Biomedical subjects
Publications and source records attributed to Michael F Marmor.
Poor night vision and pigmentary retinopathy are hallmarks of retinitis pigmentosa, but variations in the type of pigmentation and in the characteristics of the electroretinogram (ERG) can point to other diagnoses. The case below (enhanced S cone syndrome) is a good example of this, and demonstrates the diagnostic importance of clinical electrophysiology.
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PURPOSE: Standard ERG a-waves represent contributions from both photoreceptor and inner retinal cells, while the leading edge of the high-intensity a-wave is produced only by photoreceptors. This has raised questions about the value of the a-wave as an indicator of photoreceptor disease, and has led to suggestions for standardizing higher-intensity stimuli. Our objective was to compare the behavior of standard and high-intensity a-waves in clinical practice. METHODS: Standard ISCEV (International Society for Clinical Electrophysiology of Vision) a-waves and high-intensity a-wave responses were recorded under scotopic and photopic conditions from normal subjects and from patients with photoreceptor dystrophies and other diseases. RESULTS: The standard scotopic a-wave amplitude followed the high-intensity a-wave closely among patients with different diagnoses, and the results did not change significantly when cone a-waves were subtracted to isolate rod signals. The only exception was one patient with the enhanced S cone syndrome (ESCS) whose dark-adapted responses were cone-driven. Initial peak times clustered in a small range for both standard and high-intensity responses, and were not very sensitive to disease. CONCLUSION: High-intensity a-waves can show photoreceptor characteristics directly, and may help analyze some rare disorders. However, in our study the amplitude of conventional scotopic a-waves mirrored that of the high-intensity responses quite closely over a wide range of patients. This suggests that for practical purposes even if it is not perfect, the standard ERG is an excellent indicator of photoreceptor disease.
BACKGROUND: The human eye is composed of multiple compartments, diverse in form, function, and embryologic origin, that work in concert to provide us with our sense of sight. We set out to systematically characterize the global gene expression patterns that specify the distinctive characteristics of the various eye compartments. RESULTS: We used DNA microarrays representing approximately 30,000 human genes to analyze gene expression in the cornea, lens, iris, ciliary body, retina, and optic nerve. The distinctive patterns of expression in each compartment could be interpreted in relation to the physiology and cellular composition of each tissue. Notably, the sets of genes selectively expressed in the retina and in the lens were particularly large and diverse. Genes with roles in immune defense, particularly complement components, were expressed at especially high levels in the anterior segment tissues. We also found consistent differences between the gene expression patterns of the macula and peripheral retina, paralleling the differences in cell layer densities between these regions. Based on the hypothesis that genes responsible for diseases that affect a particular eye compartment are likely to be selectively expressed in that compartment, we compared our gene expression signatures with genetic mapping studies to identify candidate genes for diseases affecting the cornea, lens, and retina. CONCLUSION: Through genome-scale gene expression profiling, we were able to discover distinct gene expression 'signatures' for each eye compartment and identified candidate disease genes that can serve as a reference database for investigating the physiology and pathophysiology of the eye.
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Our purpose was to explore S-cone ERG protocols for a commercial full-field hand-held stimulator that contains colored LEDs, and to see whether the test would be useful as a part of routine ERG testing. S-cone responses were elicited by blue flashes over a longer-wavelength background. With the standard stimulator containing blue (461 nm), green (513 nm) and red (652 nm) LEDs, we were unable to obtain satisfactory responses. Reproducible S-cone ERGs were obtained with a stimulator that had been custom-fitted with shorter-wavelength blue (440 nm) LEDs for stimulation, and orange (590 nm) LEDs for background adaptation. S-cone responses took only a few minutes to record, and the typical waveform showed a slow peak at 45-50 ms with amplitude 3-9 microV, but ranging from 0 microV to more than 10 microV. Larger waves appeared in a patient with enhanced S-cone syndrome. S-cone responses could also be obtained with an alternating blue-orange flicker protocol. We added the S-cone response to our regular ERG protocol for a number of months. Although most normal subjects and patients showed recognizable S-cone responses with this stimulator, the amplitudes were small and there was too much variability to make the technique effective for routine clinical testing. In general, the S-cone responses followed the standard cone ERG responses in disease.
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PURPOSE: To examine the electroretinographic findings derived by full-field electroretinography (ERG) and multifocal electroretinography (mfERG) in patients taking HCQ for different periods of time, including those without clinically visible evidence of toxicity. METHODS: The records for 26 consecutive patients (51 eyes, age 19-79) who had used HCQ for 1-30 years and who had an ERG and/or mfERG were reviewed. RESULTS: The patients fell into 5 groups, according to the results from their electrophysiological and clinical evaluation: no abnormalities (n = 13), cone b-wave delay (n = 2), decreased ERG amplitude (n = 6), borderline toxicity (n = 2) and toxicity (bull's-eye maculopathy; n = 3). Oscillatory potential (OP) amplitudes were decreased in many of the patients, even in the absence of any other clinical or ERG abnormality. MfERGs were normal in these patients without other abnormalities, but showed a bull's eye pattern of damage in a patient with clear toxicity. The full-field ERG parameters (including OPs) showed little relationship to the duration of HCQ usage or the cumulative dose. CONCLUSIONS: A substantial subgroup of patients showed varying degrees of diffuse ERG abnormality despite having no clinical signs (visual or fundus changes) of toxicity, and despite a range of cumulative doses. The mfERG showed toxicity, but its sensitivity in detecting early change remains to be determined. Further work is needed in order to separate pharmacological actions of the drug, retinopathy from the systemic disease, and potential toxic effects.
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We sought to determine whether routine ERGs using ISCEV standard stimuli, would show a pattern of circadian variation. We examined ERGs from 40 successive normal subjects who were tested at different times during regular laboratory operating hours of 9 am to 4 pm, and also reviewed high intensity a-waves from a subgroup. There were no obvious associations of either ERG amplitude or implicit time with time of day. No statistically significant difference was found between average ISCEV ERG parameters or high-intensity a-wave parameters obtained in the morning (9 am to 1 pm) and afternoon (1 pm to 4 pm). We conclude that time of day is not critical for routine ERG recordings, although small, variable, circadian changes may well be present. We suggest that the time of day be noted on clinical recordings, in case this information becomes relevant for a particular patient.
PURPOSE: Retinal prosthetic devices that use microelectrode arrays to stimulate retinal nerve cells may provide a viable treatment for degenerative retinal diseases. Current devices are based on electrical field-effect stimulation of remaining functional neural elements. However, the distance between target neurons and electrodes limits the potential density of electrodes and the ability to stimulate specific types of retinal neurons that contribute to visual perceptions. This study was conducted to investigate the use of microcontact printing (muCP) to direct cultured or explant retinal ganglion cell (RGC) neurites to precise and close stimulation positions and to evaluate the cell types that grow from a retinal explant. METHODS: RGCs and whole retinal explants were isolated from postnatal day-7 Sprague-Dawley rats using immunopanning purification and microdissection, respectively. Aligned muCP was used to direct the growth of RGC neurites from pure cultures (n=105) and retinal explants (n=64) along laminin patterns and to individual microelectrodes. Immunofluorescence stains (n=39) were used to determine the cell types that grew out from the retinal explants. RESULTS: RGC neurite growth was directed reproducibly along aligned laminin micropatterns to individual microelectrodes in pure RGC cultures and from full-thickness explanted rat retinas in 92% of experiments, neurites from pure RGC cultures extended along the laminin lines with an average length of 263 +/- 118 microm (SD; n=27) after 24 hours. Neurites from retinal explants extended in more than 80% of experiments and were observed to grow to an average length of 279 +/- 78 microm (n=64) after 2 days in culture. These neurites grew up to 3 mm after 1 month of culture on the laminin micropatterns. Immunohistochemical stains demonstrated that extended processes from both RGCs and glial cells grew out of retinal explants onto stamped laminin lines. CONCLUSIONS: Using muCP to pattern surfaces with growth factors, individual neuronal processes from pure RGC culture and whole retinal explants can be directed to discrete sites on a microelectronic chip surface. By directing RGC neurite processes to specific sites, single cell stimulation becomes possible. This may allow discrete populations of retinal neurons to be addressed so that physiologic retinal processing of visual information can be achieved.
BACKGROUND: We have developed a new surgical instrument, called the pulsed electron avalanche knife (PEAK; Carl Zeiss Meditec, Jena, Germany), for precise, "cold," and tractionless dissection of tissue in liquid media. OBJECTIVE: To evaluate the 3-dimensional damage zone induced by the PEAK compared with 2 other standard intraocular surgical instruments, diathermy and retinal scissors. METHODS: Damage zone and minimum safe distance were measured in vitro on chick chorioallantoic membrane and in vivo on rabbit retina with the use of propidium iodide staining. RESULTS: The PEAK produced a paracentral zone of cellular structure disruption surrounding a crater and a peripheral zone of structurally intact but abnormally permeable cells. The instrument induced a damage radius that varied from 55 to 300 micro m for the range of voltages and pulses typically used during surgery. For comparison, damage radius for microsurgical scissors was 50 micro m, and for diathermy, 400 to 850 micro m. The PEAK also damaged tissue up to 1.4 mm away by the creation of water flow that formed at the tip of convex probes during collapse of a cavitation bubble. Concave probes, which prevent formation of the water jet, eliminated this effect. CONCLUSIONS: The PEAK operated well within accept-able safety limits and may greatly facilitate both posterior segment surgeries (eg, membrane dissection and sheathotomy) and anterior segment procedures (eg, capsulotomy, nonpenetrating trabeculectomy, and iridectomy).
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PURPOSE: To investigate the effects of 0.5, 1.0 and 2.5% methylcellulose coating agents on the ERG in normals. METHODS: A total of 15 healthy volunteers underwent photopic ERG recordings in three experimental protocols comparing 0.5, 1.0 and 2.5% methylcellulose solutions. The conductivity of the solutions was measured. RESULTS: The difference between 0.5 and 1.0% solutions showed significant changes (p < 0.05) in ERG amplitudes. The 0.5% solution produced approximately 15% higher ERG amplitudes than the 1.0% solution. Comparison between 1.0 and 2.5% solutions did not show significant changes in ERG amplitudes. The conductivity was essentially the same for 0.5 and 1.0% solutions, but conductivity of the 2.5% solution was roughly half of that of the other two solutions. CONCLUSIONS: Although the 0.5% solution did yield significantly higher ERG values than the 1.0% and 2.5% solutions, the exact mechanism by which this occurs is not known. The source of these differences could arise from a combination of factors such as conductivity, viscosity, or other unknown components of the solutions. ERG laboratories should be consistent in the use of coating agents, and be aware that any change in solution might alter normative values by a modest percentage.
Computational analysis of high-intensity a-waves yields direct information about the rod and cone receptor potential. However, it is not clear whether such information adds materially to the diagnostic value of the standard ERG in a routine clinical setting. We recorded both conventional ISCEV standard and computational high intensity ERG parameters from 38 patients referred to a clinical laboratory for ERG testing, and also from eight normal volunteers. The patients were grouped as: (1) macular dysfunction; (2) diffuse cone dysfunction; (3) diffuse rod-cone dysfunction. The results showed moderate variation in both conventional and computational parameters, but in general a similar pattern of normality or abnormality for both among the disease groups. There were only a few outlying subjects for which one or the other approach seemed more sensitive. We conclude that a-wave analysis is an important tool for clinical research and the study of special patients, but adding it to the standard ERG protocol does not, at our present state of knowledge, add markedly to clinical evaluations in a routine clinical setting.