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Biomedical subjects

George A Cioffi

Publications and source records attributed to George A Cioffi.

32 records · Page 2Linked to original sources
PubMed2004

Inter-ocular and inter-session reliability of the electroretinogram photopic negative response (PhNR) in non-human primates.

PURPOSE: To assess the inter-ocular and inter-session reliability for a range of parameters derived from the photopic electroretinogram (ERG) in a group of normal non-human primates. METHODS: Inter-ocular differences for photopic ERGs were assessed in a group of normal anesthetized adult rhesus monkeys (Macaca mulatta, n=29); inter-session reliability was assessed for 23 eyes of 23 animals tested 3 months later. Signals were acquired using Burian-Allen contact lens electrodes, whereby the contralateral cornea served as a reference. Photopic ERGs were elicited using red Ganzfeld flashes (-0.5-0.67 log photopic cd.sm(-2)) on a rod suppressing blue-background (30 scotopic cdm(-2)). Measurement reliability was established for a-wave, b-wave, photopic negative response (PhNR) and oscillatory potential (OP) amplitudes, as well as for their implicit times, by calculation of the 95% limits-of-agreement (LOA) and the coefficient-of-variation (COV) for each parameter. RESULTS: OP and a-wave amplitudes increased with intensity up to 0.67 log photopic cd.sm(-2), following a typical saturating function, whereas b-wave and PhNR amplitudes both declined above 0.42 log photopic cd.sm(-2). Inter-session variability was greater than inter-ocular variability. The inter-session COVs for PhNR amplitude (10-20%) were similar to the other photopic ERG components (a-wave: 12-17%, b-wave: 12-17%, OPs: 13-19%). Inter-session LOAs were also similar across components, but on average, were smallest for responses to moderate intensities (0.0-0.42 log photopic cd.sm(-2)). CONCLUSION: In non-human primates, the 95% LOA for inter-session measurements of the photopic ERG a-wave, b-wave, OPs and PhNR are all similar. Inner-retinal damage may best be measured using the PhNR amplitude for moderately bright stimulus intensities. B-wave and PhNR amplitudes for brighter flashes are smaller and more variable. The ratio of PhNR:b-wave amplitudes manifests smaller variability and may therefore be useful for detection of selective PhNR loss.

Analysis of Variance↗
PubMed2004

Selective ganglion cell functional loss in rats with experimental glaucoma.

PURPOSE: To characterize retinal functional consequences of elevated intraocular pressure (IOP) in a rat model of experimental glaucoma. METHODS: Unilateral elevation of IOP was produced by hypertonic saline injection into an episcleral vein in 20 adult male Brown-Norway rats. IOP was measured in both eyes of awake animals four to five times per week. After 5 weeks, animals were dark adapted overnight (>12 hours) and full-field electroretinograms (ERGs) were obtained simultaneously from both eyes. Scotopic ERG stimuli were brief white flashes (-6.64-2.72 log cd-s/m(2)). Photopic responses were also obtained (0.97-2.72 log cd-s/m(2)) after 15 minutes of light adaptation (150 cd/m(2)). Eyes were processed the following day for histologic evaluation by light microscopy, including masked determination of optic nerve injury grade (ONIG; 1, normal; 5, severe, diffuse damage). RESULTS: Among experimental eyes, the group average IOP (+/-SD) was 34.5 +/- 4.1 mm Hg, whereas the average for control eyes was 28.1 +/- 0.5 mm Hg (t = 7.1, P < 0.0001). The average ONIG for experimental and control eye groups, respectively, was 3.4 +/- 1.7 and 1.0 +/- 0.02 (t = 6.3, P < 0.0001). The ONIG increased with mean IOP in experimental eyes (r(2) = 0.78, P < 0.0001) and was unrelated to mean IOP in control eyes (r(2) = 0.09, P = 0.18). In experimental eyes with relatively mild IOP elevation (mean IOP < 31 mm Hg) and no structural (histologic) damage to the optic nerve evident by light microscopy (ONIG = 1.1 +/- 0.2, n = 5), there was a selective reduction of the positive scotopic threshold response (pSTR; P < 0.001), whereas other ERG components remained unaltered. In four of the five eyes, pSTR amplitude was reduced by more than 50%, whereas all five had normal scotopic a-wave, b-wave, and OP amplitudes. Eyes with mean IOP of more than 35 mm Hg had reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes. CONCLUSIONS: As demonstrated by prior studies, selective loss of the pSTR is indicative of selective retinal ganglion cell (RGC) injury. In this rat model of experimental glaucoma, selective RGC functional injury occurred before the onset of structural damage, as assessed by light microscopy of optic nerve tissue. The highest IOP levels resulted in nonselective functional loss. Thus, in rodent models of experimental glaucoma, lower levels of chronically elevated IOP may be more relevant to human primary chronic glaucoma.

Animals↗
PubMed2003

Structure and function evaluation (SAFE): II. Comparison of optic disk and visual field characteristics.

PURPOSE: To evaluate the relationship between glaucomatous structural damage to the optic nerve and development of visual field loss with standard automated perimetry (SAP) and short wavelength automated perimetry (SWAP). DESIGN: Cohort study. METHODS: Patients with elevated intraocular pressure and normal SAP visual fields were enrolled in this prospective study. Stereo optic disk photographs, SAP, and SWAP visual fields were obtained annually over a period of 4 or more years. Trained readers evaluated baseline and follow-up optic disk photographs for evidence of glaucomatous damage. Standard automated perimetry and SWAP examinations were evaluated according to previously validated criteria for development of confirmed visual field changes. RESULTS: Two-hundred ninety-five subjects (479 eyes) were enrolled. Following masked assessment of stereo photographs by an optic disk reading center, 272 of the 479 eyes were judged to have glaucomatous optic neuropathy at the time of study entry. Depending on the criteria employed, approximately 10% to 17.5% of all eyes developed confirmed visual field loss for SAP (conversions). Of the conversions, 75% to 80% had baseline glaucomatous optic disk damage, whereas normal and glaucomatous optic disks were equally divided (50%) among the nonconversion eyes. This difference was statistically significant (P <.003). Depending on the criteria employed, 4% to 12% of the eyes had confirmed SWAP deficits at baseline, and 4% to 8% developed confirmed SWAP defects at a follow-up examination. There was a greater percentage of eyes with a glaucomatous optic neuropathy in the group with SWAP deficits (75%-100%) than for those eyes in which SWAP remained normal (45%-60%). Some of these differences were statistically significant (P <.05). CONCLUSIONS: A strong relationship exists between glaucomatous optic disk damage at study entry and the subsequent development of a confirmed glaucomatous SAP visual field defect. A higher percentage of glaucomatous optic disks were also found in patients with SWAP deficits at baseline and in those who later developed SWAP deficits. These findings support the premise that a glaucomatous optic disk is predictive of the subsequent development of glaucomatous visual field loss.

Follow-Up Studies↗
PubMed2003

Estimating normal optic nerve axon numbers in non-human primate eyes.

PURPOSE: The goal of the present study is to develop a semi-automated method to estimate accurately, with minimum variance, the total number of axons by counting a subset of the axons within a primate optic nerve. METHODS: Using an imaging analysis system, axons in 50% of the area of cross-sections of the retrobulbar optic nerve from five adult Rhesus monkeys were counted and extrapolated as an estimate of total axon number of the optic nerves. Both neural and non-neural areas were sampled. With the coordinates of the counts topographically registered, axon numbers within areas ranging from 1 to 50% were resampled. A Monte Carlo and theoretical estimate of the standard deviation of the total axon count for each sampled area was computed. RESULTS: The mean cross-sectional area of the five optic nerves counted was 7.26 +/- 0.6 mm2, and the mean total axon count of the optic nerve area was 1,304,8168 +/- 89,112. When sampling less than 8% of the optic nerve, the standard deviation within the individual of the total estimated axon number increased sharply. CONCLUSION: With this technique, the variance within each individual increased only slightly when the counting area was reduced from 50 to 8%, but increased sharply when the counted area became less than 8%. While counting less than 8% of the optic nerve area gives a good estimation of total axon count, the effect of a substantial increase in the standard deviation on the statistical power needed to differentiate group differences will depend on the study design.

Anatomy, Cross-Sectional↗
PubMed2003

Varicosities of intraretinal ganglion cell axons in human and nonhuman primates.

PURPOSE: To describe varicosities of intraretinal ganglion cell axons in the nerve fiber layer of human and nonhuman primate retinas. METHODS: Intraretinal ganglion cell axons of seven human donors (1-85 years old) and two nonhuman primates (Macaca mulatta, 15 and 17 years old) were immunohistochemically stained with an antibody of neurofilament on flatmounted retinas and examined with light microscopy. In addition, the axons within the retinal nerve fiber layer were examined with transmission electron microscopy in one human and one nonhuman retina. The variations of diameters of single axons were measured on transverse- and parallel-cut sections, and the frequency distributions of the diameters were statistically evaluated. RESULTS: Varicosities of the intraretinal ganglion cell axons were found throughout the retinas in both nonhuman primate and human eyes of all ages examined. The varicosities were rich in mitochondria and had desmosome- and hemidesmosome-like junctions with other axons and retinal glial cells. Measured on parallel-cut axons, the mean diameter (+/-SD) of varicosities was 2.7 +/- 0.9 micro m, whereas the mean diameter of intervaricosity regions was 0.7 +/- 0.3 micro m. The diameter distribution for transverse-cut axons was also bimodal, but the two peaks were much closer because the peak of the larger-diameter group decreased. CONCLUSIONS: The results demonstrated that intraretinal ganglion cell axons are predominantly varicose fibers in both human and nonhuman primates. Size variations exist within a single axon's diameter and thereby affect the patterns of diameter distribution seen in transverse-cut preparations. The mitochondria-rich varicosities and the presence of intercellular junctions suggest that the varicosities may be functional sites that serve local high-energy demands of unmyelinated fibers and signal transmission.

Adolescent↗
PubMed2003

Local ganglion cell contributions to the macaque electroretinogram revealed by experimental nerve fiber layer bundle defect.

PURPOSE: To assess the structural and functional consequences of local ganglion cell (GC) loss in an experimental model of a retinal nerve fiber layer (NFL) bundle defect. To evaluate and compare three commonly used multifocal electroretinogram (mfERG) stimuli, as well as the standard transient pattern-reversal ERG (pERG) and the photopic full-field ERG, for detection of local GC damage. METHODS: Intraretinal axotomy was achieved by multiple treatments with a diode laser adapted to a slit lamp biomicroscope. Retinal laser burns were applied along an arc, subtending approximately 60 degrees, about one disc diameter superotemporal to the optic nerve. Functional measures were acquired before laser application and at numerous time points thereafter. These included mfERGs for three different stimuli: a standard fast m-sequence flicker, a global-field flash paradigm (MOFO), and a slowed m-sequence (with seven dark frames inserted to each m-step [7F]). pERGs were measured for a 24 degrees x 32 degrees checkerboard stimulus (0.56 cyc/deg, 90% contrast, 75 cd/m(2), 5 reversals/s). Photopic full-field ERGs were measured for red flashes (0.42 log photopic cd-s/m(2)) on a blue rod-saturating background (30 scotopic cd/m(2)). Retinal photography, fluorescein angiography and postmortem histologic evaluation of the optic nerve, NFL, and retinal tissues were performed. RESULTS: After six laser sessions, the NFL bundle defect appeared to be complete and contiguous and was visible both proximal to and distal to the site of the photoablation by clinical examination of the fundus and stereoscopic photographs. Histologic evaluation demonstrated localized loss of GC axons, confirmed at the level of the retrobulbar optic nerve. Retinal cross sections in the temporal retina (distal to the axotomy) showed loss of GC soma and NFL degeneration, whereas all other layers appeared intact. mfERGs showed loss of high-frequency components (HFCs) for responses located within the arcuate region corresponding to the NFL defect. Local GC damage was most easily detected using the slowed 7F m-sequence stimulus. This stimulus elicited relatively large HFCs that were significantly reduced from local responses after axotomy and that were tetrodotoxin (TTX)-sensitive in a control experiment. Low-frequency component loss with the 7F stimulus did not reach statistical significance. The photopic full-field ERG was not significantly affected. pERG amplitudes declined significantly from baseline but remained within normal limits. CONCLUSIONS: Focal loss of GC function in the macaque retina is most easily detected using the slowed-sequence mfERG. Local 7F HFCs depend on intact GC function.

Animals↗
PubMed2002

Short-wavelength sensitivity deficits in patients with migraine.

OBJECTIVE: To examine short-wavelength sensitivity in patients with migraine using short-wavelength automated perimetry (SWAP) and Stiles 2-color increment threshold procedures. METHODS: Twenty-five subjects with migraine with (n = 11) and without (n = 14) aura and 20 age-matched headache-free subjects underwent testing. All subjects underwent standard automated perimetry (SAP) and SWAP (using a Humphrey field analyzer; 24-2 presentation pattern). In 2 migraine patients (one with and another without aura), the 2-color increment threshold procedure was used to determine whether sensitivity losses were specific to short-wavelength sensitivity pathways or a generalized loss to multiple pathways. RESULTS: No statistically significant differences between migraine patients and controls were found for mean deviation (MD) or pattern-standard deviation (PSD) for SAP. However, for SWAP, MD and PSD were worse for the migraine group (P =.04). Twelve migraine patients had more than 4 locations with sensitivity worse than the 5% probability level (reference value). Increment threshold determinations in the 2 selected migraine patients indicated a selectively greater loss for short-wavelength sensitivity mechanisms. CONCLUSIONS: Approximately 50% of subjects with migraine (with or without aura) demonstrate SWAP sensitivity losses, at times between migraine events. These findings, in conjunction with previous results for SAP and flicker perimetry, suggest that migraine patients should be excluded from normative databases of visual function, and warrant further investigations of the relationship between migraine and glaucoma.

Adolescent↗
PubMed2002

Structure and function evaluation (SAFE): I. criteria for glaucomatous visual field loss using standard automated perimetry (SAP) and short wavelength automated perimetry (SWAP).

PURPOSE: To develop criteria for detecting glaucomatous visual field loss for standard automated perimetry (SAP) and short wavelength automated perimetry (SWAP). DESIGN: Longitudinal observational study. METHODS: Three populations were evaluated: (1) 348 normal subjects (348 eyes) were tested to develop normative databases and statistical analysis packages for SAP and SWAP. (2) An independent group of 47 normal subjects (94 eyes) with 4 years of longitudinal follow-up was evaluated to determine specificity of different criteria. (3) A group of 298 patients (479 eyes) with elevated intraocular pressure and normal baseline SAP visual fields were evaluated to determine the sensitivity of different criteria for detecting early glaucomatous visual field loss. RESULTS: Six criteria demonstrated high specificity for correctly identifying eyes with normal visual fields (98%-100%) for both SAP and SWAP: (1) a pattern standard deviation (PSD) worse than the normal 1% level, (2) a glaucoma hemifield test (GHT) "outside normal limits," (3) one hemifield cluster worse than the normal 1% level, (4) two hemifield clusters worse than the normal 5% level, (5) four abnormal (P <.05) locations, (6) five abnormal locations (P <.05) on the pattern deviation probability plot. For all criteria, confirmation on a second visual field was required for high specificity. The GHT "outside normal limits," two hemifield clusters worse than the normal 5% level and four abnormal (P <.05) test locations on the pattern deviation probability plot provided the highest percentages of conversion from a normal to a glaucomatous visual field. CONCLUSIONS: Criteria based on the GHT, GHT hemifield clusters, and the pattern deviation probability plot provide high sensitivity and specificity for detecting early glaucomatous visual field changes.

Adolescent↗
PubMed2002

Factors affecting the use of multifocal electroretinography to monitor function in a primate model of glaucoma.

While elevated intraocular pressure (IOP) undoubtedly plays a crucial role in many glaucoma patients, vascular dysregulation and chronic regional ischemia are also thought to contribute to the pathophysiology of glaucoma. In an effort to critically evaluate hypotheses involving vascular abnormalities in glaucoma, Cioffi, Van Buskirk and co-workers have developed a model of optic neuropathy based on chronic regional ischemia. The multifocal electroretinogram (MERG) has previously been used to assess function in non-human primates with experimental glaucoma induced by high-IOP. In this study, the MERG was used to monitor function in macaque monkeys with experimental glaucoma induced by chronic anterior optic nerve ischemia. Initial recordings from experimental eyes, which were later documented histologically to have moderate axon loss, revealed little difference from recordings of control eyes. This suggested that many of the signal components in the macaque MERG, which are known (from other studies) to be eliminated by intravitreal injections of NMDA/TTX or by high-IOP experimental glaucoma, may also be affected by the choice of anesthetic agents and MERG recording parameters. Subsequent experiments were performed to specifically evaluate the effects of bipolar versus monopolar signal derivation, anesthetic agents, MERG stimulus design and spatial scale. The results demonstrate that successful measurement of inner retinal and optic nerve head MERG components, especially those which have been shown by other investigators to originate with ganglion cell spiking activity, will depend critically upon the choice of anesthetic agents and recording parameters. One of the most important parameters seems to be use of a monopolar signal derivation, with the contralateral cornea serving as the reference position.

Anesthesia, General↗
PubMed2002

Immunohistologic evidence for retinal glial cell changes in human glaucoma.

PURPOSE: Glial cells are structurally and functionally linked to neuronal tissues. Pathologically, the cells may be activated and characterized by increased size and number and altered cellular properties. In glaucoma, pathologic mechanisms within the anterior optic nerve may include glial activation. This study examines morphologic changes of glial cells in the retinas of glaucomatous eyes compared with age-matched control retinas. METHODS: Paraffin-processed or flatmounted retinas from 17 human donor eyes [7 normal (donor age, 87.3 +/- 8.3 years) and 10 glaucomatous (donor age, 87.1 +/- 6.9 years)] were examined. With immunohistochemical methods, retinal glial cells were stained with an antibody to glial fibrillary acidic protein (GFAP). The morphology of the glial cells in normal and glaucomatous retinas was evaluated with fluorescence microscopy. RESULTS: Three types of glial cells were identified in flatmounted retinas with differing distributions in the peripapillary region, the nerve fiber layer (NFL), and along the capillaries. Compared with normal eyes, in glaucomatous retinas the glial cells in the peripapillary region showed an increase in density and exhibited a deformation of the end feet. The astrocytes distributed among the NFL showed little difference from normal. The astrocytes accompanying the capillary bed showed a redistribution in the glaucomatous retinas. The quantification of glial cells in paraffin-processed glaucomatous retinas exhibited a profound increase in density and a significant increase of GFAP immunoreactivity in contrast to the lightly stained glial cells in normal retinas. CONCLUSIONS: The activation of glial cells in the glaucomatous retina was characterized in changes of intensity of GFAP immunoreactivity and morphology around the larger blood vessels, compared with age-matched normal retinas. The relationships between glial cells, neuronal cells, and the vasculature, as well as the potential role of glial cells in pathologic mechanisms during different stages of neuronal damage in glaucoma, are discussed.

Aged↗
PubMed2002

Selective loss of an oscillatory component from temporal retinal multifocal ERG responses in glaucoma.

PURPOSE: To evaluate electrophysiologic function in glaucoma by using a new stimulus designed to enhance ganglion cell and optic nerve head component (ONHC) contributions to multifocal electroretinogram (mfERG) responses. METHODS: mfERGs of 16 individuals with glaucoma (POAG) and 18 normal control subjects were recorded and analyzed with a VER imaging system. The stimulus had three frames inserted between each m-sequence step: a full-field dark frame (1.0 cd/m(2)), a full-field flash (200 cd/m(2)), and another dark frame. Multifocal flashes were 100 cd/m(2). The stimulus subtended approximately 40 degrees total diameter and contained 103 scaled hexagonal elements. Signals were obtained using Burian-Allen bipolar electrodes, amplified x10(6), band-pass filtered at 10 to 300 Hz, and sampled at 1200 Hz. RESULTS: Local first-order responses (kernels) consisted of a direct component (DC) followed by an induced component (IC). Nasal-temporal response asymmetries in normal eyes were most easily observed in the IC. A small but distinct oscillation in the ICs of temporal retinal responses distinguished them from nasal IC waveforms. In individuals with glaucoma, there was less asymmetry between nasal and temporal responses, mostly because of the reduction of the oscillation in the temporal retinal ICs. The amplitude of this oscillation was 4.4 +/- 2.1 nV/deg(2) in the control group and 1.8 +/- 1.2 nV/deg(2) in the glaucoma group (P < 0.0001). Amplitude and latency measures of other response features were not significantly different from normal. Amplitude of the IC oscillation was not correlated with age in either the normal or glaucoma groups. In a group of normal subjects retested 3 months later, the average test-retest repeatability was +/-12%. CONCLUSIONS: Selective loss of an oscillatory feature from IC responses in glaucoma may represent abnormalities in the inner plexiform layer of the temporal retina, where classic oscillatory potentials (OPs) are thought to arise. However, evidence suggests that this effect may also be due in part to loss of the ONHC.

Adult↗