Relationships between 24h observations in intraocular pressure vs blood pressure, heart rate, nitric oxide and age in the medical chronobiology aging project.

OBJECTIVE: To evaluate associations between intraocular pressure (IOP) and blood pressure (BP), heart rate (HR), serum nitric oxide (NO), diurnal variations, diabetes and aging in data collected during 24h studies of men conducted over 34y. MATERIALS AND METHODS: As part of the Medical Chronobiology Aging Project, male Army veterans, ages 22 to 81y, without a history of eye disease, were studied around-the-clock in May 1969 (n = 13), 1979 (n = 11), 1988 (n = 11), 1993 (n = 11), 1998 (n =12) and 2003 (n = 10). Measurements of IOP (R & L eyes, supine position), BP and HR (sitting position), and collection of blood were obtained every 3h (8 readings/24h) from 19:00h to 16:00h the next day. Individual time series were analyzed for circadian characteristics by the least-squares fit of a 24& 12h cosine. After normalizing all data to percent of mean to reduce inter-subject variability in levels, grouped data were analyzed for time-effect by ANOVA and for circadian rhythm by multiple component (24h&12h) cosine fitting. Individual 24h averages were analyzed by simple and multiple regression for relationships between IOP and systemic variables, diabetic status and age. RESULTS: Over the 34y study span, 22 men provided sixty-three 24h profiles for IOP & HR, 61 for BP, and 21 for NO. Using all normalized data, a significant circadian rhythm was found for each variable at p <0.001. Circadian peaks (orthophases) are located in the late morning for IOP-R (10:20h) and IOP-L (10:52h), and in the evening for HR (18:52h), NO (20:00h), SBP (20:40h) and DBP (21:44h). An out-of-phase relationship of about 10h is noted on a group basis between IOP vs BP, HR and NO. The locations of individual circadian peaks for IOP-R were found around the clock, but with a significant predominance between 10:00 and 16:00h (day type), and 04:00-10:00h (morning type). In contrast, BP, HR and NO showed a significant clustering of evening type or night type peaks. The overall mean IOP for the right eye was slightly, but not significantly, higher than the left eye (17.60+/-0.21 vs 17.34+/-0.18 mmHg; p = 0.385), with a strong positive correlation between both eyes (R = 0.952, p <0.0001). IOP showed a significant positive correlation with SBP (R = 0.49, p <0.001), diabetic status (R = 0.47, p <0.001), age (R = 0.32, p = 0.011), and HR (R = 0.28, p = 0.031). A multiple regression using SBP, DBP, HR, age and diabetic status (5 men became diabetic over the 34y study span) as independent variables resulted in SBP being the strongest predictor of IOP (p = 0.0001), followed by DBP (p = 0.0103). After adjustment for BP, independent effects of age (p = 0.187), HR (p = 0.789) and diabetic status (p = 0.153) were eliminated from the prediction equation. CONCLUSIONS: The results of these studies reveal significant circadian variations in IOP, BP, HR and NO, with peak levels, on average, near noon for IOP and in the evening for BP, HR and NO. An increase in SBP was associated with an increase in IOP. While SBP and DBP are significant predictors of IOP levels, single measurements during regular clinic hours may not reveal the full functional relationship between the variables measured in our studies. Therefore, circadian information on total 24h patterns may contribute to the reliability of diagnosis and guide proper individualized timing of optimal patient management (e.g., for glaucoma, hypertension, diabetes, among other conditions).

Uveal metastatic carcinoma in human immunodeficiency virus infection.

We report the occurrence of uveal metastatic carcinoma in two patients with longstanding HIV infection presenting with decreased visual acuity. In the first case, a 49-year-old man with a 6-year history of HIV infection presented with a 4-5 month history of blurred vision in his right eye. In the second case, a 53-year-old man with a 5-year history of HIV infection presented with a 3-week history of distorted and blurred vision in both eyes. In both cases, a choroidal metastatic carcinoma was ultimately discovered. To our knowledge, these are the first reported cases of metastatic uveal carcinoma in individuals with HIV infection. Currently, there have been dramatic improvements in treatment for HIV infection and longer survival times of infected individuals. This fact, together with reported increased frequencies and aggressiveness of carcinomas in HIV-infected individuals will likely result in increasing occurrences of uveal metastases from primary carcinomas in HIV.

Implantation of silicon chip microphotodiode arrays into the cat subretinal space.

There are currently no therapies to restore vision to patients blinded by photoreceptor degeneration. This project concerns an experimental approach toward a semiconductor-based subretinal prosthetic designed to electrically stimulate the retina. The present study describes surgical techniques for implanting a silicon microphotodiode array in the cat subretinal space and subsequent studies of implant biocompatibility and durability. Using a single-port vitreoretinal approach, implants were placed into the subretinal space of the right eye of normal cats. Implanted retinas were evaluated post-operatively over a 10 to 27 month period using indirect ophthalmoscopy, fundus photography, electroretinography, and histology. Infrared stimulation was used to isolate the electrical response of the implant from that of the normal retina. Although implants continued to generate electrical current in response to light, the amplitude of the implant response decreased gradually due to dissolution of the implant's gold electrode. Electroretinograms recorded from implanted eyes had normal waveforms but were typically 10-15% smaller in amplitude than those in unimplanted left eyes. The nonpermeable silicon disks blocked choroidal nourishment to the retina, producing degeneration of the photoreceptors. The laminar structure of the inner retinal layers was preserved. Retinal areas located away from the implantation site appeared normal in all respects. These results demonstrate that silicon-chip microphotodiode-based implants can be successfully placed into the subretinal space. Gold electrode-based subretinal implants, however, appear to be unsuitable for long-term use due to electrode dissolution and subsequent decreased electrical activity.

Immunohistochemical studies of the retina following long-term implantation with subretinal microphotodiode arrays.

This study evaluates the feline retina following surgical placement of a semiconductor-based microphotodiode array (MPA) into the subretinal space. Post-operative evaluations of implant durability and clinical biocompatibility have been carried out in these animals. Here, we examine the integrity of the implanted retina using anatomical techniques and immunocytochemical metabolic indicators. After appropriate fixation, the retina was divided into strips to compare areas directly over the implant versus those adjacent to the implant or in the opposite, unimplanted eye. In addition to histological analyses, the distribution of glial fibrillary acidic protein (GFAP), Na, K-ATPase, and the neurotransmitters (glutamate, glycine, and GABA) was examined using immunohistochemistry. Directly above the implant there was a near-complete loss of photoreceptor outer and inner segments and the outer nuclear layer. In comparison, the retina immediately adjacent to the implant appeared normal. In the inner nuclear layer overlying the implant, some cellular disorganization was present, however, the content was not significantly reduced. Also GFAP was up-regulated in the Müller cells directly overlying the MPA, but the retina adjacent to the implant showed a normal distribution of GFAP in the astrocytes located in the ganglion cell layer. The distributions of Na, K-ATPase adjacent to and overlying the implant were not different. Glutamate showed a decrease in overall labeling, but no change in the inner retinal layers. Glycine was found to be up-regulated in the inner nuclear layer immediately overlying the implant, while GABA showed decreased labeling over the MPA. Since photoreceptors overlying the implant degenerate, we compared the changes observed in the implanted retina to those in the Abyssinian cat model of photoreceptor degeneration. Generally, the retinal changes observed over the implant were similar to those seen in the Abyssinian cat, indicating that they may be associated with photoreceptor degeneration. Future studies will concentrate on MPAs designed to improve circulation to the outer retina which may decrease cell loss.

Systemic adverse effects of ophthalmic beta-blockers.

OBJECTIVE: To review published clinical information on the systemic adverse effects of ophthalmic beta-blockers for the purpose of developing a pilot contraindication/warning system for active prescriptions in the Veterans Affairs dispensing database. DATA SOURCES: Articles were identified by searching MEDLINE (1966-October 2000) and International Pharmaceutical Abstracts (1970-October 2000). STUDY SELECTION AND DATA EXTRACTION: Article relevance was determined by review of titles, abstracts, and key words. DATA SYNTHESIS: The preponderance of the evidence suggests that ophthalmic beta-blockers may be associated with bronchospasm and adverse cardiovascular effects including bradycardia. Depression and other central nervous system effects are reported less commonly. Data are inadequate to suggest that ophthalmic beta-blocker use is routinely associated with adverse metabolic effects. CONCLUSIONS: The strongest level of evidence (grade A1) supports a contraindication for use of ophthalmic beta-blockers for respiratory disease, with a moderate level of evidence (grade B1) for cardiovascular disease. Data are insufficient to support or refute contraindications for other disease states. The search technique and classification scheme described in this article provide a methodology for evaluating, grading, and applying evidence on potential adverse effects of drug therapy.

Co-prescribing of medications used to treat obstructive lung disease, congestive heart failure and depression among users of topical beta blockers: estimates from three US Veterans Affairs Medical Centers.

PURPOSE: To estimate the frequency of co-prescribing of medications used to treat obstructive lung disease, congestive heart failure, and depression among US armed service veterans for whom topical beta blockers (TBB) have been prescribed. METHODS: Prescription data from the computerized medical record systems of three US Veterans Affairs Medical Centers were obtained during Fall 1999 to identify patients for whom active prescriptions existed for TBB and/or drugs commonly used to treat obstructive lung disease, congestive heart failure, and depression. RESULTS: Among TBB users, the estimated co-prescribing rate of medications used to treat obstructive lung disease is in the range of 7.8-9.7%, of medications used to treat congestive heart failure is in the range of 4.3-25.1%, and of medications used to treat depression is in the range of 8.8-11.7%. The total number of TBB users with a concurrent prescription for one or more of the conditions studied was in the range of 30.2-45.7%. CONCLUSIONS: Since TBB may cause systemic side-effects and thus potentially cause exacerbations of selected chronic conditions, it is important for researchers and prescribers to be aware of the frequency with which their patients with glaucoma may have other concomitant conditions.

Effect of topical anti-inflammatory drugs on corneal and limbal wound healing.

PURPOSE: To examine the effect of topical treatment with either steroidal or nonsteroidal anti-inflammatory drugs (NSAIDs) on the wound healing of corneal and limbal incisions using histologic criteria. SETTING: Loyola University Medical Center, Maywood, Illinois, USA. METHODS: Eighteen eyes of 9 cats were used for the study. All right eyes received a temporal limbal incision and the left eyes, a clear corneal incision. All eyes were treated with ofloxacin 0.3% postoperatively for 3 days. The animals were equally divided among 3 groups. Group 1 received topical steroid drops (prednisolone acetate 1%) for 7 days maximum; Group 2 received topical NSAID drops (ketorolac tromethamine 0.5%) for 7 days maximum; Group 3 received no additional treatment. One animal from each group was killed and the eye enucleated 3, 7, or 28 days postoperatively. The eyes were processed for staining with hematoxylin-eosin and smooth muscle actin, and corneal sections were evaluated in a blind fashion by an ophthalmic pathologist. RESULTS: Three and 7 days after surgery (1) the limbal incision exhibited more prominent wound healing than the similarly treated clear corneal incision, and (2) the steroid-treated corneas had less wound healing than untreated or NSAID-treated corneas. At 28 days, the wounds in all eyes were almost completely healed. CONCLUSIONS: Limbal incisions heal faster than clear corneal incisions. Steroids, but not NSAIDs, inhibit wound healing. Cataract surgery using limbal incisions and postoperative topical NSAIDs may result in faster wound healing and provide a reduced risk of related postoperative complications.

Neodymium:YAG laser posterior capsulotomies performed by residents at a Veterans Administration Hospital.

PURPOSE: To assess the initial efficacy of neodymium:YAG (Nd:YAG) laser posterior capsulotomies performed by residents at a teaching institution and to evaluate the associated complications over an extended follow-up. SETTING: Department of Ophthalmology, Edward Hines, Jr. Veterans Administration Hospital, Hines, Illinois, USA. METHODS: This retrospective noncomparative case review comprised 212 pseudophakic eyes having Nd:YAG laser posterior capsulotomies from April 1992 through March 1995. Evaluated were postoperative changes in best corrected visual acuity (BCVA), intraocular pressure (IOP) elevations, and complications related to the procedure. RESULTS: In all 212 eyes, Snellen visual acuity was obtained at least 1 week after the capsulotomy. The BCVA in 96 eyes (45.3%) improved by 3 or more lines, in 43 (20.3%) by 2 lines, and in 51 (24.1%) by 1 line. Nineteen eyes (9.0%) did not improve by 1 or more lines, and 3 eyes (1.4%) had decreased Snellen acuity. All but 4 eyes with less than 1 line of improvement had underlying ocular pathology or a previous incomplete capsulotomy. For evaluation of postoperative complications, long-term follow-up was available for 133 of 212 eyes (62.7%). The mean follow-up for this group was 3.18 years. Postoperative complications were found in 14 of these eyes (10.5%). Nine (6.8%) had a rise in IOP greater than 10 mm Hg after the capsulotomy. One eye (0.8%) developed a persistent iritis, 2 (1.5%) had vitreous prolapse into the anterior chamber, and 2 (1.5%) developed rhegmatogenous retinal detachments. CONCLUSION: Postoperative Snellen acuity results and complication rates compare favorably with those in previous studies. The results indicate that Nd:YAG laser posterior capsulotomies performed by residents with attending supervision are safe, effective, and carry a low associated complication rate over a long follow-up.

A collaborative regional ocular anesthesia training program: successes and failures.

STUDY OBJECTIVE: To describe a collaborative effort of the departments of ophthalmology and anesthesiology to teach anesthesiology residents regional ocular anesthesia; to detect any differences in positive or negative outcomes after blocks performed by anesthesiology residents versus blocks performed by ophthalmology residents. DESIGN: Prospective descriptive, study. SETTING: Outpatient surgery in a university-affiliated veterans affairs hospital. PATIENTS: 614 patients requiring elective ocular surgery. INTERVENTIONS: Outcomes from patients who underwent regional anesthesia performed by ophthalmology residents were compared to outcomes from patients who received anesthesia from anesthesiology residents. MEASUREMENTS AND MAIN RESULTS: A detailed description of the collaborative teaching program in ocular anesthesia is presented. Ophthalmology residents performed the majority of regional ocular blocks (87% vs. 13%). There was no statistical difference in the incidence of negative outcomes, such as retrobulbar hemorrhage, between ophthalmology residents and anesthesiology residents (3/534 vs. 1/80) or in the incidence of successful blocks (90% for ophthalmology residents vs. 88% for anesthesiology residents). CONCLUSIONS: Regional ocular anesthetic techniques can be safely and successfully taught to residents in anesthesiology.

Unilateral Blastomyces dermatitidis endophthalmitis and orbital cellulitis. A case report and literature review.

PURPOSE: The authors report the clinical, cytologic, and histopathologic findings of a unique presentation of concomitant unilateral endophthalmitis and orbital cellulitis secondary to Blastomyces dermatitidis. DESIGN: Case report. METHODS: A 29-year-old healthy woman with a history of pulmonary tuberculosis presented with a painful right eye and rapidly decreasing vision. Fundus examination showed a diffuse elevated choroidal lesion at the posterior pole. With an otherwise unremarkable systemic work-up, the patient was treated with systemic antibiotics and corticosteroids for a presumed diagnosis of choroidal tuberculous granuloma. After an initial response to the treatment, the patient's condition deteriorated rapidly with visual acuity decreasing from 20/25 to no light perception in 3 months. Ipsilateral proptosis developed with magnetic resonance imaging showing a poorly defined orbital mass. Surgical enucleation and an orbital biopsy were performed. RESULTS: Histopathologic examination of the orbital specimen and an intact enucleated globe showed a diffuse necrotizing granulomatous process with the presence of numerous yeasts consistent with B. dermatitidis. This subsequently was confirmed by positive culture of B. dermatitidis from the orbital specimen. CONCLUSIONS: This is a unique case of concurrent unilateral endophthalmitis and orbital cellulitis secondary to B. dermatitidis. Intraocular dissemination of blastomycosis should be suspected in the differential diagnosis of endophthalmitis in patients with previous or active pulmonary lesions of equivocal nature. Early diagnosis and prompt treatment with antifungal medications are essential.

Subretinal semiconductor microphotodiode array.

BACKGROUND AND OBJECTIVE: To examine the function of a semiconductor microphotodiode array (SMA) surgically implanted in the subretinal space. MATERIALS AND METHODS: Positive-intrinsic layer-negative (PiN) or negative-intrinsic layer-positive (NiP) SMAs were surgically placed into the subretinal space of rabbits through a pars plana incision and a posterior retinotomy. The implants required no external connections for power and were sensitive to light over the visible and infrared (IR) spectrum; IR stimuli were used to isolate implant-mediated responses from the activity of native photoreceptors. A stimulator ophthalmoscope was used to superimpose IR stimuli on the implant and adjacent retinal areas, and responses were recorded during the postoperative recovery period. SMA responses were also evaluated in vitro. The animals were given lethal anesthetic overdoses, and the retinas were examined histologically. RESULTS: The in vitro implant response consisted of an electrical spike, followed by a small-amplitude DC offset that followed the time course of the IR stimulation, and an overshoot at the stimulus offset. The SMAs placed in the subretinal space retained a stable position and continued to function throughout the postoperative period. The SMA responses recorded in vivo included additional slow-wave components that were absent from the in vitro recordings. These responses reverted to the in vitro configuration following the death of the animal. There was a significant loss of retinal cells in areas overlying the implant, and the retina appeared normal away from the implant and surgical site. CONCLUSION: SMAs can be successfully implanted into the subretinal space and will generate current in response to light stimulation during an extended period of time.

Effect of tunicamycin on histological organization and Na, K-ATPase distribution in the adult cat retina.

Intravitreal injection of tunicamycin (TM) was evaluated as a method for inducing photoreceptor-specific degeneration in cat retina. TM (1 microg, 5-weeks duration) markedly decreased electroretinogram amplitudes. A polyclonal antibody directed against the Na, K-ATPase was used to further assess cell-specific retinal injury induced by TM. TM-treatment induced marked alterations in the differential distribution of the Na, K-ATPase within the retina. Histology confirmed photoreceptor degeneration in TM-treated retina, but further showed a severe, non-selective degradation of most retinal layers. Therefore, long-term intraocular exposure to TM results in a progressive general toxicity to the cat retina.

Disturbances in the distribution of neurotransmitters in the rat retina after ischemia.

PURPOSE: Disturbances in neurotransmitter distribution have been observed in cerebral ischemia in the pathophysiologic process of excitotoxicity. The goal of this study was to examine the effect of pressure-induced retinal ischemia on the distribution of the retinal neurotransmitters glutamate and gamma-aminobutyric acid (GABA) within the rat retina. METHODS: Animals were subjected to increased intraocular pressure of 110 mm Hg for 45 min using an intracameral hydrostatic pressure device. The distribution of glutamate and GABA immunoreactivity (IR) was determined at 0, 2, 4, 8 and 24 hrs after reperfusion by immunogold with silver intensification. RESULTS: Three phases of neurotransmitter immunoreactivity patterns were discernible following retinal ischemia. Immediately following reperfusion (Phase I), a shift of GABA-IR from inner retinal neurons to the Mueller cells and their processes was noted. In contrast, despite marked decreases in neuronal glutamate-IR, a less pronounced shift of glutamate-IR to the Muller cells was simultaneously noted. This shift of neurotransmitter IR to the Mueller cells was transient with the gradual reappearance of IR within the inner retinal neurons noted 2-8 hrs after reperfusion (Phase II). Phase III began at 8 hrs after reperfusion with progressive loss of GABA-IR noted in the inner retina; by 24 hrs, secondary loss of inner retinal glutamate-IR was evident with corresponding dropout and pyknosis of inner retinal neurons apparent. CONCLUSIONS: The distribution of glutamate-IR and GABA-IR was significantly altered following retinal ischemia. The alteration noted in Phase I suggested that the regulation of glutamate by Mueller cells was disrupted by this ischemic insult leading to glutamate excitotoxicity, and delayed neuronal cell degeneration as evidenced by the subsequent loss of inner retinal immunoreactivity in Phase III.

Oncocytic adenocarcinoma of the lacrimal sac: report of a case with paranasal sinus and orbital extension.

A 92-year-old man has had multiple recurrent oncocytic tumors involving the right paranasal sinuses and orbit. A benign oncocytoma that arose from the right lacrimal sac was initially diagnosed at age 80 years. The tumor recurred at 3 and 7 years after initial resection. There was greater histologic atypia in the first recurrent tumor, which extended into the right paranasal sinuses. The second recurrence had zones on oncocytic adenocarcinoma exhibiting prominent nuclear atypia and mitotic activity; this tumor massively invaded the right paranasal sinuses and orbit. We describe the clinical and pathologic features of this rare case.

Syringocystadenoma papilliferum of the eyelid.

Syringocystadenoma papilliferum is a benign adnexal tumor of the scalp and face. We treated syringocystadenoma papilliferum in a 31-year-old man who had a circumscribed cup-shaped lesion of the left upper eyelid with a central crater. On histologic examination, the epidermal edge showed hyperkeratosis and invasive acanthosis with papillary projections that filled the central crater. The deeper portions of the projections resembled ductal structures lined by an inner columnar epithelium, which demonstrated luminal apical decapitation secretions, and an outer layer of smaller cuboidal cells. The fibrovascular dermal tissue exhibited prominent plasmacytic infiltration underlying the papillary epithelium. Although rare, syringocystadenoma papilliferum should be considered in the differential diagnosis of umbilicated squamous or basal cell tumors, especially if noted in a young individual.

Retrobulbar ischemic optic neuropathy associated with sickle cell disease.

A 52-year-old black man with a history of sickle cell SS disease presented with sudden loss of vision in his right eye. Examination of the right eye revealed no light perception and an amaurotic pupil, but an otherwise normal neuro-ophthalmic examination. On initial presentation, there was no evidence of an acute vascular event on funduscopy. Computed tomography failed to demonstrate pathology of the brain or orbit. Repeat fundus examination, 2 weeks later, still failed to demonstrate retinal or optic nerve disease. However, optic nerve pallor and central cupping became evident after 2 months and continued to progress in the ensuing year. Magnetic resonance imaging performed at that time did not disclose the presence of demyelinating disease, or aneurysmal dilation of the carotid or ophthalmic artery. A diagnosis of retrobulbar ischemic optic neuropathy is considered likely in this patient. The association of retrobulbar ischemic optic neuropathy and sickle cell anemia has not been previously reported.