Arthur J. Mueller

Stereotactic radiosurgery of large uveal melanomas with the gamma-knife.

OBJECTIVE To present our experience with the Gamma-knife in treating large uveal melanomas with stereotactic radiosurgery. DESIGN Prospective, noncomparative, interventional case series. PARTICIPANTS Fifty-eight patients with unilateral uveal melanomas were treated from 1996 through 1999 with stereotactic radiosurgery using the Gamma-knife. From these we report the results of 35 patients who had a follow-up of more than 1 year after irradiation. INTERVENTION Stereotactic radiosurgery with the Gamma-knife. MAIN OUTCOME MEASURES Tumor control, maximum apical tumor height, eye retention rate, and visual acuity. RESULTS In 34 eyes (97%), local tumor control was achieved. The maximum apical tumor height decreased from a median of 9.1 mm (95% confidence interval [CI], 3.2-13.9 mm) before treatment to 6.2 mm (95% CI, 2.1-11.9 mm) at 1 year after treatment (P<0.001, paired t test). The tumor volume decreased from a median of 0.8 cm(3) before treatment to 0.5 cm(3) 1 year after treatment (P<0.001, paired t test). Two eyes required enucleation (one radiation failure, one secondary glaucoma). The median visual acuity decreased from 20/60 (95% CI, hand movement [HM] to 20/20) before treatment to 20/200 (95% CI, HM to 20/30) at 1 year after treatment (P = 0.001, paired t test). CONCLUSIONS Stereotactic radiosurgery using the Gamma-knife is an alternative to enucleation in treating large uveal melanomas. The visual function may be preserved in selected cases.

Trypan blue in macular pucker surgery: an evaluation of histology and functional outcome.

Purpose: To evaluate possible adverse effects of trypan blue on the ultrastructure of the human retina, to report on functional outcome of macular pucker surgery with and without the use of trypan blue, and to evaluate the ultrastructure of tissue harvested during surgery. Design: Experimental study and prospective matched-pair analysis of two consecutive, interventional case series. Methods: Possible adverse effects on the ultrastructure of the human retina by trypan blue were evaluated in three donor eyes in an experimental study using trypan blue in concentrations of 0.02%, 0.15%, and 0.25%. The retinas were histologically evaluated. In the clinical study, the functional outcome (visual acuity, Goldmann perimetry) of 10 eyes of 10 consecutive patients with intraoperative use of trypan blue (0.15%) was analyzed (group 1) and compared with the functional outcome in a matched group of patients (preoperative visual acuity, pre- and postoperative lens status) who had undergone vitrectomy without trypan blue assistance (group 2). Only patients with an idiopathic macular pucker were included. Epiretinal tissue of all eyes was harvested and prepared for ultrastructural analysis using light and electron microscopy. Results: In the postmortem study, no significant alterations of the inner retina suggesting adverse effects of trypan blue concentrations of 0.02% were observed. In contrast, a disorganization of the innermost retina and an absence of the internal limiting membrane (ILM) was seen after the application of undiluted 0.15% and 0.25% trypan blue. In the clinical study, the median best-corrected visual acuity was 20/50 in both groups (range, 20/200–20/40) before surgery. Mean age was 70 years in group 1 (with trypan blue) and 69 years in group 2 (without trypan blue). Mean follow-up time was 4 months in group 1 and 5.6 months in group 2. Postoperatively, median visual acuity had increased to 20/32 (range, 20/100–20/25; Wilcoxon test P = 0.01) in group 1 and to 20/40 (range, 20/100–20/25; P = 0.09) in group 2. The difference between the two groups was not statistically significant (P = 0.4). Four of 10 patients without and 7 of 10 patients with trypan blue staining experienced an improvement of visual acuity (gain of 2 lines or more). No postoperative visual field defects were noted in either group. Histologic analysis of tissue harvested intraoperatively revealed the regular picture of undisturbed fibrocellular membranes. In some specimens, a layer of interspersed collagen was noted between epiretinal cells and the ILM, suggesting two different morphologic types of macular pucker. In a few sections, areas of cellular elements were detected adjacent to the retinal surface of the ILM. Conclusion: Trypan blue in a concentration of 0.02% is not associated with morphologic alterations of the inner retinal layers in our postmortem study. After application of 0.15% and 0.25% trypan blue solutions, a disorganization of the inner retinal layers was observed; the ILM was absent. We did not find any adverse effects of an intraocular trypan blue concentration of 0.02% on functional status. Our study further indicates that the functional results of surgery with and without the use of trypan blue are comparable. As the question of toxicity of a dye can not be answered by morphological observations alone, further experimental studies will be needed.

The effect of deep posterior subtenon injection of corticosteroids on intraocular pressure

PURPOSE To investigate the effect of posterior subtenon injections of corticosteroids on intraocular pressure in a variety of ocular diseases. METHODS We retrospectively analyzed 202 consecutive posterior subtenon corticosteroid injections (148 of methylprednisolone acetate, 80 mg, and 54 of triamcinolone acetonide, 40 mg) in 63 eyes of 55 patients (26 male, 29 female; mean age +/- SD, 60.17 +/- 26.55 years). All patients had received topical or systemic corticosteroids before the injection, and no rise in intraocular pressure had been noted. Preinjection and postinjection intraocular pressure measurements were compared by two-tailed paired t test. Statistical analysis was performed separately by patient (first injection of first injected eye), by eye (first injection of each eye), and by all injections. To detect increase in intraocular pressure during follow-up, statistical analysis was performed separately 14 to 90 days, 91 to 150 days, and 151 to 270 days after injection. RESULTS No statistically significant difference was found between preinjection and postinjection intraocular pressure measurements. A power calculation in the most stringent subanalysis (by patient) proved that there is only a 3.87% chance to statistically miss a clinically significant rise in intraocular pressure from 15 to 21 mm Hg. CONCLUSIONS Posterior subtenon injection of corticosteroids does not cause an increase in intraocular pressure. All patients in our study had been treated previously with topical or systemic corticosteroids and did not react with an excessive increase in intraocular pressure. This safety of repository corticosteroids may therefore not apply to patients whose status in responding to corticosteroids is not known.

Complex microcirculation patterns detected by confocal indocyanine green angiography predict time to growth of small choroidal melanocytic tumors: MuSIC Report II

PURPOSE Multiple independent laboratories have confirmed the histologic observation that some tumor microcirculation patterns (MCPs) in uveal melanomas are associated strongly with death resulting from metastatic disease. Because these patterns are imageable with confocal indocyanine green angiography (ICG), we designed a prospective study to evaluate whether these angiographically detectable MCPs predict time to tumor growth. DESIGN Observational case series, prospective, non-randomized. PARTICIPANTS Ninety-eight patients with unilateral, small, choroidal melanocytic tumors. METHODS The following information and tumor characteristics were recorded for each patient: demographic parameters, best-corrected visual acuity, intraocular pressure, related visual symptoms, location and dimension of tumor, pigmentation, orange pigment, drusen, tumor-associated hemorrhage, subretinal fluid, and confocal ICG angiographically determined microcirculation patterns-silent (avascularity), normal (preexisting normal choroidal vessels within the tumor), straight vessels, parallel without and with cross-linking, arcs without and with branching, loops, and networks. MAIN OUTCOME MEASURES Time to growth of the tumor, with growth defined as an increase in the maximal apical tumor height of 0.5 mm measured by standardized A-scan ultrasonography, photographic documentation of an increase of the largest basal diameter of at least 1.5 mm, advancement of one tumor border of at least 0.75 mm, or a combination thereof. RESULTS Twenty-eight of the 98 tumors in this study (29%) met the predetermined criteria for tumor growth. The median time to growth was 127 days (range, 51-625 days). The following tumor characteristics were significantly associated with time to tumor growth: flashes (P = 0.0224), orange pigment (P = 0.012), subretinal fluid (P < 0.001), maximum basal tumor diameter at initial examination (P = 0.015), maximum apical tumor height (P < 0.001), parallel with cross-linking MCP (P < 0.001), arcs with branching MCP (P = 0.006), loops (P < 0.001), and networks (P < 0.001). Of these, the angiographic documentation of any of the complex MCPs (parallel with cross-linking, arcs with branching, loops, networks, or a combination thereof) showed the strongest association with the time to tumor growth in a Cox proportional hazard model. CONCLUSIONS The characteristics of our patient cohort are comparable by clinical and echographic parameters with cohorts for predicting tumor growth, described previously in the literature. In addition, we detected a novel clinical predictor of tumor growth: the confocal ICG angiographic detection of complex MCPs.

Analysis of Visual Dysfunctions in HIV-positive Patients Without Retinitis

PURPOSE To investigate visual dysfunctions in ophthalmoscopically normal human immunodeficiency virus (HIV)-positive patients and to correlate the results to the stage of HIV disease and neuropsychological status. METHODS Fifty-one randomly selected eyes (26 right, 25 left) of 51 HIV-positive patients with visual acuity measurements of 20/20 or better and no ophthalmoscopically detectable disorders were prospectively examined using achromatic and short-wavelength automated perimetry, color vision testing, and contrast sensitivity testing. CD4+ T-lymphocyte count, presence of systemic infection, hemoglobin, hematocrit, serum beta 2-microglobulin levels, and results of neuropsychological testing were also analyzed. RESULTS On achromatic automated perimetry, 21.6% (11/51) of patients performed abnormally according to the mean defect and 27.5% (14/51) according to the Glaucoma Hemifield Test; 29.4% (15/51) performed abnormally on short-wave-length automated perimetry according to the mean defect and 23.5% (12/51) according to the Glaucoma Hemifield Test. On contrast sensitivity, 5.9% (3/51) of patients performed abnormally in the 1.5-cycles per degree (cpd) line, 2.0% (2/51) in the 3-cpd line, 23.5% (12/51) in the 6-cpd line, 25.5% (13/51) in the 12-cpd line, and 33.3% (17/51) in the 18-cpd line. On the Farnsworth-Munsell 100-hue test, 29.4% (15/51) of patients performed abnormally. After correction for multiple correlations, two statistically significant correlations were found: sum of log contrast sensitivity with achromatic automated perimetry and sum of log contrast sensitivity with the Farnsworth-Munsell 100-hue test. CONCLUSIONS A significant percentage of HIV-positive patients with visual acuity of 20/20 or better and no ophthalmologic evidence of retinitis performed abnormally on visual psychophysical tests. The severity of visual dysfunction was not correlated with the stage of HIV infection or the degree of neuropsychological dysfunction.

Adverse events and autopsy findings after intravitreous cidofovir (HPMPC) therapy in patients with acquired immune deficiency syndrome (AIDS)

OBJECTIVE The purpose of the study is to evaluate the adverse events and autopsy findings in a series of consecutive 20-microg intravitreous cidofovir injections at a single institution. DESIGN The study design was a nonrandomized, consecutive case series. PARTICIPANTS Seventy-six patients with acquired immune deficiency syndrome with cytomegalovirus retinitis were studied prospectively. Sixty-three patients had 1 months follow-up or longer, and this comprised the study group. In addition, histopathologic findings from 18 eyes of 9 patients were studied at autopsy. INTERVENTION A total of 296 injections of 20 microg cidofovir were given in 115 eyes. Sixty-three patients who had 246 injections in 93 eyes had 1 months follow-up or longer for the evaluation of adverse events. MAIN OUTCOME MEASURES Postinjection chronic hypotony associated with permanent visual loss, transient hypotony, iritis, and its long-term sequela (posterior synechia and cataract, retinal detachment, extraocular cytomegalovirus involvement) were the outcomes of interest in this study. Additionally, light and electron microscopic studies of human eyes were performed. RESULTS The most severe adverse event was postinjection chronic hypotony. This phenomenon was associated with permanent visual loss. This was observed in 1% of the injections and 3% of the eyes of the patients (95% confidence interval, 0%-6%). Transient hypotony associated with mild-to-moderate visual loss developed in 14%, but vision recovered to baseline levels in these eyes subsequently. Analysis showed that transient hypotony in the injected eye could predict postinjection chronic hypotony in the fellow eye (two-tailed Fishers exact test, P = 0.02). The incidence of iritis was 32%; posterior synechia and cataract were the long-term sequela of the iritis and developed in 19% and 11% of the eyes, respectively. The incidence of retinal detachment was lower (6%). Histopathologic evaluation of the eyes showed mild-to-moderate atrophy of the nonpigmented epithelium of the ciliary body and no other evidence of intraocular toxicity. CONCLUSIONS The most serious adverse event was postinjection chronic hypotony, which occurred in 3% of eyes. Episodes of transient hypotony appear to indicate that the fellow eye was predisposed to chronic hypotony. Therefore, it may be prudent to give intravitreous injections at least 2 weeks apart in the fellow eye to evaluate the clinical response of the injected eye.

Evaluation of microvascularization pattern visibility in human choroidal melanomas: comparison of confocal fluorescein with indocyanine green angiography

Abstract · Background: The presence of specific microvascularization patterns (networks, parallel with and without crosslinking, silent) in histological sections of human choroidal melanomas has prognostic significance for survival. We showed previously in selected patients that the identification of these microvascularization patterns is possible in vivo by using confocal scanning laser indocyanine green angiography and that this technique is superior to fluorescein angiography using a conventional acquisition technique with a fundus camera. We now routinely use simultaneous confocal fluorescein/indocyanine green angiography to study microvascularization patterns in choroidal melanomas. The purpose of this study was to compare the visibility of tumor vessels and microvascularization patterns in fluorescein and indocyanine green angiography in simultaneous confocal series taken with the same instrument in a large prospective series of patients. · Patients and methods: The simultaneously procured confocal fluorescein and indocyanine green angiograms of 50 patients with untreated choroidal melanomas (maximal apical height according to standardized A-scan between 2 and 8 mm) were studied for the visibility of tumor vessels and microvascularization patterns. At least one simultaneous confocal optical series (32 images in sequential depth order) during the early arterial venous phase was obtained per patient. · Results: Confocal forescein angiography disclosed signs of tumor vascularization in 12 (24%) of the 50 patients examined. However, in only 3 patients (6%) could microvascularization patterns be identified using confocal fluorescein angiography, and only in the very early arterial phase, which is often difficult to capture. In contrast, simultaneously obtained confocal indocyanine green angiograms disclosed tumor vessels in 47 (94%) of the examined 50 patients and microvascularization patterns could be identified in all of these cases. In 3 patients (6%) no tumor vessels could be detected within the tumor borders. · Conclusion: This study demonstrates that confocal indocyanine green angiography images microvascularization patterns in choroidal melanomas better than fluorescein angiography, even when the images are acquired with the same technique. This can be explained with the different absorption, fluorescence and exudation characteristics of these dyes. In vivo imaging of these microvascularization patterns using confocal indocyanine green angiography offers the possibility of assessing the prognosis of choroidal melanomas without the removal of tissue.

Optical coherence tomography for the detection of laser in situ keratomileusis in donor corneas.

Purpose. In 2001, more than one million laser in situ keratomileusis (LASIK) procedures were performed worldwide. Considering the increasing number of refractive procedures, eye banks will be increasingly confronted with the problem of how to identify those donors with prior refractive surgery. To date, efficient screening methods to identify LASIK surgery in donor eyes have not been established. Therefore, the purpose of the current study was to determine whether optical coherence tomography (OCT) can be used to detect the presence of LASIK-induced changes in human corneas. Methods. Laser in situ keratomileusis was performed on 20 organ-cultured human cornea disks. The excimer laser ablation performed ranged from 0 to 12 diopters. The corneas were maintained in culture, and the visibility of flap-stromal interface by OCT was assessed up to 6 months after the LASIK procedure. Additionally, two donor corneas with the history of LASIK treatment before death were screened for structural changes. Results. Optical coherence tomography scans were able to detect the interface between the corneal flap and the residual stromal tissue in all corneas and at all examined time intervals. There were no differences in signal intensity among the different depths of ablation. The relative signal intensity of the interface compared with the averaged stromal intensity ranged from 2.1 to 6.0. In both donor corneas with suspected prior LASIK surgery, OCT scanning showed the characteristic stromal interface as found in the in vitro model. Conclusions. Corneal examination by OCT could be an appropriate technique for eye banks to screen donor corneas for prior LASIK surgery.

Retinal Blood Flow Measurements in Branch Retinal Vein Occlusion Using Scanning Laser Doppler Flowmetry

PURPOSE To determine capillary blood flow measurements in eyes with branch retinal vein occlusion using a scanning laser Doppler flowmeter. METHODS Retinal capillary blood flow in branch retinal vein occlusion areas and corresponding ipsilateral nonbranch retinal vein occlusion areas, 11 equivalent areas of the contralateral fellow eye of 12 consecutive untreated branch retinal vein occlusion patients, and 16 eyes of 11 age-matched normal control subjects were measured with scanning laser Doppler flowmetry. A template consisting of eight squares, each with a field of 100 x 100 microm (10 x 10 pixel) with space interval of 500 microm equidistant horizontally and vertically was used to obtain blood flow measurements in all subjects. Mean blood volume, flow, and velocity were obtained by averaging the mean values measured in each field. We avoided measurement over large retinal vessels to prevent the aliasing artifact of blood cells from moving faster than the sampling frequency. RESULTS Branch retinal vein occlusion areas have significantly decreased microvascular blood volume (P = .0009), flow (P = .02), and velocity (P = .016) compared with ipsilateral nonbranch retinal vein occlusion areas in the same eye. Branch retinal vein occlusion areas also have decreased blood volume (P = .001), flow (P = .0042), and velocity (P = .0044) compared with areas of contralateral fellow eyes of branch retinal vein occlusion subjects. Branch retinal vein occlusion areas have significantly decreased blood volume (P = .0012), flow (P = .008), and velocity (P = .02) compared with age-matched normal areas. CONCLUSION Average retinal blood volume, flow, and velocity in areas of branch retinal vein occlusion are significantly lower than in healthy retinas. The ability to noninvasively measure hemodynamic changes in the retinal capillary bed may be relevant to development of new therapies for retinovascular disease.

Stereotaktische Konvergenzbestrahlung großer uvealer Melanome mit dem Gamma-Knife

ZusammenfassungHintergrund. Wir berichten über unsere 3-Jahres-Ergebnisse mit der stereotaktischen Konvergenzbestrahlung (Gamma-Knife) bei großen und ungünstig gelegenen uvealen Melanomen. Patienten und Methode. Seit 1997 wurden 100 Patienten (51 männlich, 49 weiblich) nach einem standardisierten Protokoll behandelt (ambulante Einzeitbestrahlung, Maximaldosis 50 Gy,Tumorranddosis mindestens 25 Gy, ausschließlich Retrobulbäranästhesie zur Bulbusfixation).Bei keinem Patienten war auf Grund der Lokalisation und/oder der Tumorgröße eine Brachytherapie mit Ru-106-Applikator möglich.Am hinteren Pol waren 61 Tumoren (61%) lokalisiert,21 Tumoren (21%) lagen ausschließlich chorioidal in der mittleren Peripherie, und 18 Tumoren (18%) lagen anterior und bezogen den Ziliarkörper mit ein. Alle Patienten wurden regelmäßig ophthalmologisch und neuroradiologisch nachuntersucht. Für 73 Patienten lagen 1-, für 33 Patienten 2- und für 17 Patienten 3-Jahres-Nachbeobachtungsdaten vor. Ergebnisse. Zwei der 100 Patienten erlitten ein Tumorrezidiv.Vor der Bestrahlung (100 Patienten) betrug die maximale apikale Tumorhöhe (MAH) median 7,8 mm (95% KI 2,9–12,5 mm).Nach 1 Jahr (73 Patienten) betrug die MAH median 5,7 mm (95% KI 2,4–10,2 mm),nach 2 Jahren (33 Patienten) median 4,3 mm (95% KI 2,2–8,8 mm) und nach 3 Jahren (15 Patienten) median 4,6mm (95% KI 2,4–8,5 mm).Alle Differenzen zur MAH der jeweiligen Patienten vor Bestrahlung waren statistisch signifikant (zweiseitiger gepaarter t-Test). Innerhalb des 1. Jahres nach Bestrahlung mussten 7 Patienten wegen eines schmerzhaften Sekundärglaukoms enukleiert werden.Innerhalb des 2. Jahres nach Bestrahlung mussten 2 Patienten (1 Tumorrezidiv,1 Sekundärglaukom) und innerhalb des 3. Jahres ein weiterer Patient (Tumorrezidiv) enukleiert werden. Schlussfolgerung. Unsere 3-Jahres-Ergebnisse zeigen, dass die stereotaktische Konvergenzbestrahlung mit dem Gamma-Knife bei 98% der Patienten mit großen und ungünstig gelegenen uvealen Melanomen in der Lage ist, eine lokale Tumorkontrolle zu induzieren. Das Risiko für eine Sekundärenukleation ist im 1. Jahr nach Bestrahlung am höchsten, aber insgesamt bei diesen großen Tumoren mit 10% als niedrig anzusehen. Die sehr gute lokale Tumorkontrollrate veranlasste uns, bei den nachfolgend behandelten Patienten die Maximaldosis auf 40 Gy(Tumorranddosis mindestens 20 Gy) zu reduzieren.AbstractBackground. We report the results over 3 years with stereotactic radiosurgery using the Gamma Knife for large and unsuitably located uveal melanomas. Patients and methods. A total of 100 patients (51 male, 49 female) have been treated since 1997 following a standardised treatment protocol (outpatient single-shottreatment, maximum dose 50 Gy,tumour margin dose min.25 Gy, retrobulbar anaesthesia alone for globe fixation).The localisation and/or dimension of the tumours did not allow radiation brachytherapy with Ru106 plaques.Of the tumours 18 were located in the ciliary body, 61 were located at the posterior pole, and 21 were located in the mid-periphery. All patients were followed and tested ophthalmologically and neuroradiologically at regular intervals. The 1-year follow-up data were available for 73 patients, 2-year follow-up data for 33 patients and 3-year follow-up-data for 17 patients. Results. Before therapy the maximum apical tumour height (MAH) was median 7.8 mm (95% CI 2.9–12.5 mm): 1 year after treatment (73 patients) the MAH was median 5.7 mm (95% KI 2.4–10.2 mm),2 years after treatment (33 patients) the MAH was median 4.3 mm (95% KI 2.2–8.8 mm),and 3 years after treatment (17 patients) the MAH was median 4.6 mm (95% KI 2.4–8.5 mm).All differences to the MAH of the corresponding patients before treatment were statistically significant (paired t-test). Within the first year after treatment seven patients were enucleated due to a painful secondary glaucoma,within the second year after radiation two patients (one tumour recurrence, and one secondary glaucoma) and within the third year one more patient (tumour recurrence) was enucleated. Conclusions. Our 3-year results demonstrate that radiosurgery using the Gamma Knife is beneficial in achieving a local tumour control in 98% of eyes with large and unsuitably located uveal melanomas. The risk for a secondary enucleation is highest in the first year after treatment with a favourable overall rate of 10%. Due to the excellent local tumour control rate we decreased the maximum dose to 40 Gy (min.tumour margin dose 20 Gy) in the subsequently treated patients.