Jay I. Perlman

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 implants 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 he unsuitable fur long-term use due to electrode dissolution and subsequent decreased electrical activity.

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.

Systemic Adverse Effects of Ophthalmic β-Blockers

OBJECTIVE: To review published clinical information on the systemic adverse effects of ophthalmic β-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 β-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 β-blocker use is routinely associated with adverse metabolic effects. CONCLUSIONS: The strongest level of evidence (grade A1) supports a contraindication for use of ophthalmic β-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.

Increased RhoA and RhoB Protein Accumulation in Cultured Human Trabecular Meshwork Cells by Lovastatin

PURPOSE This study aimed to determine the effect of lovastatin on Rho G-protein expression and activation in human trabecular meshwork (TM) cells. METHODS Confluent cultures of low-passage (primary) or transformed (GTM3) human TM cells were incubated overnight with vehicle (0.01% ethanol) or activated lovastatin (10 microM). Changes in Rho mRNA, protein content, and activation were quantified by qRT-PCR, immunoblotting, and ELISA, respectively. F-actin organization was determined using Alexa Fluor 488-conjugated phalloidin. RESULTS Low-passage or transformed TM cells treated with lovastatin exhibited marked increases in RhoA and RhoB mRNA and protein content. Actinomycin D prevented lovastatin-dependent increases in RhoB, but not RhoA, protein accumulation. In contrast, cycloheximide prevented lovastatin from increasing both RhoA and RhoB. Supplementation with mevalonate or geranylgeranyl pyrophosphate prevented, whereas inhibition of geranylgeranyl transferase mimicked, the effects of lovastatin on RhoA and RhoB accumulation. The effect of lovastatin was dose dependent, with newly synthesized protein accumulating in the cytosol. The amount of functionally active (GTP-bound) RhoA in cell lysates was significantly reduced by lovastatin. Lovastatin altered the morphology of TM cells by disrupting F-actin organization. CONCLUSIONS Lovastatin enhances the accumulation of RhoA and RhoB in human TM cells, in part, by limiting geranylgeranyl isoprenylation of these G-proteins. We propose that post-translational geranylgeranylation serves as a regulator of both RhoA and RhoB protein expression and processing in human TM cells. Increased accumulation of unprenylated forms of RhoA and RhoB may disrupt Rho-dependent regulation of TM cell cytoskeletal organization.

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 patients 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.

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.

Granulocyte colony-stimulating factor facilitates recovery of retinal function following retinal ischemic injury

The purpose of the present study was to investigate whether systemically administered granulocyte colony-stimulating factor (G-CSF) can protect against acute ischemic reperfusion injury. Two groups of anesthetized adult male Lewis rats (n = 8 per group) were subjected to an acute (45 min) episode of retinal ischemic injury followed by subcutaneous administration of vehicle (5% dextrose) or G-CSF (0.1 mg/kg/day) once per day x 5 days. Prior to and one week following ischemic insult, retinal function was measured by scotopic electroretinography (ERG). Retinas were harvested and morphologically analyzed one week after ischemic insult. ERG a- and b-wave amplitudes were significantly reduced following ischemic reperfusion injury. G-CSF treatment attenuated ischemic-induced loss of retinal function. In control vehicle-treated rats, ischemic reperfusion injury elicited marked and selective thinning of inner retinal layers while only minimally affecting outer retinal layers. Therapeutically administered G-CSF minimized ischemic-mediated thinning of whole retina and inner retinal layers. G-CSF may be of therapeutic interest for the management of retinal ischemic disorders.

Response Characteristics of Subretinal Microphotodiode-Based Implant-Mediated Cortical Potentials

Presently, there is no treatment by which to restore vision to patients blinded by outer retinal diseases such as retinitis pigmentosa and age-related macular degeneration. We have developed a retinal prosthetic that is designed to be placed in the sub-retinal space and thereby stimulate second-order retinal neurons spared by disorders that induce selective photoreceptor degeneration. The device is semiconductor-based and does not require an external power supply for operation. Previous studies have characterized the device with respect to biocompatibility and function. The present study concerns cortical potentials elicited when the implant is stimulated with infrared light, to which the native retina is insensitive. The results indicate that these potentials share several response characteristics with conventional visual evoked potentials and support the conclusion that the implant is capable of electrically activating the visual system.

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.

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.