George L. Spaeth

Color Doppler Analysis of Ocular Vessel Blood Velocity in Normal-tension Glaucoma

The pathogenesis of normal-tension glaucoma remains unknown. Because ocular vasospasm has been proposed as a possible mechanism, we investigated ocular vessel flow velocity in normal-tension glaucoma patients at rest and under treatment with a cerebral vasodilator. Ten normal-tension glaucoma patients and nine age- and gender-matched controls had flow velocity measured in three vessels (ophthalmic artery, central retinal artery, and temporal short posterior ciliary artery) by using color Doppler imaging, under baseline conditions and during carbon dioxide supplementation sufficient to increase end-tidal PCO2 by 15%. Peak systolic and end-diastolic velocities were measured, and the resistance index (peak systolic velocity minus end-diastolic velocity, divided by peak systolic velocity) was calculated. Compared with controls, these normal-tension glaucoma patients had significantly lower end-diastolic velocities (P = .002) and higher resistance indices (P = .007) in the ophthalmic artery at baseline. When PCO2 was increased, control subjects remained unchanged, whereas it increased end-diastolic velocity in patients (P = .003) and abolished the difference in resistance index between the two groups. Patients and control subjects differed little in their baseline or carbon dioxide response velocities or in resistance in the other two vessels. These results indicate that at baseline these normal-tension glaucoma patients may have increased vascular resistance distal to the ophthalmic artery, although this increased resistance cannot be specifically ascribed to the central retinal arterial or to temporal short posterior ciliary arterial vascular beds. The responsiveness of these patients to a cerebral vasodilator (increased PCO2) indicates further that the increased resistance distal to the ophthalmic artery may be the reversible result of vasospasm.

Compliance in Patients Prescribed Eyedrops for Glaucoma

We studied the rate of failure to use eyedrops as prescribed for glaucoma and some of the factors possibly associated with that noncompliance by interviewing 100 patients being followed in a setting emphasizing correct usage. Fifty-nine reported they had not used their eyedrops precisely as prescribed. Factors significantly influencing compliance included daily dose frequency, forgetfulness, inconvenience, and unaffordability. Gender and race were marginally significant factors, with men and blacks reporting somewhat higher rates of missed doses than women and whites. Side effects and age were not significant causes of noncompliance.

Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- And tissue-specific microRNAs

Significance MicroRNAs (miRNAs) are small ∼22-nt RNAs that are important regulators of posttranscriptional gene expression. Since their initial discovery, they have been shown to be involved in many cellular processes, and their misexpression is associated with disease etiology. Currently, nearly 2,800 human miRNAs are annotated in public repositories. A key question in miRNA research is how many miRNAs are harbored by the human genome. To answer this question, we examined 1,323 short RNA sequence samples and identified 3,707 novel miRNAs, many of which are human-specific and tissue-specific. Our findings suggest that the human genome expresses a greater number of miRNAs than has previously been appreciated and that many more miRNA molecules may play key roles in disease etiology. Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.

Test/retest reproducibility of color Doppler imaging assessment of blood flow velocity in orbital vessels

PurposeThe purpose of this study was to evaluate the test-retest reproducibility of measures of blood flow velocities using color Doppler imaging (CDI) in orbital arteries. Patients and MethodsMeasures of peak systolic velocity, end-diastolic velocity, and resistive index were performed in a group of 15 normal tension glaucoma patients and in 15 healthy subjects using the Siemens Quantum 2000 CDI system with a 7.5 MHz linear probe. After each velocity measure in each vessel, the probe was removed and then replaced to repeat the measurement −2 min later. ResultsFor all subjects, the coefficients of reliability for measures of peak systolic velocity were 12% in the ophthalmic artery, 25% in the central retinal artery, and 19% in a short posterior ciliary artery. For end diastolic velocity, the coefficients were 6%, 11%, and 25%, respectively. The coefficients for resistive index were 4%, 11%, and 38%. ConclusionCDI produces highly reproducible measures in the ophthalmic artery. Measures in the central retinal artery are somewhat more variable but seem reasonably reproducible. Short posterior ciliary measurements were the most variable, suggesting that current methods for assessing these vessels may not be sufficiently reliable.

Retrobulbar arterial hemodynamic effects of betaxolol and timolol in normal-tension glaucoma.

PURPOSE beta-Adrenergic blocking drugs lower intraocular pressure. The question of whether these drugs also alter, either directly or indirectly, orbital hemodynamics is potentially of great importance for patients with normal-tension glaucoma who may have some degree of reversible vasospasm. METHODS We compared the effect of selective (betaxolol) and nonselective (timolol) beta-adrenergic blocking drugs on flow velocities (as determined by color Doppler imaging) in orbital vessels in 13 patients with normal-tension glaucoma (mean age, 62 +/- 3 years; mean intraocular pressure, 15 +/- 2 mm Hg). A one-month drug treatment double-masked crossover design, with a three-week washout before each drug, was used. RESULTS Neither drug changed peak systolic velocity in any of the four vessels studied (ophthalmic, nasal and temporal posterior ciliary, and central retinal arteries). Additionally, timolol did not alter end-diastolic velocity or resistance index (defined as [peak systolic velocity minus end-diastolic velocity] divided by peak systolic velocity) in any of the vessels measured. In contrast, betaxolol tended to increase end-diastolic velocity and to decrease resistance index: the four-vessel average end-diastolic velocity increased 30% (P = .08), and the four-vessel average resistance index decreased significantly (P = .04). These reductions in resistance index occurred despite that betaxolol, in contrast to timolol, did not significantly decrease intraocular pressure. CONCLUSIONS These results suggest that, in patients with normal-tension glaucoma, selective beta-adrenergic blockade (betaxolol) may have ocular vasorelaxant effects independent of any influence on intraocular pressure, whereas nonselective blockade (timolol) lowers intraocular pressure without apparently altering orbital hemodynamics.

Agreement among Optometrists, Ophthalmologists, and Residents in Evaluating the Optic Disc for Glaucoma

PURPOSE To determine the agreement among optometrists, ophthalmologists, and ophthalmology residents in assessing glaucomatous optic nerve damage. The authors also determined the sensitivity of each group of observers for identifying glaucomatous optic nerve damage. METHODS Six optometrists, six general ophthalmologists, and six third-year ophthalmology residents evaluated 75 stereoscopic optic disc photographs. Observers estimated the vertical cup:disc ratio (C:D) and assessed the presence of glaucomatous damage. Agreement among and within observers was estimated by the kappa statistic (KW, k). The sensitivity and specificity for the identification of glaucomatous optic nerve damage were determined for each group of participants. RESULTS Intraobserver agreement (KW 0.69-0.79) was greater than interobserver agreement (KW 0.56-0.68) in assessing the C:D ratio and glaucomatous optic nerve damage for optometrists, ophthalmologists, and residents. Interobserver agreement for ophthalmologists (KW 0.68) was substantial and significantly higher than for optometrists (KW 0.56) and residents (KW 0.56) when estimating the C:D ratio. Ophthalmologists and residents had higher sensitivity (78%) in identifying glaucomatous optic nerve damage than did optometrists (56%). The specificity for all three groups was relatively poor (range, 47%-60%). CONCLUSION The moderate interobserver agreement across all three groups of observers suggests the need to develop standardized criteria for assessing glaucomatous optic disc damage. Ophthalmologists in this study have a higher interobserver agreement in estimating the C:D ratio and are more sensitive than optometrists in assessing glaucomatous optic nerve damage.

Short- and Long-Term Effects of Postoperative Corticosteroids on Trabeculectomy

All patients with primary open-angle or primary angle-closure glaucoma requiring trabeculectomy between January 1982 and January 1983 were entered into a randomized prospective study to evaluate the effect of postoperative corticosteroids. Twenty-three eyes in Group 1 received a cycloplegic and topical antibiotic. Twenty-nine eyes in Group 2 received the same treatment, with the addition of topical 1% prednisolone acetate. Twenty-three eyes in Group 3 received the same treatment as Group 2, with the addition of systemic prednisone. Success rate was significantly improved with the use of topical corticosteroids. Systemic steroids did not prove to be of any added benefit over topical use alone.

Reversible Optic Disk Cupping and Visual Field Improvement in Adults With Glaucoma

To assess change over time in the optic disk and the associated change in visual field, we retrospectively reviewed perimetry results and optic disk photographs of adult patients treated for glaucoma. Three glaucoma specialists masked to the clinical course independently reviewed optic disk stereophotographs and visual fields taken before and after treatment. Each member of each pair of stereophotographs or perimetry results, which were presented in a random sequence, were graded as better, worse, or unchanged. Of the 75 eyes, 16 (21%) showed a reversal of optic disk cupping; 20 of the 63 visual fields (31%) were classified as improved. In six of 17 eyes (35%) with a change in the disk (better or worse), a corresponding change was also noted in the visual field. The frequency of improvement in optic disk and visual field appearance was significantly (P less than .05) associated with the degree of intraocular pressure reduction.

Electron Microscopy of Argon Laser Therapy in Phakic Open-angle Glaucoma

In 22 subjects with phakic open-angle glaucoma, trabeculectomies were performed at intervals of three hours to one year after argon laser treatment (ALT). In ten patients the ALT was done with informed consent anticipating that trabeculectomy would be performed at a scheduled time (three hours to two weeks following laser therapy). In 12 other patients, trabeculectomies were required for failure of ALT (one month to one year later). Scanning and transmission electron microscopy of the specimens examined at earlier intervals after laser therapy revealed evidence of heat effects with disruption of trabecular beams, fibrinous material, and necrosis of occasional cells, including melanin-containing endothelial cells, followed by shrinkage of the collagenous components of the trabecular meshwork. The specimens excised at longer intervals after laser treatment showed partial or total occlusion of intertrabecular spaces by a cellular layer of abnormal corneal and/or trabecular endothelial cells with widened cellular interdigitations and numerous prominent filopodial processes typical of migrating cells.

Extracapsular cataract extraction and posterior chamber intraocular lens implantation combined with trabeculectomy in patients with glaucoma.

We reviewed 75 consecutive cases of extracapsular cataract extraction and posterior chamber intraocular lens implantation combined with trabeculectomy in 69 patients with glaucoma. The mean preoperative intraocular pressure was 19.3 mm Hg on an average of 2.3 glaucoma medications. Visual acuity improved in 58 eyes (77%) at two months, with an average improvement of 3.3 and 3.6 lines at two and 12 months, respectively. Of the 75 eyes, 49 (65%) achieved a visual acuity of 20/40 or better; three patients (4%) had further deterioration in vision at the completion of follow-up because of progressive glaucoma or macular disease. Postoperatively, the average intraocular pressure was 3.8 and 3.0 mm Hg lower than the preoperative level at two and 12 months (P less than .001) on 0.63 and 0.79 glaucoma medications, respectively. However, 27 (36%) of the 75 eyes had a recorded intraocular pressure greater than 30 mm Hg and 30 (40%) had a pressure 7 mm Hg or more above their preoperative level during the first six months after surgery. Despite improved long-term control of intraocular pressure, detectable conjunctival filtering blebs were present in only 31 (41%) of 75 eyes at two months and in seven (12%) of 56 eyes at 12 months. Hyphema occurred in 34 (45%) of the cases.