HbA1c variability is associated with an increased risk of retinopathy requiring laser treatment in type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment. METHODS: The effect of HbA1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n = 1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n = 1,346). The ratio of intrapersonal SD and mean of serially measured HbA1c was considered an estimate of HbA1c variability. RESULTS: A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2 ± 2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA1c variability and 10% (95% CI 7, 12) in the lowest quartile (p < 0.001, Gray's test) with a corresponding HR of 1.6 (95% CI 1.1, 2.5; p = 0.02) adjusted for renal status, diabetes duration, mean HbA1c, blood pressure, sex and number of HbA1c measurements. In a subcohort of 1,346 patients, 434 patients had proliferative diabetic retinopathy (PDR). Patients in the highest quartile of HbA1c variability had an increased risk of PDR compared with the lowest quartile (HR 1.7 [95% CI 1.3, 2.2]; p < 0.001]). CONCLUSIONS/INTERPRETATION: HbA1c variability was associated with an increased cumulative incidence and risk of retinopathy requiring laser treatment in type 1 diabetes.

Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.

BACKGROUND: Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. METHODS: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50-75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study-was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. FINDINGS: Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3.4%] patients on fenofibrate vs 238 [4.9%] on placebo; hazard ratio [HR] 0.69, 95% CI 0.56-0.84; p=0.0002; absolute risk reduction 1.5% [0.7-2.3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9.6%] patients on fenofibrate vs 57 [12.3%] on placebo; p=0.19) or in the subset of patients without pre-existing retinopathy (43 [11.4%] vs 43 [11.7%]; p=0.87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3.1%] patients vs 14 [14.6%]; p=0.004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0.66, 95% CI 0.47-0.94; p=0.022). INTERPRETATION: Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.

Family histories of Type II diabetes and hypertension predict intima-media thickness in patients with Type I diabetes.

AIMS/HYPOTHESIS: Hyperglycaemia predicts microvascular complications but data on macrovascular disease are limited. We searched for predictors of carotid artery intima-media thickness in young adults with Type I (insulin-dependent) diabetes mellitus. METHODS: A total of 71 children (F/M = 34/37) were followed after their diagnosis until they reached 32 +/- 1 years of age, when duration of diabetes averaged 22 +/- 1 years. Cardiovascular risk markers [lipids, blood pressure, smoking, urinary albumin excretion rate, lifetime glycaemic exposure (A(1c) months), exercise habits, alcohol consumption, family history] were evaluated at age 21 +/- 1 for the baseline examination and at age 32 +/- 1 years for the follow-up examination years. During follow-up, intima-media thickness of common and internal carotid arteries and the carotid bulb were quantitated using a high-resolution B-mode ultrasound. RESULTS: In univariate analysis, age, BMI, blood pressure, lifetime glycaemic exposure, a positive family history of Type II (non-insulin-dependent) diabetes mellitus, hypertension and cardiovascular disease were predictors of carotid intima-media thickness. In multivariate analysis, a positive family history of Type II diabetes predicted maximal ( p< 0.05) and common ( p< 0.005) carotid artery intima-media thickness, family history of hypertension predicted increases in maximal ( p< 0.04), and far wall ( p< 0.006) carotid artery intima-media thickness, and lifetime glycaemic exposure was an independent predictor of increased carotid bulb thickness ( p< 0.03). CONCLUSION/INTERPRETATION: Positive family histories of Type II diabetes and hypertension are independent predictors of carotid intima-media thickness in patients with Type I diabetes, and could therefore predispose these patients to atherosclerosis

Exudative retinal detachment from malignant uveal melanoma: predictors and prognostic significance.

PURPOSE: To determine independent predictors of exudative retinal detachment (RD) in eyes with uveal melanoma and the significance of RD in melanoma-specific survival. METHODS: The extent of exudative RD was recorded retrospectively in a population-based cohort of 167 consecutive patients with eyes enucleated from 1972 through 1981 because of choroidal and ciliary body melanoma, representing all melanomas treated during that period. Histopathologic features including microvascular loops and networks, microvascular density (MVD), and tumor-infiltrating macrophages were determined. Clinical and histologic predictors of RD were modeled by multiple logistic regression with a split-sample, cross-validation design. Survival was assessed by Kaplan-Meier analysis and adjusted for the effect of competing predictors by Cox proportional hazards regression. RESULTS: Of 142 (85%) eyes with adequate data, 25% had no RD, 16% had subretinal fluid around the tumor, 43% had clinical RD in one to two quadrants, and 16% had RD in three to four quadrants. The RD was more extensive if the tumor was large (P < 0.0001) and had microvascular loops and networks (P = 0.0094) and less extensive if it involved ciliary body (P = 0.011). High MVD (P = 0.054) and ruptured Bruch's membrane (P = 0.065) tended to be associated with RD. Multiple logistic regression showed largest basal diameter (odds ratio [OR] 1.43 for each 1-mm change, P < 0.0001), microvascular loops and networks (OR 1.95 for each category change, P = 0.0095), and ciliary body involvement (OR 0.20, P = 0.0039) to be independently associated with RD; ruptured Bruch's membrane (P = 0.96) and MVD (P = 0.87) were not associated. Clinical RD predicted poor survival (0.59 vs. 0.37 at 20 years; P = 0.029) by Kaplan-Meier analysis, but not after adjusting for other prognostic factors by Cox regression (hazard ratio [HR] 1.00, P = 1.0). CONCLUSIONS: Tumor size, which may be a surrogate measure for total vascular content and decompensation of choriocapillaris and retinal pigment epithelium, is a strong predictor of exudative RD. Microvascular loops and networks are likewise associated with exudative RD. Exudative RD is not associated with survival after adjusting for tumor size and microvascular loops and networks.

Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma.

PURPOSE: To investigate the hypothesis that tumor-infiltrating macrophages contribute to prognosis of uveal melanoma and to study their association with tumor characteristics, especially microvessels. METHODS: This was a retrospective, population-based cohort study of 167 consecutive patients who had had an eye with choroidal and ciliary body melanoma removed between 1972 and 1981. Macrophages were identified with mAb PG-M1 to the CD68 epitope, and their number and morphologic type were recorded. Kaplan-Meier and Cox regression analyses of melanoma-specific survival were performed. RESULTS: CD68-positive macrophages could be assessed in 139 (83%) of the 167 melanomas. Their number was moderate to high in 115 (83%) of the 139 tumors, and their morphology ranged from dendritic to round. A high number of macrophages was associated with presence of epithelioid cells (P = 0.025), heavy pigmentation (P = 0.001), and high microvascular density (P = 0.001). The 10-year melanoma-specific mortality rate increased with higher numbers of macrophages (0.10 for low versus 0.57 for high numbers, P = 0.0012). The morphologic type of infiltrating macrophages was not associated with mortality. The number of macrophages was modeled by stratification, which significantly improved a Cox regression model (P < 0.001). Adjusting for the other independent indicators of metastatic death 10-year melanoma-specific mortality was 0.17 for low versus 0.45 for high numbers of macrophages. CONCLUSIONS: The number of tumor-infiltrating CD68-positive macrophages contributes to prognosis and associates with cell type and microvascular density, which merits a further analysis of the biological role of these cells in uveal melanoma.

Interferon alpha-2a therapy in 18 hemangioblastomas.

Multiple hemangioblastomas (HBs) of the central nervous system (CNS) and retina are associated with von Hippel-Lindau disease (VHL) and also predispose individuals to renal cell carcinomas and visceral cysts. In VHL, microsurgery or radiosurgery cannot prevent new HBs from arising in the CNS or coagulation of retinal HBs. Multiple but thus far asymptomatic HBs pose a therapeutic problem. IFN-alpha-2a has antiangiogenic activity with an especially favorable effect on life-threatening hemangiomas of the liver in children. This is the first study to assess the efficacy of IFN-alpha-2a in treatment of asymptomatic HBs of the CNS and retina. Four patients (three with VHL) with a combined total of 15 HBs of the CNS, 3 HBs of the retina, and 14 renal and 2 pancreatic cysts were treated with s.c. IFN-alpha-2a for 12 months at 3 x 10(6) IU, 3 times/week. Baseline workup consisted of detailed neurological, ophthalmological, and radiological examinations. Follow-up studies at 3, 13, and 21 months were used to monitor the response. No de novo HBs were detected during the therapy, but one appeared 9 months after cessation of IFN-alpha-2a therapy. HBs of the CNS did not shrink markedly during the therapy. IFN-alpha-2a may decrease blood flow in HBs as suggested by shrinkage and diminished leakage of two retinal HBs. However, the therapy did not prevent visceral cysts from growing. The systemic response was also monitored by measurement of serum levels of vascular endothelial growth factor and erythropoietin, which remained essentially unchanged during the treatment. No serious side effects were recorded.

Retinal breaks before and after neodymium:YAG posterior capsulotomy.

PURPOSE: To determine the frequency of asymptomatic retinal breaks before and after neodymium:YAG (Nd:YAG) laser posterior capsulotomy. SETTING: Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland. METHODS: Of 350 consecutive patients referred for their first laser Nd:YAG posterior capsulotomy, 235 eligible eyes were enrolled and 220 eyes completed the study. A vitreoretinal surgeon looked for retinal breaks using binocular indirect ophthalmoscopy with scleral indentation. The eyes were examined 1 week before and 1 hour and 1 month after the posterior capsulotomy. The number, type, and location of retinal breaks were recorded. RESULTS: The median age of eligible patients who did not participate in the study was higher than that of enrolled patients (79.6 versus 74.4 years; P =.0005). The mean axial length, median time from cataract surgery, and the course of cataract surgery were comparable in both groups. Before the posterior capsulotomy, an untreated retinal break was diagnosed in 4 of the 235 eyes (1.7%; 95% confidence interval [CI] 0 to 4) scheduled for surgery and an undiagnosed retinal detachment was present in 2 additional eyes (0.9%; 95% CI 0 to 3). An asymptomatic retinal break was also present in 4 fellow eyes (1.7%, 95% CI 0 to 4). No new breaks developed during Nd:YAG posterior capsulotomy using a median total energy of 51 mJ (range 10 to 901 mJ) and a median number of 22 applications (range 4 to 341 applications) and resulting in an opening with a median largest diameter of 3.4 mm (range 2.0 to 4.6 mm). In 1 treated eye (0.4%; 95% CI 0 to 2), a new retinal break had developed by 1 month postoperatively. CONCLUSIONS: The observed 2.1% frequency of asymptomatic retinal breaks that had escaped the attention of the referring ophthalmologist or had developed by 1 month after Nd:YAG posterior capsulotomy can be contrasted with the 0.5% to 2.0% frequency of retinal detachment reported in the literature. However, it is not known which proportion of such asymptomatic breaks, if any, will progress to detachment after Nd:YAG laser posterior capsulotomy.

Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression before and after treatment.

OBJECTIVE: To obtain estimates of growth rate of metastatic uveal melanoma to infer appropriate follow-up programs and to assess the impact of current chemoimmunotherapy regimens. DESIGN: Retrospective case series. PARTICIPANTS: Of 70 consecutive patients diagnosed with metastatic uveal melanoma from 1986 through 1998, 37 patients who attended regular follow-up and had measurable metastases were eligible for this study. METHODS: Tumor doubling time (DT) was calculated by the Schwartz formula using three presumed sizes of metastasis at last negative follow-up. DT was compared according to tumor characteristics, and time of micrometastasis was estimated. MAIN OUTCOME MEASURES: Doubling time of untreated and treated metastases. RESULTS: Doubling time of untreated metastases ranged from 34 to 220 days (median, 63 days). Regardless of the presumed size of metastasis at last screening, two thirds of the metastases had a DT between 30 and 80 days. No significant correlation between DT and the observed disease-free interval was detected. Assuming constant growth rate, most metastases had predictably initiated within 5 years before primary treatment. Mean DT during active treatment of metastases in 18 patients who did not show an objective response ranged from 25 to 2619 days (median, 255 days). CONCLUSIONS: Based on the estimated growth rates, a rational follow-up interval to detect metastatic uveal melanoma would be 4 to 6 months. Primary uveal melanomas that develop clinically detectable metastasis after conservative therapy may micrometastasize several years before treatment. These estimates are rough and must be confirmed by prospective studies. Current chemoimmunotherapy regimens slow down the growth rate of metastases even if objective response is not obtained.

Hemangioblastomas of the retina: impact of von Hippel-Lindau disease.

PURPOSE: To assess the prevalence of von Hippel-Lindau (VHL) disease and prognosis of vision in patients with retinal hemangioblastomas (HBs). METHODS: Thirty-six consecutive patients with retinal HBs were treated at Helsinki University Hospital between 1974 and 1998. Detailed neurologic, ophthalmologic, and radiologic examinations; pedigree; mutation analyses; and collection of all relevant clinical, imaging, operative, and autopsy data were performed to identify VHL. RESULTS: The median follow-up time was 10 years. No patient was lost to follow-up. There were three patient groups: 1) 11 patients with clinically definite VHL; 2) 10 patients with clinically suspected VHL with more than one retinal HB (5/10) or visceral cysts (5/10), but with no family history, no detected germ-line mutations, and no VHL-related neoplasms; and 3) 15 patients without VHL with a single retinal HB but no other data suggestive of VHL. In the 11 patients with definite VHL, retinal HBs were detected at a median age of 27 years versus 40 years in the 15 non-VHL patients, and 21 of the 22 eyes were affected. Two VHL patients were totally blind at the end of follow-up compared with one legally blind patient with suspected VHL, but none of the non-VHL patients was blind. The clinical appearance of HBs did not differ among the patient groups. CONCLUSIONS: The prevalence of VHL among patients with retinal HBs was 30% to 58% (11-21 of 36). Visual prognosis was more favorable in non-VHL than VHL patients. All patients with retinal HB should undergo thorough VHL exclusion.

Long-term prognosis of haemangioblastoma of the CNS: impact of von Hippel-Lindau disease.

The aim was to assess the frequency of von Hippel-Lindau disease (VHL) and the long-term prognosis of VHL and non-VHL patients among 110 consecutive patients with haemangioblastoma (HB) of the CNS treated between 1953 and 1993 at one neurosurgical unit. To reveal VHL manifestations we performed a detailed clinical and radiological examination (neuraxis and abdomen) (61/110), VHL-gene mutation analysis (40/110), and collection of all available clinical, imaging, operative and autopsy data from the hospitals involved. All patients were followed-up with a median of 14 years (excluding 14 operative deaths), and no patient was lost to follow-up. Altogether 49 patients died during the follow-up. In the 14 VHL patients (13%), HB(s) of the CNS were detected at a median age of 33 years, retinal HB(s) at 39 years, and renal cell carcinoma (RCC) at 43 years. The frequency of VHL in patients operated on for HB(s) was 29% before the age of 25 years, 19% between 25 and 45 years, and only 2% after 45 years. HB patients not meeting the VHL criteria had internal organ cysts in 14%. One non-VHL patient (4%) had two adjacent HBs in the same cyst wall. The growth rates of non-VHL and VHL-related HBs were similar as indicated by the median time to recurrence and the proliferation indices (MIB-1). Recurrence of the HB in patients whose primary operation was considered radical developed in four of the 10 VHL patients at a median of 19 years, and in nine of the 74 non-VHL patients at a median of 11 years. The median length of life of all VHL and non-VHL patients was 46 and 63 years, respectively. In VHL, RCC and HBs were equal causes of death.

Microvascular density in predicting survival of patients with choroidal and ciliary body melanoma.

PURPOSE: Although malignant uveal melanoma disseminates predominantly hematogenously because of the absence of intraocular lymphatics, consensus about prognostic impact of microvascular density (MVD) has not been reached. This study was undertaken to investigate whether MVD, microvascular patterns, or both determine prognosis of uveal melanoma. METHODS: A population-based retrospective cohort study of melanoma-specific and all-cause mortality of 167 consecutive patients who had an eye enucleated because of choroidal or ciliary body melanoma from 1972 through 1981 was conducted. MVD was determined by counting tumor vessels in a masked fashion from areas of highest vessel density after immunostaining for CD34 epitope, factor VIII-related antigen (FVIII-RAg), and alpha-smooth muscle actin (SMA). Kaplan-Meier and Cox regression analyses of survival were performed. The association between MVD and tumor size and location, cell type, and microvascular patterns was assessed. RESULTS: MVD could be determined from 134 of 167 melanomas (80%). Based on globally highest count obtained with antibodies to CD34, MVD ranged from 5 to 121 vessels/0.313 mm2 (median, 40) and its association with presence of microvascular loops and networks (P = 0.0006), epithelioid cells (P = 0.028), and largest basal tumor diameter (P = 0.0029) was statistically significant. The 10-year melanoma-specific mortality increased with MVD (0.09, 0.29, 0.59, and 0.64, according to quartiles; P < 0.0001), as did all-cause mortality (P = 0.0022). Equivalent results were obtained with immunostaining for FVIII-RAg, whereas MVD obtained with antibodies to SMA was not associated with prognosis. Cox regression showed a hazard ratio of 2.45 (95% CI, 1.43-4.18) for presence of epithelioid cells, 1.11 (95% CI, 1.03-1.20) for largest basal diameter, 1.23 (95% CI, 1.06-1.43) for square root-transformed MVD, and 1.51 (95% CI, 1.09-2.10) for presence of loops and networks, all of which independently contributed to prognosis. CONCLUSIONS: The findings support the theory that both MVD and microvascular patterns contribute independently to prognosis in uveal melanoma in addition to cell type and size of the tumor.

Screening for metastatic malignant melanoma of the uvea revisited.

BACKGROUND: The purpose of the current study was to assess the value of routine imaging and liver function tests in detecting metastases from malignant melanoma of the uvea. METHODS: Forty-six consecutive patients diagnosed with metastatic uveal melanoma between 1985 and 1996 who had participated in a screening program that included annual liver function tests (LFT), chest X-ray, and abdominal ultrasonography (US) were eligible for this retrospective cohort study. Main outcome measures were the sensitivity of screening tests, presence of symptoms, recurrence free interval, and metastatic burden. RESULTS: Metastases were diagnosed in 74% of patients (95% confidence interval [95% CI], 59-86) at screening and in 26% (95% CI, 14-41) when the patient consulted a physician because of symptoms that developed before the next scheduled visit. Of all the patients, 59% (95% CI, 43-73) were asymptomatic, and 80% (95% CI, 66-91) had only hepatic metastases. The median recurrence free interval, greatest dimension of the largest metastasis, and metastatic burden of the two groups did not differ. US was diagnostic in 78% (95% CI, 64-89), at least 1 LFT test was abnormal in 70% of patients (95% CI, 54-82), and a chest X-ray was abnormal in 2% of patients (95% CI, 0-12). LFTs and US did not reveal hepatic metastases in 33% and 4% of patients, respectively. The sensitivity of individual LFTs ranged from 0.27 to 0.67, and their specificity from 0.90 to 0.96, with lactate dehydrogenase being the most sensitive LFT used. CONCLUSIONS: The authors believe that annual screening with LFTs and abdominal US will identify 59% of patients while they are still asymptomatic and that semiannual screening will detect >95% of such patients. Chest X-ray has a very low yield and is recommended only at baseline to exclude metastatic disease to the eye and if pulmonary symptoms develop.

Microvascular loops and networks as prognostic indicators in choroidal and ciliary body melanomas.

BACKGROUND: Malignant melanoma of the ciliary body and choroid of the eye is a tumor that disseminates frequently, and 50% of the diagnosed patients die within 10 years. We investigated the hypothesis that, by histopathologic analysis of the arrangement of microvessels (i.e., small blood vessels) in loops and networks, we might be able to differentiate better those patients with a favorable prognosis from those with a poor prognosis. METHODS: We conducted a population-based, retrospective cohort study of melanoma-specific and all-cause mortality for 167 consecutive patients who had an eye surgically removed because of malignant choroidal or ciliary body melanoma during the period from 1972 through 1981. Microvascular loops and networks were evaluated independently by two pathologists who were unaware of patient outcome. RESULTS: Microvascular patterns could be assessed in 134 (80%) of 167 melanoma specimens. The 10-year probability of melanoma-specific survival was worse if microvascular loops (0.45 versus 0.83; two-sided P<.0001) and networks (0.41 versus 0.72, two-sided P<.0001) were present. In multivariate Cox regression analysis of melanoma-specific survival, the hazard ratios were 1.66 (95% confidence interval [CI] = 1.19-2.30) for the presence of loops and networks as a combined three-category variable, 2.36 (95% CI = 1.37-4.05) for the presence of epithelioid cells, 1.11 (95% CI = 1.03-1.19) for the largest basal tumor diameter (evaluated as a continuous variable), and 2.14 (95% CI = 1.25-3.67) for ciliary body involvement. CONCLUSIONS: Patients with malignant uveal melanoma who have a favorable prognosis can be distinguished from those with a poor prognosis by histopathologic analysis of microvascular patterns in uveal melanoma tumor specimens.

Retinoinvasive malignant melanoma of the uvea.

AIMS: To define a retinoinvasive phenotype of uveal melanoma based on an informative case and survey of literature. METHODS: A 65-year-old woman developed a circumscribed mixed cell type melanoma of the ciliary body that was locally excised. After 6 years, secondary glaucoma evolved. Three years later a ring melanoma was diagnosed and the eye was enucleated. The histopathological material was analysed by immunohistochemistry. RESULTS: A spindle cell type ring melanoma infiltrated the iris and ciliary body diffusely, and extended through the aqueous outflow channels and iridocyclectomy flap extrasclerally. The choroid was uninvolved. Instead, tumour cells spread to the vitreous and along the ciliary epithelium, adhered to the hyaloid face and retinal surface, and extensively invaded the neuroretina, the retrobulbar optic nerve, and perineural space. They were labelled for S-100 protein, vimentin, and in the neuroretina for cytokeratins 8 and 18. No evidence of systemic disease is evident 5 years after enucleation. Three identical tumours of the iris and ciliary body that extensively infiltrated the neuroretina and retrobulbar optic nerve were identified from previous literature. CONCLUSION: Retinoinvasive melanoma is a rare but distinct phenotype of uveal melanoma, different from circumscribed and most diffuse melanomas that may erode the overlying retina and infiltrate the optic nerve that do not invade non-adjacent retina. Retinoinvasive tumours tend to evolve from a ring melanoma and they grow slowly, which may favour emergence of tumour clones able to migrate, adhere to, and invade into the neuroretina, analogous to the metastatic cascade. Frequent secondary angle closure glaucoma may promote invasion into the optic nerve.

Hemangioblastoma and oculomotor pathology.

We examined voluntary eye movements of 20 ophtalmologically screened patients (mean age of 51 years) with operated hemangioblastoma (HAB) in the cerebellum. Constant and pseudo-random saccades and pseudo-random smooth pursuit eye movement (PRPEM) test (with 4 frequency combinations) were evaluated. As controls 38 healthy subjects were examined. In the logistic regression analysis latency and accuracy of constant saccades were the best predictors for operated HAB with correct overall classification rate of 79.3%. Accuracy was worse and latency longer in operated HAB group than in control group. In pseudo-random saccades correct classification between the groups was achieved in 82.8% of all cases with latency and accuracy as predictors. In PRPEM test the best frequency combinations in differentiating operated HAB patients from controls were 0.25 and 0.425 Hz for gain, and 0.3 and 0.7 Hz for phase and gain, the correct overall classification rate being 73.3% in both cases. The characteristic changes in voluntary eye movements after removal of cerebellar hemangioblastoma seem to be insufficient timing of initiating the eye movement.

Radiation related complications after ruthenium plaque radiotherapy of uveal melanoma.

AIMS/BACKGROUND: To analyse radiation related complications and secondary enucleation after irradiation of malignant uveal melanoma with ruthenium-106 plaques. METHODS: A series of 100 consecutive eyes irradiated in 1981-91 was analysed using the life table method and the Cox proportional hazards model. The median apical and scleral tumour dose was 100 Gy (range 15-200 Gy) and 1000 Gy (range 200-1200 Gy), respectively. The median follow up time was 2.8 and 2.0 years (range 1 month to 10 years) for anterior and posterior segment complications, respectively. RESULTS: The 3 and 5 year probabilities of being without radiation cataract were 73% and 63%, without neovascular glaucoma 91% and 81%, without vitreous haemorrhage 83% and 74%, without radiation maculopathy 85% and 70%, and without radiation optic neuropathy 90% and 88%, respectively. The risk of radiation cataract was highest with large tumour size (T1 + T2 v T3, p = 0.0027; height < or = 5 v > 5 mm, p = 0.029; largest basal diameter (LBD) < or = 15 v > 15 mm, p < 0.0001) and location of anterior tumour margin anterior v posterior to the equator (p = 0.0003); the risk of neovascular glaucoma with large size (T1 + T2 v T3, p = 0.039; LBD < or = 15 mm v 15 mm, p = 0.021); and the risk of maculopathy and optic neuropathy with proximity of the posterior tumour margin to the fovea and the optic disc (< or = 1.5 v > 1.5 mm; p = 0.030 and p = 0.0004, respectively). In Cox's multivariate analysis the strongest risk indicator for radiation cataract (RR 1.5, 95% CI 1.4-1.6) and vitreous haemorrhage (RR 1.6, 95% CI 1.4-1.8) was the height of the tumour; for neovascular glaucoma the TNM class (RR 6.2, 95% CI 2.7-13.8); for radiation maculopathy location of posterior tumour margin within 2 mm from the fovea (RR 3.4, 95% CI 2.0-6.0); and for radiation optic neuropathy location of tumour margin within 1 DD of the optic disc (RR 6.1, 95% CI 3.0-12.4). The 3 and 5 year probabilities of avoiding enucleation were 92% and 85%, respectively. Ten eyes were enucleated--six because of recurrent tumour growth, three because of treatment complications, and one because of mistakenly suspected extraocular growth. CONCLUSION: The results suggest that the frequency of radiation related complications after ruthenium brachytherapy of uveal melanoma is acceptable, in particular as regard irradiation of small and medium sized tumours for which ruthenium therapy generally is recommended.

Long-term follow-up of chronic Lyme neuroretinitis.

PURPOSE: The authors report sequential fluorescein angiographic and color photographic findings of the fundi and response to treatment in a patient with chronic Lyme neuroretinitis. METHODS: A Lyme enzyme-linked immunosorbent assay with purified 41-kd flagellin as antigen was used to detect immunoglobulin G and immunoglobulin M antibodies to Borrelia burgdorferi in serum, cerebrospinal fluid, and vitreous. The changes were documented by fluorescein angiography and color photography tests performed during a 5 1/2 year follow-up. RESULTS: The diagnosis of Lyme neuroretinitis was based on the history of erythema migrans and positive Lyme enzyme-linked immunosorbent assay tests from cerebrospinal fluid and vitreous and by the exclusion of other infectious and systemic diseases and uveitis entities. Fluorescein angiography results disclosed bilateral chronic neuroretinal edema with areas of cystoid, patchy, and diffuse hyperfluorescence peripapillary and in the macular areas. The hyperfluorescent lesions enlarged despite a 9-month period of antibiotic therapy. CONCLUSION: Lyme borreliosis may cause neuroretinitis with unusual angiographic findings. Chronic Lyme neuroretinitis may be unresponsive to antibiotic therapy.

Visual outcome of eyes with malignant melanoma of the uvea after ruthenium plaque radiotherapy.

BACKGROUND AND OBJECTIVE: To analyze the overall visual outcome in 100 consecutive eyes with malignant uveal melanoma irradiated with ruthenium-106 plaques between 1981 and 1991. PATIENTS AND METHODS: The follow-up ranged from 4 months to 10.1 years (median 3.0 years). Scattergrams of equal follow-up periods, life-table survival analysis, and Cox's proportional hazards analysis were used to analyze visual outcome. RESULTS: VA increased for some time in 14 eyes. By 3 years, VA of at least 20/70, 20/200, counting fingers, and light perception were retained in 27%, 41%, 67% and 82% of eyes, respectively. Macular pathology cause loss of reading vision; neovascular glaucoma or enucleation caused loss of light perception. In univariate analysis, large tumor size (height > 5 mm or TNM class T3) predicted visual loss of all VA levels. For the loss of light perception, the tumor's largest basal diameter > 15 mm reached significance. In Cox's multivariate analysis tumor height > 5 mm was the only significant independent risk indicator for loss of VA levels 20/70 and 20/200. For the level CF, largest basal tumor diameter also reached significance, but location of the tumor within 1 disc diameter of the optic disc, either alone or in addition to the fovea, had the greatest risk ratio (6.3, 95% CI 4.1-9.8). For losing light perception, large TNM size (T3) was the strongest risk indicator (risk ratio 10.0; 95% CI 4.5-22.5), followed by proximity of the tumor to the optic disc (risk ratio 4.3, 95% CI 2.4-7.8). CONCLUSION: Ruthenium brachytherapy may retain vision in an eye with a malignant melanoma of the uvea for a considerable period of time. The data presented are useful in patient counseling and allow comparison to subsequent series.

Fatal sepsis due to a beta-lactamase-producing strain of Fusobacterium nucleatum subspecies polymorphum.

A patient with Waldenström's macroglobulinemia was treated empirically with imipenem for sepsis related to oropharyngeal infection and responded within 24 hours. When blood cultures yielded Streptococcus agalactiae, the regimen was changed to ampicillin and gentamicin. The patient's condition rapidly deteriorated, and she died 3 days later. After her death, a strain of Fusobacterium nucleatum subspecies polymorphum producing beta-lactamase (PEN-Y; group 2a) was isolated from blood cultures. A literature review revealed increasingly frequent isolation of beta-lactamase-producing strains of F. nucleatum. Thus strains of F. nucleatum isolated from blood and other specimens from patients with serious infections should be tested for beta-lactamase production.

Suboptimal vision after vitreous surgery in diabetics.

Between 1979-1985, 105 diabetic patients underwent vitreous surgery for diabetic eye disease in one or both eyes. By spring 1991, 40 patients (38%) had died, and 36 (55%) of the living 65 patients had good or moderate vision (visual acuity, VA > or = 0.3 in the better eye), 13 (20%) had low vision (VA 0.05-0.25), and 16 (25%) were blind (VA < 0.05). For 19 of the 65 patients (29%) impaired vision was the main factor that limited independent activities. Of the 29 patients with suboptimal vision, 2 were employed, and none needed institutional care. Nine (31%) participated in all household activities, and 14 (48%) were able to read. Near vision aids were used by 14 of the 19 patients (74%) with ambulatory vision (VA > or = CF), but only 2 of them (11%) had accepted telescopic aids. Eight patients (28%) had a guide dog. In spite of vitreoretinal surgery, almost half of diabetic patients may end up with suboptimal vision, emphasizing the need for active visual rehabilitation.