal photoreception independent of the visual retinoid cycle

Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd/rd or rdta). Inner retinal photoresponses are mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65−/−; rdta and lrat−/−; rd/rd mutant mice. Unexpectedly, both rpe65−/−; rdta and lrat−/−; rd/rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd/rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65−/−; rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65−/− and lrat−/− ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.

Making (a) sense of non-visual ocular photoreception

A subset of intrinsically photosensitive retinal ganglion cells transduce information about ambient lighting conditions to areas of the brain involved in tasks including entrainment of the circadian clock, pupillary light reflexes and melatonin synthesis. The phototransduction system(s) utilized by these cells are unknown. Melanopsin and cryptochromes have been proposed as candidate photopigments for this system. Recent analyses of retinal degenerate mice lacking melanopsin or cryptochromes indicates that outer and inner photoreceptors can both contribute to non-visual photoresponses, and that both melanopsin and cryptochromes play important roles in this process.

Comparison of photorefractive keratectomy, astigmatic PRK, laser in situ keratomileusis, and astigmatic LASIK in the treatment of myopia

Purpose: To determine factors affecting refractive and visual outcomes in patients treated with astigmatic and spherical photorefractive keratectomy (A‐PRK and PRK) and laser in situ keratomileusis (A‐LASIK and LASIK). Setting: University referral refractive surgery clinic. Methods: Refractive and visual acuity results in 619 eyes of 388 consecutive patients having refractive surgery over a 2‐year period by a single surgeon were retrospectively analyzed. Patients were divided into mild‐to‐moderate myopia (spherical equivalent [SE] less than −6.12 diopters [D]) and high myopia (SE −6.12 D or higher). Multivariate and logistic regression analyses were performed. Results: Refractive results in flap‐based and PRK‐based procedures were comparable in mild‐to‐moderate myopia patients but were significantly better in high‐myopia patients having flap‐based procedures. Refractive stability was greater in flap‐based procedures than in PRK‐based procedures. Elliptical ablations yielded a marked reduction in the astigmatic cylinder in patients having A‐LASIK and A‐PRK, while spherical PRK induced small amounts of with‐the‐rule astigmatism. Complications were uncommon in both groups, consisting primarily of epithelial ingrowth in flap‐based procedures and haze in PRK‐based procedures. Multivariate regression identified the preoperative SE as a significant determinant of PRK outcomes (with higher success for lower myopia) and intraocular pressure as a minor determinant of outcomes in PRK‐based and flap‐based procedures. Logistic regression suggested that only the preoperative SE was a significant factor in predicting the likelihood of poor outcomes in PRK patients. Conclusions: Refractive outcomes were almost identical in patients having elliptical or spherical ablations with flap‐based or PRK‐based procedures. In eyes with mild‐to‐moderate myopia, there was little difference in refractive or visual outcomes between flap‐based and PRK‐based procedures; in eyes with high myopia, flap‐based procedures offered more predictable refractive outcomes and better visual outcomes.

Tales from the Crypt(ochromes)

Cryptochromes are a family of flavoproteins found in organisms ranging from Arabidopsis to man. Across phylogeny, these proteins have been used for pleiotropic functions ranging from blue-light-dependent development in plants and blue-light-mediated phase shifting of the circadian clock in insects to a core circadian clock component in mammals. Review of the roles of cryptochromes in model organisms reveals several common themes: Multiple cryptochrome family members within individual organisms have redundant functions; cryptochromes used in photic entrainment pathways of the circadian clock are partially redundant with other photopigments; and cryptochromes may function in circadian phototransduction and core clock mechanisms in the same organism, with different functions in different tissues. The present review summarizes recent research on the functions of cryptochrome in the circadian timekeeping and photic entrainment pathways.Cryptochromes are a family of flavoproteins found in organisms ranging from Arabidopsis to man. Across phylogeny, these proteins have been used for pleiotropic functions ranging from blue-light-dependent development in plants and blue-light-mediated phase shifting of the circadian clock in insects to a core circadian clock component in mammals. Review of the roles of cryptochromes in model organisms reveals several common themes: Multiple cryptochrome family members within individual organisms have redundant functions; cryptochromes used in photic entrainment pathways of the circadian clock are partially redundant with other photopigments; and cryptochromes may function in circadian phototransduction and core clock mechanisms in the same organism, with different functions in different tissues. The present review summarizes recent research on the functions of cryptochrome in the circadian timekeeping and photic entrainment pathways.