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Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

The purpose of this study was to investigate the cytotoxic effect of heat as induced by transscleral thermotherapy (TSTT), which may be of interest in the treatment of patients with choroidal melanoma. The aim of TSTT is to heat both the sclera and the tumor up to a cytotoxic temperature of about 60 degrees C. TSTT was performed in hamsters with subcutaneously implanted Greene melanoma covered by a specimen of human donor sclera of thickness 0.5, 0.7 or 0.9 mm. A newly developed applicator, which combines conductive episcleral heating at 60 degrees C with laser-induced heating, was used at laser powers ranging from 500 to 1500 mW delivered by an 810 nm diode laser, beam diameter 3 mm, and exposure time 1 min. Temperatures were measured at the scleral surface and at the sclera-tumor interface. The extent of tumor necrosis was examined by light microscopy and the sclera was examined by polarized light microscopy. Maximal depth of tumor necrosis without scleral damage was 4.4 (SD 1.5) mm. The temperature at the scleral surface after TSTT was 58.8 (SD 2.4) degrees C. The temperature at the sclera-tumor interface ranged from 56.4 (SD 3.7) degrees C at 500 mW to 65.3 (SD 4.4) degrees C at 1250 mW laser power. Structural changes to the scleral collagen started to develop at 1250 mW. TSTT with combined laser-induced and conductive heating caused cytotoxic temperatures in the tumor and the sclera, which were well tolerated by the scleral collagen.

Aim: To evaluate the results of combined plaque radiotherapy and transpupillary thermotherapy (TTT) in 50 consecutive patients 5 years after treatment., Methods: 50 adult patients with choroidal melanoma were treated with ruthenium-106 ((106)Ru) plaque radiotherapy combined with TTT. A flat scar was the preferred end point of treatment. The mean tumour thickness was 3.9 mm (range 1.5-8.0 mm), the mean tumour diameter was 11.3 mm (range 5.8-15.0 mm). TTT was performed with an infrared diode laser at 810 nm, a beam diameter of 2-3 mm, and 1 minute exposures. Tumours >5 mm thick received an episcleral contact dose of 800 Gy (106)Ru; tumours 3 mm thick (log rank test p = 0.01). Eight melanomas were amelanotic, seven of which required multiple TTT sessions. In one patient the tumour recurred at the central margin of the treated area; this eye was enucleated. In one patient the tumour failed to regress 6 months after treatment and enucleation was performed at the patient's request. Three eyes developed severe proliferative retinopathy. Radiation maculopathy caused a loss of the best corrected visual acuity: before treatment 31 patients had a best corrected visual acuity of 20/60 or better but in only 12 patients did it remain in this range 5 years after treatment. Three patients developed distant metastasis to the liver., Conclusion: The 5 year results for combined plaque radiotherapy and TTT as treatment for choroidal melanoma are favourable in terms of complete tumour regression and low rate of recurrences; however, there was considerable loss of visual acuity as a result of radiation maculopathy.

Objective: To determine the highest safe treatment temperature, at 30- and 60-second exposure durations, for transscleral thermotherapy (TSTT) of choroidal melanoma., Methods and Design: Transscleral conductive heating was performed in 15 rabbits at 50 degrees C to 70 degrees C for 30 or 60 seconds. The thermal lesions in the ocular fundus were monitored for 4 months with ophthalmoscopic, photographic, and fluorescein angiographic examination. Histologic examination included polarized light microscopy., Results: The effect of TSTT was similar for both exposure durations. Vascular occlusion in the retina and choroid developed at temperatures of 55 degrees C and higher. After heating at 60 degrees C, scleral collagen fibers developed a minimal undulation; at 65 degrees C, they became clearly undulated. The undulation resolved in the 3 to 4 months after heating. Heating at 70 degrees C caused persistent severe damage to the sclera. Retinal tears developed after heating at 65 degrees C and 70 degrees C., Conclusions: A temperature of 65 degrees C was found to be the highest temperature that did not cause permanent damage to the sclera at both exposure durations. A temperature of 60 degrees C may be the optimal temperature for TSTT of choroidal melanoma because retinal tears may develop at 65 degrees C., Clinical Relevance: In TSTT, the temperature levels reached are cytotoxic for choroidal melanoma as well as intrascleral tumor cells. Occlusion of choroidal vessels induced by TSTT may contribute to tumor necrosis because these vessels serve as feeder vessels for the tumor.

Aim: A pilot study of the feasibility of using dye laser thermotherapy (LTT) at a subcoagulation temperature to occlude newly formed vessels in patients with age related macular degeneration (AMD)., Methods: Choroidal neovascularisation (CNV) in 24 eyes with exudative AMD was treated with a continuous wave yellow laser at 578 nm. Parameters were an exposure time of 2 or 5 seconds, a spot size of 750 or 1000 microm, and a laser power of 100-200 mW. The clinical end point was a greyish discoloration at the treatment site. The effect of thermotherapy was documented by ophthalmoscopic and fluorescein angiographic examination. The follow up after LTT was 4-16 months, mean 5 months., Results: LTT resulted in total occlusion of newly formed vessels in 15 eyes (62.5%). Neovascular outgrowth within 6 weeks and recurrences 2-4 months after LTT were observed, each in three eyes. In six of the nine eyes with occlusion of CNV without recurrence the choriocapillaris remained perfused; in two eyes only the large choroidal vessels remained perfused. In six eyes pigmentary changes were the only ophthalmoscopic and fluorescein angiographic signs of treatment. The effect of LTT is rather unpredictable., Conclusion: CNV in AMD can effectively be treated by yellow dye laser thermotherapy with preservation of choroidal perfusion. The technique requires dosimetric adaptation.

Twenty-seven patients with characteristic, mostly bilateral, fundus lesions of chronic central serous chorioretinopathy (CSC) and a progressive course, and 80 of their relatives, mainly siblings, were examined. Ophthalmologic examination included assessment of visual acuity, Amsler grid testing, ophthalmoscopy and fluorescein angiography. The fundus findings were classified as normal fundus, multiple areas of retinal pigment epithelium (RPE) atrophy or chronic CSC: RPE atrophy with leakage of fluorescein. In 14 (52%) of the 27 families, 1 or more relatives were affected. Thirty-five (44%) of the 80 investigated relatives had fundus lesions: 22 had chronic CSC in one eye, 20 of these had chronic CSC or RPE atrophy in the fellow eye. Thirteen relatives had RPE atrophy in one or both eyes. The mode of inheritance could not be established., (Copyright 2001 S. Karger AG, Basel)

Thermal damage to the human sclera in relation to temperature and duration of exposure was studied in order to determine the heat tolerance of the sclera with respect to transscleral thermotherapy of choroidal melanoma. Samples of human sclera were submerged in saline for 10 sec to 10 min at temperatures of 37-100 degrees C. The effects of heat on the shape, weight and size of the samples were studied. Thermal damage of scleral collagen was examined by polarized light microscopy (LM) and electron microscopy (EM). The sclera was embedded in epoxy resin and stained with toluidine blue for LM and with uranyl acetate and lead citrate for EM. Thermal damage of scleral collagen on polarized LM was graded on a five point scale. Scleral damage was visible on macroscopic examination and on LM and EM in sclera heated at 65 degrees C for 20 sec or longer, at 70 degrees C for 10 sec or longer, and at higher temperatures. A sigmoidal function was used to define the relation between temperature and changes in diameter, thickness, and weight of scleral samples. Using fitted functions, the threshold temperature for thermal damage was estimated to be 59-61 degrees C when samples were heated for 10 min, 62-63 degrees C when heated for 1 min, and 66-67 degrees C when heated for 10 sec; the threshold exposure time at 60 degrees C was estimated to be 7-12 min. These results indicate a temperature of 60 degrees C for 1 min is well tolerated by human donor sclera; information of in vivo studies is required to validate whether this setting can be used in transscleral thermotherapy (TSTT) for choroidal melanoma.

Background and Purpose: To update our results of the treatment of uveal melanomas using ruthenium applicators in 49 patients treated with graded doses and subsequently in 52 patients with maximal scleral doses of 800 Gy and an effective top dose of at least 160 Gy., Material and Methods: One hundred and one patients were treated with brachytherapy only, in 25 patients it was combined with transpupillary thermotherapy (TTT)., Results: A complete remission was found in 62.6% of the patients and in 31.3% a stable disease with an average follow-up of 74.6 months. Above a top dose of 120 Gy only in one of 95 patients continuous tumour growth after treatment was observed. Useful vision could be preserved in 51.5% of the patients. The initial tumour prominence and top dose strongly correlated with treatment outcome., Conclusions: Ruthenium application for uveal melanomas with the doses we have used is successful, with a substantial number of patients having their eyes preserved, their tumour controlled and their vision retained. Further improvements can be obtained with ruthenium irradiation with lower maximal scleral doses combined with TTT.

Aim/background: In a new autosomal dominant syndrome (which the authors called hereditary vascular retinopathy (HVR)) cerebral ischaemia, Raynaud's phenomenon, and migraine are the most striking features. As serotonin (5-HT) is known to play a role in vasospastic processes, Raynaud's phenomenon, and migraine they wondered whether the serotoninergic status in patients with HVR is different. Therefore, it was decided to investigate some serotoninergic variables in these patients., Methods: The study was conducted in 12 patients with HVR, 10 relatives, and 19 healthy controls. The levels of intraplatelet and plasma 5-HT were measured, as well as the plasma levels of its precursor amino acid tryptophan and the ratio of tryptophan to the large neutral amino acids, which compete with the transport of tryptophan through the blood-brain barrier., Results: In both the patients with HVR and in nine relative the concentrations of 5-HT in plasma and platelets were significantly lower than in controls. The plasma levels of tryptophan and the tryptophan ratio were also found to be lower in the patient group compared with the control group, but not in the relatives., Conclusion: The observed alterations in 5-HT and its precursor tryptophan strongly suggest the existence of a malfunctioning of the serotoninergic system in the HVR syndrome.

Objective: To evaluate the efficacy and safety of transpupillary thermotherapy in treating choroidal melanoma., Methods and Patients: To perform transpupillary thermotherapy, infrared diode laser energy at 810 nm was used with a beam diameter of about 3 mm and 1-minute exposure time. All 50 patients had choroidal melanoma. We performed transpupillary thermotherapy in 21 tumors that had responded insufficiently to 800 Gy ruthenium 106 brachytherapy; it was combined with 800 Gy106Ru brachytherapy for 10 tumors greater than 5 mm in height and with 600 Gy for 19 tumors 5 mm or less in height., Results: All but 1 tumor exhibited reduction in tumor height within a mean follow-up of 20.5 months (range, 6-49 months). In 41 eyes (82%), the tumor flattened completely. Visual acuity was 20/60 or better in 43 eyes (86%) before treatment and in 14 eyes (28%) at the last examination because of radiation vasculopathy. Neovascular glaucoma developed in 1 eye, and total retinal detachment developed in 2 eyes. Tumor recurrence was observed in 1 patient., Conclusions: Although long-term results are necessary to properly appraise this new therapy, transpupillary thermotherapy may be useful as a complementary modality to brachytherapy.

We studied the effect of transpupillary thermotherapy (TTT) by a diode laser at 810 nm combined with episcleral ruthenium-106 plaque treatment (106Ru) on lens transparency in patients with choroidal melanoma. Lens transmission of blue-green light was measured by fluorophotometry in 17 patients treated with 106Ru treatment and TTT (measured 0.36 years after treatment), 12 patients treated with 106Ru alone (measured 19 years after treatment) and 25 age-matched healthy controls. Differences in lens transmission were not significant between treated and untreated fellow eyes (p > 0.15) nor between patient and control eyes (p > 0.25). TTT of choroidal melanoma combined with 106Ru plaque irradiation did not have a significant effect on the lens transparency up to 6 years after treatment.

Aims: The effect of transpupillary thermotherapy (TTT) on human choroidal melanomas was investigated by means of histopathology., Methods: Before enucleation TTT was performed in 11 eyes with a xenon are photocoagulator with a red filter or a diode laser at 810 nm. The exposure time was 1 minute; the estimated temperature at the top of the tumour was about 65 degrees C., Results: Seven of 11 tumours developed necrosis to a maximum depth of 3.9 mm with a sharp demarcation between the necrotic and the viable part of the tumour. The depth correlated with penetration of heat into the tumour. Scattered small haemorrhages in the transitional zone between the necrotic and the viable part of the tumour were observed in three eyes but large haemorrhages were absent. Ocular media were not affected owing to the low rate of absorption of radiation at 810 nm. TTT did not cause significant scleral damage. Intrascleral tumour cells with a viable appearance were observed in one eye, where the tumour was almost totally necrotic., Conclusion: Results show that TTT has potential as a conservative therapeutic treatment for choroidal melanomas.

The purpose of this study was to determine the threshold energy for light-induced functional damage of the retinal pigment epithelium at various wavelengths. Retinas of 58 pigmented and 21 albino rabbits were exposed to low intensity broadband blue light (400-520 nm), yellow light (510-740 nm), and narrowband blue light (408, 417, 439, 455, 485, 501 nm, respectively; deltalambda = 10-13 nm). The intensity values were 50, 280, and 5 mW x cm (-2), respectively, and the illumination time was 0.5 up to 5 h. The cumulative dose of light energy was calculated from these data (J x cm(-2)). The blood-retinal barrier dysfunction was evaluated in vivo using fluorophotometry to measure the leakage of fluorescein into the vitreous after intravenous injection and in vitro using light and electron microscopy after an in vivo intraarterial injection of horseradish peroxidase (HRP). The threshold energy for fluorescein leakage was 50 J x cm (-2) for blue light and 1,600 J x cm(-2) for yellow light. After broadband blue light exposure, the HRP reaction product was seen in the cytoplasm of the retinal pigment epithelium (RPE) cells and in the subretinal space but only if fluorescein leakage had been observed. Threshold energy and fluorescein leakage as a function of light energy were similar for albino and pigmented rabbits (P > 0.5). Only after yellow light exposure in excess of 3,700 J x cm(-2) was fluorescein leakage found. In that case complete disruption of the RPE was seen, but no HRP was observed in the RPE cytoplasm. Of the narrow-band blue light exposures, only that at lambda = 418 nm caused a significant increase in fluorescein leakage; the threshold energy was 18 J x cm(- 2). Blue light was found to be at least 30 times more efficient than yellow light in causing dysfunction of the blood-retinal barrier. The most efficient wavelength was 418 nm, corresponding with the absorption spectrum of cytochrome c oxidase. Melanin seemed to play no role. The presence or absence of melanin in the RPE appeared to have no influence on the threshold energy.

Purpose: To study the familial occurrence of central serous retinopathy (CSR)., Methods: We pooled data from eight eye clinics in Western Europe., Results: We collected 11 families that each had two to four members with CSR. In 10 families siblings and in one family a mother and son were affected. Sixty percent of the patients were male and 40% female. CSR was found in 55 (92%) of 60 eyes, 44 (80%) showing a chronic course. In 25 patients (83%) both eyes were affected. Most recent visual acuity was 0.5 or less in 17 (39%) and 0.2 or less in 8 (18%) of the eyes with chronic CSR., Conclusion: Our findings of familial occurrence and a chronic disorder that is progressive, diffuse, and bilateral suggest an inborn disposition to develop a clinically manifest disintegration of the retinal pigment epithelium in adulthood.

The effect of hyperthermia, 50 degrees C applied for 5 min, on the development of lesions in hamster Greene melanomas was investigated. Hyperthermia was induced by a laser that produced radiation at 780-880 nm. Hamster melanomas were also examined after arrest of the blood circulation to differentiate between heat-induced lesions and those caused by ischaemia due to vascular occlusion. Tumours were removed 5 and 30 min and 1, 3, 6 and 24 h after thermotherapy. The cytotoxic effects of heat and ischaemia were examined by light and electron microscopy. Hyperchromatic nuclear staining, the first hyperthermia-induced lesion, was detected in the superficial layers of the tumour 5 min after heat treatment. The lesions had progressed to severe pyknosis and extended into deeper layers of the tumour 1 h after hyperthermia. At 24 h necrosis was observed at a depth of 6 mm. The hyperthermia-induced lesions differed markedly from the ischaemia-induced lesions, in that the latter showed early mitochondrial damage but nuclear pyknosis did not become manifest until 3 h after arrest of the blood circulation.

Objective: To determine safety and efficacy of transpupillary thermotherapy (TTT) as a new treatment for choroidal melanoma., Methods and Patients: To perform TTT, diode laser energy at 810 nm was used with a beam diameter of 1.5 to 4.5 mm for a 1-minute exposure. All 12 patients had choroidal melanoma. Six had had insufficient response to ruthenium 106 (106Ru) brachytherapy. Three patients with tumors more than 5 mm in height were treated simultaneously with 106Ru and TTT. Three patients with juxtapapillary or macular tumors were treated by TTT only., Results: All but one tumor exhibited a reduction of tumor height in a follow-up period of 3 to 14 months. Side effects were minimal. Severe visual loss occurred in two patients due to radiation retinopathy, in two patients whose foveas were included in the TTT area, and in one patient resulting from a serous retinal detachment that extended over the posterior pole., Conclusions: Treatment with TTT may be useful as a complementary modality to brachytherapy. A longer follow-up period is required for final evaluation.

Secretory immunoglobulin A, lactoferrin, lysozyme and tear specific pre-albumin were analyzed in stimulated tear fluid of 25 diabetic patients without retinopathy and in 29 diabetic patients with (pre) proliferative retinopathy using high performance liquid chromatography. Results were compared to those obtained in 26 healthy controls to determine the effect of diabetes mellitus on the exocrine function of the main lacrimal gland. Sodium dodecyl sulfate polyacrylamide gel electrophoresis onto minigels was performed on 20 tear samples for verification of high performance liquid chromatography fractions recorded. The mean total protein values in tear fluid (Bradford assay) of diabetics without retinopathy, with retinopathy and healthy controls did not differ significantly (mean in mg/ml +/- SD: 6.4 +/- 2.2, 5.9 +/- 2.0 and 5.7 +/- 1.7, respectively; Mann-Whitney; p > 0.02). High performance liquid chromatography showed an increased secretory immunoglobulin A and decreased peak 5 OD280 (+56% and -38%, respectively; p < 0.02) in patients without retinopathy, whereas in patients with retinopathy lysozyme was increased (+27%; p < 0.01) and tear specific pre-albumin and peak 5 OD280 decreased (-24% and -42%, respectively; p < 0.04), when compared to healthy controls. These inconsistent differences do not uniformly suggest an exocrine dysfunction of the main lacrimal gland in diabetic patients.

A prospective clinical study to assess the value of immunoscintigraphy with a monoclonal antibody (MoAb) against high molecular weight melanoma associated antigen (225.28S) was performed in 43 patients with choroidal melanoma; in six patients with a lesion suspected of being choroidal melanoma, and in seven patients with a benign lesion simulating a choroidal melanoma. The results of immunoscintigraphy in choroidal melanoma were compared with results of conventional diagnostic modalities like ultrasonography and fluorescein angiography. Planar scintigraphy showed a detection rate of 49% which is comparable with other studies. The detection with scintigraphy was correlated to the size of the choroidal melanoma. The use of single photon computed tomography did not increase the sensitivity of immunoscintigraphy. Ultrasonography yielded a correct diagnosis in 37 of 42 melanomas (88%). With fluorescein angiography a correct diagnosis was obtained in 11 of 30 melanomas (36.6%). The value of immunoscintigraphy with MoAb 225.28S in small choroidal melanomas is limited; its reliability increases in large tumours. Immunohistochemistry with MoAb 225.28S showed antigen expression in 95% of the stained tissue specimens of choroidal melanoma.

The purpose of this study was to determine the role of epithelial melanin in blue light phototoxicity of the retina. The first manifestation of the phototoxicity has been shown to be a breakdown of the blood-retinal barrier at the retinal pigment epithelium. The blood-retinal barrier function of six New Zealand albino rabbits was compared to that of four pigmented chinchilla rabbits after exposure to broad-band blue light (400-520 nm). Additionally, the spectral sensitivity of blood-retinal barrier dysfunction was determined by exposing 15 New Zealand albino rabbits to narrow-band blue light with peak intensity at lambda = 408 nm, 418 nm, 439 nm, 455 nm and 485 nm (bandwidth: 11.7-13.5 nm). The blood-retinal barrier function was evaluated with vitreous fluorophotometry. Ultrastructural changes and permeability of the retinal pigment epithelium for horseradish peroxidase were evaluated in the albino rabbits with electron microscopy. Exposure to broad-band blue light up to 832 J cm-2 demonstrated the blood-retinal barrier of albino and pigmented rabbits to be equally sensitive. Electron microscopy of albino rabbits exposed to above-threshold energy demonstrated an increase of inclusion bodies in the retinal pigment epithelium and vacuolation of the cytoplasm. Transcellular passage of intra-arterially administered horseradish peroxidase through the pigment epithelium into the subretinal space was seen. The narrow-band exposures demonstrated that light of 439 nm was more effective than the light of other wavelengths in inducing barrier dysfunction in albino rabbits. This implies that chromophores absorbing at 439 +/- 6 nm were responsible for the phototoxicity in albino rabbits. The results indicate that melanin does not have a damaging nor a protective role in phototoxicity since (1) the presence of melanin is not essential for blue-light-induced photochemical damage to the blood-retinal barrier at the retinal pigment epithelium, and (2) protection from this sort of damage is not greater in melanin containing epithelia than in non-melanin containing epithelia.

The follow-up results are presented for the radiotherapeutic treatment of 49 patients with uveal eye melanoma using ruthenium-106 (106Ru/106Rh) applicators. Graded doses were applied and the degree of regression was found to be correlated with the dose at the top of the tumour. Complete regression is found in 66% of the patients treated with a top dose above 150 Gy, in which case the initial tumour prominence diminishes in about three years to a stable disease or to a flat scar. At this dose a marginal increase in complications was observed as compared with lower dose groups. Useful vision could be preserved in 75% of the eyes.

To specify the spectral sensitivity of the retinal pigment epithelium (RPE) for blue light damage, pigmented rabbits were exposed to light of 408, 418, 439, 455, 485, and 500 nm (half-peak bandwidth approximately 12 nm). The range of radiant exposure was 15-275 J cm-2 (1.7-19 mW cm-2 for 0.5-5 h). Vitreous fluorophotometry was used to functionally evaluate the blood-retinal barrier at the RPE in vivo, and electron microscopy to visualize RPE ultrastructure in vitro. A significant increase in permeability of the blood-retinal barrier was seen only after exposure to light of 418 nm. Radiant exposure at threshold for permeability increase was 18 J cm-2. Electron microscopy of the RPE demonstrated dispersion and clumping of melanin granules. The results suggest that the RPE is most sensitive to light in the range 412-425 nm, possibly due to damage-mediating chromophores such as cytochrome c oxidase and lipofuscin.

Clinical identification of tapioca melanoma of the iris is important because its medical treatment may differ from that of other malignant iris melanomas. The characteristic iris nodules must be differentiated from granulomatous uveitis, metastases, and Lisch nodules (neurofibromatosis). We will discuss the anterior segment findings, secondary glaucoma, and fluorescein iris angiographic and histopathologic data from two patients, one with a single nodular type and one with a seeding type of tapioca melanoma of the iris.

Exposure to low-intensity white light can induce dysfunction of the blood-retinal barrier (BRB) at the retinal pigment epithelium (RPE). To determine whether the shorter wavelengths white light are responsible for this dysfunction, rabbit retinas were exposed to blue light (400-520 nm) or yellow light (510-740 nm). The permeability of the BRB, a parameter for the integrity of the barrier, was quantified with vitreous fluorophotometry. Morphologically, the barrier at the RPE was visualized on light and electron microscopy using horseradish peroxidase (HRP) as a tracer. Seventeen pigmented rabbits were exposed to blue light and 11 were exposed to yellow light. Vitreous fluorescein leakage increased with the exposure energy according to a power function (correlation coefficient > 0.79). The threshold energy for an increase in BRB permeability was 50 J/cm2 (0.014 W/cm2 for 1 hr) after blue and 1600 J/cm2 after yellow light. HRP tracing demonstrated that after blue light exposure, a significant fluorescein leakage on fluorophotometry corresponded to the presence of HRP in the RPE cells and in the subretinal space. After yellow light exposures of < 3700 J/cm2 and in rabbits with no significant fluorescein leakage, the HRP was limited to the choroidal capillaries and Bruch's membrane. These results demonstrate that the blue component of white light causes dysfunction of the BRB at the RPE 30 times more effectively than the longer wavelength fraction of white light. As a result, a blue light blocking filter should be used in ocular surgery on humans when an operating microscope is being used (light power 0.1-0.9 W/cm2).

We investigated 111 members of a five generation family with X linked cone dystrophy. The patients showed the characteristic picture of cone dystrophy. Routine ophthalmological examination of the carrier women showed no abnormalities. However, with detailed colour vision testing we were able to detect 87% of all obligate carriers.

A dominant cone dystrophy spanning seven generations was found in a pedigree from the Netherlands. The onset of the decline of visual acuity started after the age of 20, while a near complete absence of blue cone function (a so-called tritan defect) already existed before the presence of any ophthalmological abnormalities.

The purpose of this study was to pinpoint the site of blood-retina barrier disruption after white light exposure and determine the course of barrier repair. The retinas of 25 anaesthetized pigmented rabbits were exposed for 1 hr to the light of a xenon arc lamp filtered to eliminate ultraviolet and infrared light. The light intensities selected were near the threshold intensity causing visible retinal lesions in order to evaluate the function of the blood-retina barrier (BRB) in this range. Functional assessment of the BRB was made with vitreous fluorophotometry (VF), and electron microscopy (EM) after intra-arterial administration of horseradish peroxidase (HRP) as tracer. In 11 of the 14 rabbits exposed to threshold intensity (90-110 mW cm-2; retinal field of illumination, 0.64 cm2), a breakdown of the BRB was demonstrated by a 2-40-fold increase in the permeability of the BRB for fluorescein and by transcellular passage of HRP through the retina pigment epithelium (RPE). All 11 rabbits developed oedematous fundus lesions. Within a week, pigmentary alterations of the fundus were seen on ophthalmoscopy, while the BRB permeability for fluorescein and HRP had returned to normal. EM of the retina showed slight swelling of RPE during the period of increased permeability but no alterations of the neuroretina. After functional barrier repair, the RPE cells demonstrated irregularity of the melanin pigment alignment and some loss of the monocellular arrangement. In six rabbits exposed to subthreshold light intensity (65-89 mW cm-2) no fundus lesion developed and EM evaluation of the BRB was normal.2+ remains altered.

The metabolic disorder in diabetics often results in progressive retinopathy with severe visual impairment. Changes in metabolism can influence corneal autofluorescence. This has led to speculation that diabetic retinopathy might be associated with changes in corneal autofluorescence. Corneal autofluorescence of both eyes was determined by fluorophotometry in 94 insulin-dependent diabetes mellitus patients and in 46 healthy controls to evaluate its correlation with diabetic retinopathy. The modified Airlie House classification was used for grading diabetic retinopathy: (1) no or negligible retinopathy; (2) minimal background retinopathy; (3) background retinopathy; and (4) (pre-) proliferative retinopathy. The corneal autofluorescence values of grade 1 retinopathy patients did not differ significantly from those of the healthy controls (mean +/- standard deviation in ng equivalent fluorescein/ml: 11.6 +/- 3.0 and 11.4 +/- 2.8, respectively; P = 0.8). The means of grade 2, 3, and 4 retinopathy patients (mean +/- standard deviation in ngEq fluorescein/ml: 16.2 +/- 4.4, 16.7 +/- 4.3, 20.9 +/- 5.4, respectively) were significantly higher than the means of grade 1 patients and healthy controls (P less than 0.004). The mean values of patients with grade 4 were significantly higher than those of patients with grades 2 and 3 (P less than 0.01). The sensitivity and specificity of corneal autofluorescence as a screening test for diabetic retinopathy were 80% and 76%, respectively; the positive predictive value for the presence of retinopathy was 90%. The values for screening on (pre-) proliferative diabetic retinopathy were 68%, 72%, and 58%, respectively. These data show corneal autofluorescence to be an adequate indicator of diabetic retinopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to assess the differentiation of histologically different types of choroidal melanomas by means of clinical and quantitative acoustic/texture parameters of echograms. Clinical parameters were graded by morphological, kinetic and quantitative statements about the A- and B-mode echograms by a skilled diagnostician. Acoustic/texture parameters were obtained by processing and analysing radio frequency, AM-demodulated and FM-demodulated echograms. The latter data were preprocessed to remove influence induced by beam diffraction and focusing. The best set of four clinical echographic parameters enabled a retrospective classification of spindle type melanomas vs. mixed+epithelioid type melanomas with an accuracy of 77% (area under the ROC-curve of 86%). The discriminant analysis performed with the best four acoustic/texture parameters (n = 30) yielded a sensitivity of 89%, a specificity of 92%, and an area under the ROC-curve which corresponds to a probability of correct classification of 96.6%. When using these data prospectively to classify tumours of unknown cell type (n = 21), this classification could be performed in 86% of cases.

We studied the destructive effect of hyperthermia at sub-photocoagulation level of 45-60 degrees C on melanomas. Optimal conditions for spreading of heat into tissue are a wavelength of 700-900 nm, a temperature of 45-60 degrees C, an exposure time of 1 minute or more, and a beam diameter of several millimeters. In hamsters with subcutaneous melanomas we obtained a tumour necrosis of 6 mm depth at 60 degrees C and one minute exposure time. We performed transpupillary thermotherapy (TTT) with a diode laser at 810 nm in patients with choroidal melanomas prior to enucleation. Treatment is based on the fortunate situation that irradiation at this wavelength combines optimal tissue penetration with a low absorption by clear ocular media of 5% or less. In 3 TTT-treated eyes histopathology showed a depth of necrosis of 0.9, 3.4, and 3.9 mm. TTT may become a new useful treatment modality for choroidal melanoma but its ultimate value has yet to be assessed.

The tear turnover was determined by fluorophotometry in 25 insulin-dependent diabetes mellitus (IDDM) patients without retinopathy and 29 IDDM patients with (pre-)proliferative retinopathy. The results were compared with those in 34 healthy controls, to investigate the lacrimal gland function in diabetic patients. The tear turnover was calculated from the decay of the relative tear fluorescein concentration values measured after instillation of one microliters of fluorescein. The tear turnover values in both patient groups did not correlate significantly with age or diabetes duration (linear correlation coefficients: r less than 0.3). The tear turnover values in patients both without retinoplathy and with (pre-)proliferative retinopathy did not differ significantly from those in healthy controls (mean +/- SD in %/min: 13.7 +/- 4.5, 14.7 +/- 5.8 and 15.5 +/- 5.1, respectively; P greater than 0.16). The tear turnover was significantly decreased in eyes having a BUT shorter than 10 seconds compared with eyes having a BUT longer than 10 seconds (P less than 0.05). The tear turnover values correlated significantly with the HbA1c and Schirmer-test values in patients with (pre-)proliferative retinopathy (r = 0.7 and r = 0.4, respectively; P less than 0.02) and with the blood glucose values in patients without retinopathy (r = 0.41, P = 0.04). Since the tear turnover was not significantly decreased in IDDM patients in comparison with healthy controls the corneal disorders which are more frequently seen in these patients than in a healthy population may not be attributed to a decrease in tear production.

The results of ophthalmological and colour vision studies are reported on 13 patients from a family with a dominant cone dystrophy spanning seven generations. The onset of visual deterioration occurred in the third or fourth decade. In the early stages of the disease, when visual acuity is still close to normal, a severe defect in the blue sensitivity is already present, as measured by spectral sensitivity curves and other tests suitable for the detection of tritan defects. In our opinion this condition represents a distinct entity with autosomal dominant inheritance.

We describe a new syndrome with autosomal dominant transmission whose most striking feature is vascular retinopathy. The retinopathy is often associated with migraine, Raynaud's phenomenon and mental changes, mainly forgetfulness, aggression and depression. To define this syndrome we collected medical data on 110 family members. General ophthalmological examination and fluorescein angiography were performed in 61 persons. The retinopathy, as diagnosed in 22 persons, is characterized by central and peripheral microangiopathy, areas of capillary non-perfusion, haemorrhages, cotton wool spots and, in a more advanced stage, occlusion of large retinal vessels, which can induce a neovascular response. A vascular occlusive disorder may be the common aetiological factor of the various manifestation of this syndrome.

The technique of near-infrared irradiation to obtain tumour necrosis in experimental pigmented melanomas is described. The xenon arch photocoagulator was modified and adapted for hyperthermia treatment. The adaptations included: filtering the light and changing the electronics, the aiming beam and the diameter of the beam.

A summary is given of data on the clinical experience with the anti-melanoma antibody 225.28S in ophthalmology and the tissue expression of the high molecular weight-melanoma associated antigen in choroidal melanoma. Results are discussed in relation to other detection methods for ocular melanoma currently employed by the ophthalmologist.

The aim of this study was to assess the differentiation of histologically different types of choroidal melanomas by means of clinical and quantitative acoustic/texture parameters of echograms. Clinical parameters were graded by morphological, kinetic and quantitative statements about the A- and B-mode echograms by a skilled diagnostician. Acoustic/texture parameters were obtained by processing and analysing radio frequency, AM-demodulated and FM-demodulated echograms. The data were preprocessed to remove influences induced by beam diffraction and focusing. The correlations between the clinical parameters were lower than 0.5 but significant in a few cases. The best set of four clinical echographic parameters enabled a retrospective classification of spindle type melanomas vs. mixed + epithelioid type melanomas with an accuracy of 77% (area under the ROC-curve of 86%). These figures do not enable, however, a prospective diagnosis. The correlations of the clinical parameters with the acoustic/texture parameters were investigated. The mutual correlations between the latter parameters were also assessed, the most significant (0.70) being between the speckle size and the slope of the linearized backscattering spectrum. The discriminant analysis performed with the best four acoustic/texture parameters (n = 30) yielded a sensitivity of 89%, a specificity of 92% and an area under the ROC-curve corresponding to a probability of correct classification of 96.6%. When using these data prospectively to classify tumours of unknown cell type (n = 21), this classification could be performed in 86% of cases.

Rabbit eyes were enucleated and frozen in liquid nitrogen. The vitreous was removed and analyzed for prostaglandin E2 (PGE2). The mean level (+/- SEM) of PGE2 in the anterior as well as in the posterior vitreous was 0.09 +/- 0.016 ng/ml (n = 12 rabbits). Animals pretreated with indomethacin 15 min before death, in order to prevent the formation of prostaglandin during enucleation, showed in both the anterior and posterior vitreous mean PGE2 levels of 0.04 +/- 0.008 ng/ml (n = 12) which were significantly lower. Ocular trauma such as paracentesis of the anterior chamber, indentation of the sclera or laser photocoagulation in the fundus 1 h before death of the animals did not increase the concentration of PGE2 in the vitreous humor. There is no evidence either for local release of PGE2 from tissues in the fundus of the eye or for diffusion of PGE2 from the anterior chamber into the vitreous humor.

We describe a family with an as yet undescribed form of X-linked progressive cone dystrophy in a five-generation pedigree, from which we report here the results of 17 male patients and 31 obligate and 13 possible female carriers. The affected males showed the characteristic picture of cone dystrophy. Foveal cone photopigment density was impaired (judged from anomaloscope settings and foveal densitometry), even at an early stage of the disease. The carriers showed no fundus abnormalities, except occasional changes due to myopia. The anomaloscope demonstrated mild pseudoprotanomaly in 27 of 31 obligate carriers and in six of 13 possible carriers. Foveal densitometry findings performed in 11 carriers always agreed with the anomaloscope findings. We conclude that the findings of pseudoprotanomaly and abnormal density differences in females of this family were the only ocular abnormalities and thus are indicative of the carrier state.

Five families with the dysplastic nevus syndrome, in each of which one member had ocular melanoma, are reported. These five families were examined within a 3-year period in one medical center. To date only five other families with such a combination have been reported. We suggest a causal relation between ocular melanoma and the familial dysplastic nevus syndrome.

We describe a new hereditary syndrome with an autosomal dominant mode of inheritance, with vascular retinopathy, migraine and Raynaud's phenomenon as the most striking features. The retinopathy is characterized by tortuosity and variable caliber of the retinal vessels, haemorrhages, telangiectases and both central and peripheral vascular occlusions, leading finally to a proliferative retinopathy.

At first it was verified that the major part of the fluorophotometer signal obtained when measuring corneal autofluorescence originated from fluorescence and not from scatter of excitation light at the corneal surface. The minimum percentage of the signal which can be attributed to fluorescence was determined using a fluorescence blocking filter placed in the excitation and fluorescence light path, respectively. The minimum percentages in two healthy controls, two diabetic patients and two patients after penetrating keratoplasty ranged from 75% to 93% (mean 84%). Then the corneal autofluorescence was determined in 22 healthy controls, 18 non-insulin-dependent diabetes mellitus (NIDDM). 23 insulin-dependent diabetes mellitus (IDDM) and 21 penetrating keratoplasty patients in order to detect a possible difference in autofluorescence as a result of diabetes or penetrating keratoplasty. The means of the corneal peak autofluorescence values in the NIDDM, IDDM and penetrating keratoplasty patient groups were significantly higher than that in the healthy control group (mean values in ng equivalent fluorescin ml-1: 18.0 +/- 4.2 S.D., 20.6 +/- 5.1 S.D., 17.9 +/- 5.5 S.D. and 13.7 +/- 3.7 S.D., respectively; P less than 0.01). The mean values in the NIDDM and IDDM patients did not differ significantly (P = 0.09). The autofluorescence values were independent of age in all four groups (linear correlation coefficient: r less than 0.47). The corneal peak autofluorescence was linearly correlated with the diabetes duration in the NIDDM and IDDM patients [r = 0.6, P = 0.02; increase: 0.36 ng equiv. fluorescein ml-1 yr diabetes-1]. Our results show that corneal autofluorescence is an easily obtained parameter which can be of assistance in evaluating corneal metabolism.

A remarkable case of a scleral melting reaction in association with conjunctival rhinosporidiosis is presented and its surgical treatment with a scleral graft described.

Radioimmunoscintigraphy with monoclonal antibodies (MoAbs) to melanoma associated antigens is a new technique that can be used as an additional test to detect ocular melanomas in clinically difficult cases. Immunoscintigraphy with 99mtechnetium-labelled monoclonal antibody fragments of MoAb 225.28S in 14 patients with melanoma yielded a positive image in only six cases (43%). The expression of high molecular weight melanoma-associated antigen (HMW-MAA) was immunohistochemically assessed in melanoma tissue obtained from these 14 patients to find a possible correlation between the results of immunoscintigraphy and expression of the HMW-MAA. The melanoma tissues were immunohistochemically stained by a sensitive immunoperoxidase procedure with three different monoclonal antibodies to the HMW-MAA: 225.28S, Mel-14, and AMF-6. Expression of the antigen detected by MoAb 225.28S was found in 13 of 14 melanomas; the MoAbMel-14 reacted positively with all 14 melanomas; staining with MoAb AMF-6 was achieved in 10 melanomas. No correlation was found between the immunohistochemical staining results, the conventional histopathological findings, and the immunoscintigraphic results. The immunohistochemical staining results suggest that anti-HMW-MAA MoAbs bind to the melanoma tissue and are therefore potentially suitable for immunoscintigraphy.