Exfoliation Syndrome: A Historical Perspective.

The discoverer of exfoliation was John Lindberg of Helsinki, Finland. He conducted his research as a young ophthalmology resident with the aim of elucidating 2 types of age-related degenerations of the iris and presenting it as an academic thesis. To this end, he had to construct a slit lamp, because they were not commercially available. During this investigation, he paid attention to greyish flakes and fringes on the anterior lens capsule and the pupillary border, which had not been previously described. His material consisted of 202 patients. The findings were recorded by time-consuming skillful drawings. His conclusions that the condition was age-related and often linked to chronic glaucoma and cataract are still valid today. The work was accepted as an academic thesis at the University of Helsinki in 1917.

Comparison of primary open-angle glaucoma and exfoliation glaucoma at diagnosis.

PURPOSE: To compare ocular findings in eyes with primary open-angle glaucoma (POAG) and exfoliation glaucoma (EG) at the time of diagnosis when identical diagnostic criteria for glaucoma were applied. METHODS: We conducted a study on records of 519 consecutive, unselected patients with chronic glaucoma filing for cost-free medication from the Finnish National Social Insurance Institute (FSII). Fourteen cases were excluded for having other types of glaucoma. The documents were provided by eye hospitals or by licensed ophthalmologists. The criteria for glaucoma were set by the Parliament of Finland and applied by FSII. A total of 329 patients had POAG and 176 had EG. The main outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), cup-to-disc ratio of the optic nerve head (C/D), and glaucomatous changes of the visual fields (VF). RESULTS: As regards sex, the 2 groups were comparable: 66% female with POAG and 68% with EG. The EG patients were older (mean ± SD 74 ± 8.6 years) vs POAG (68 ± 11.4 years). The EG eyes had slightly lower BCVA. The POAG eyes had mean intraocular pressure (IOP) 24 ± 5.4 mm Hg. A total of 12% in this group had highest IOP of less than 18 mm Hg (low-tension glaucoma [LTG]) but there were none of EG. All EG eyes had a mean IOP 28.3 ± 9.3 mm Hg. Among EG patients, 26% had unilateral disease, with a mean IOP of 33.7 ± 8.7 mm Hg, while the opposite eyes had a mean of 19 ± 3 mm Hg. There was not much difference in the C/D ratios of POAG and EG eyes and the VF profiles were similar. CONCLUSIONS: At diagnosis, patients with EG were older than those with POAG and had higher mean IOP values. Among patients with POAG, there were 12% with LTG, but none among EG. A total of 26% among EG had unilateral disease with marked IOP asymmetry. The C/D and VF profiles were similar because the patients had been seen early in the disease course. Early recognition and lifelong most effective therapy of EG are strongly advocated.

Vascular comorbidity in patients with low-tension glaucoma.

PURPOSE: To report vascular comorbidities, arterial hypertension (HT), ischemic heart disease (IHD), and diabetes mellitus (DM) in patients with low-tension glaucoma (LTG) with maximum intraocular pressure (IOP) of 18 mm Hg or less. Uniform criteria for glaucoma and the comorbidities were applied. METHODS: We reviewed records of 519 consecutive patients to whom the Finnish National Social Insurance Institution (FSII) had granted cost-free medication for the treatment of glaucoma. The FSII operates national health insurance, which is compulsory for all Finnish citizens. There were 344 patients with primary open-angle glaucoma (POAG) and 155 with exfoliative glaucoma (EG). Twenty cases were discarded for having other types of glaucoma. In the POAG group, there were 38 patients, with a median IOP of 16 mm Hg (range 12-18). We were masked to the systemic comorbidities when the registry provided us data on those to whom FSII had also granted cost-free medication for HT, IHD, or DM according to the uniform national criteria. RESULTS: None of the patients with LTG had exfoliation syndrome. There was a female predominance, 81%, compared to 68% in high-tension POAG. Hypertension had been diagnosed in 34%, which is the same as in high-tension POAG. A total of 24% had IHD, which is the same as in the Finnish population registry. Diabetes mellitus was present in only 5%. In all groups, patients with LTG with systemic comorbidity were markedly older than those without. CONCLUSIONS: In patients with LTG with median IOP 16 mm Hg (range 12-18), glaucomatous optic disc cupping and glaucomatous visual field defects probably developed independently of the systemic vascular comorbidity. However, the diagnostic criteria for HT, IHD, and DM used in the current study were based on the severity of stages set in the FSII system.

Mortality in primary open-angle glaucoma and exfoliative glaucoma.

PURPOSE: To study mortality among unselected Finnish patients with either primary open-angle glaucoma (POAG) or exfoliative glaucoma (EG) after a minimum follow-up of 7 years after enrollment. METHODS: A total of 344 patients with POAG and 155 patients with EG had received free medication for the treatment of glaucoma from the Finnish National Social Insurance Institution (FSII). The FSII operates national health insurance, which is compulsory for all Finnish citizens. To be granted free medication, the patient has to file an application with a certificate from an ophthalmologist. If the predefined criteria for glaucoma specified by the Finnish Parliament are met, full reimbursement for glaucoma medications is granted and the patient is listed in the registry of FSII. We reviewed the records of 519 consecutive patients who had been diagnosed with glaucoma and to whom free medication had been granted between June 2004 and December 2005. Patients with acute glaucoma or secondary glaucoma were excluded. Those with open angles were classified into POAG or EG. The quality of the ophthalmologists' records was high. The Finnish Population Registry, a governmental institute, provided information on those patients who had died before January 2013. RESULTS: At enrollment, the groups with POAG and EG were comparable as regards sex: 66% female with POAG and 68% with EG. The patients with POAG were younger (median 68 years) than those with EG (median 74 years). By January 2013, 59 patients with POAG and 48 with EG had died. At death, the patients with POAG were younger (median 81.8 years) than those with EG (87.9 years). In both groups, the women lived longer than the men, but among patients with POAG, women and men died at a younger age than those with EG. CONCLUSIONS: As has been reported previously, life expectancy of patients with EG was longer when compared to those with POAG. Higher death rate among patients with EG is explained by higher median age at baseline.

[Master violinist Isaac Stern - music surpassing health]. / Viulun mestari Isaac Stern - musiikki meni terveyden edelle.

Even though the career of violinist Isaac Stern was influenced by his illnesses, he gave copious concerts almost until his death. Despite a stressful life and incessant traveling across time zones, Stern stayed fairly healthy. According to his own words he had, however, performed while suffering from flu, fever and diarrheal disease. Even a wrist fracture didn't stop him, and it was only the first cardiac infarction that led to a sick leave. After his second infarction at the age of 67 Stern against the objection by his cardiologist went on a concert tour in Israel, although he should have been preparing for bypass surgery.

Blindness of Johann Sebastian Bach.

Johann Sebastian Bach (1685-1750) was one of the greatest composers of all time. Apart from performing as a brilliant organist, he composed over 1.100 works in almost every musical genre. He was known as a hardworking, deeply Christian person, who had to support his family of 20 children and many students staying at his home. At the age of 64 years, his vision started to decline. Old biographies claim that it was the result of overstressing his vision in poor illumination. By persuasion of his friends, he had his both eyes operated by a travelling British eye surgeon. A cataract couching was performed. After surgery, Bach was totally blind and unable to play an organ, compose or direct choirs and orchestras. He was confined to bed and suffering from immense pain of the eyes and the body. He died <4 months after surgery. In this paper, as the plausible diagnosis, intractable glaucoma because of pupillary block or secondary to phacoanaphylactic endophthalmitis is suggested.

Is exfoliation syndrome a sign of systemic vascular disease?

Exfoliation syndrome (ES) is an age-related disorder in which greyish-white flakes accumulate in different tissues in the anterior eye. Its pathogenesis is not completely known, but it results in electron-dense microfibrils. The finding that these can be seen outside the eye in many visceral organs inspired the theory that ES might be a part of a generalized disorder. It was postulated that ES might contribute to increased morbidity, mainly of systemic vascular diseases. This review is a summary of the existing knowledge. The prevalence of arterial hypertension (AHT) in elderly populations is > 30%. No differences have been found in the frequency of AHT among patients with ES or exfoliative glaucoma (EG) compared with those with primary open-angle glaucoma (POAG) or no ES. There are conflicting reports of frequencies of ischaemic heart disease (IHD). A recent registry-based study that used uniform criteria for IHD found no difference in the rate of IHD between patients with EG and those with POAG. However, findings of elevated homocysteine levels in the plasma and aqueous humour of patients with ES or EG suggest an increased vascular risk. No studies have yet been conducted to assess possible links between ES and systemic vascular diseases. In a single-blind study, ES was associated with abdominal aortic aneurysm, but this was not found in a large, cross-sectional investigation. The frequency of ES in patients with diabetes mellitus (DM) is only about half of that when compared in patients with no ES or with POAG. This finding warrants further studies. Molecular genetics research has found no common denominator for ES and the vascular diseases. There is no evidence that ES or EG are related to increased mortality for cardiovascular diseases. Further large-scale, randomized clinical studies are required. At present there are no known medical indications that infer an increased systemic vascular risk or imply a need for the complete internal medical examination of a symptom-free patient with newly diagnosed ES in the eye.

Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma.

PURPOSE: To evaluate genetic susceptibility of lysyl oxidase-like 1 (LOXL1) gene polymorphisms to exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) in a case-control cohort of American and European patients. METHODS: DNA from a total of 620 individuals including 287 exfoliation patients and 333 healthy control subjects were extracted by standard methods. Three single nucleotide polymorphisms (SNPs) of rs1048661 (R141L), rs3825942 (G153D), and rs2165241 were genotyped in these individuals by SNaPshot Assay. The seven coding exons of the LOXL1 gene and their immediate flanking regions were directly sequenced in 95 affected patients. Data management and case-control association studies were performed with SNP-STAT and PLINK programs. The obtained DNA sequences were evaluated with the STADEN package. RESULTS: The 287 unrelated exfoliation cases comprised of 171 American patients (mostly of European background) and 116 patients from 12 European countries. This phenotype was further divided into patients with exfoliation only and no glaucoma (XFO; n=95), exfoliation with glaucoma (XFG; n=133), and exfoliation unclassified (XFU; n=59). Genotypic data were analyzed separately for XFO, XFG, XFU, and XFS (all exfoliations; n=287) and for Americans and Europeans. The observed genotypic frequencies for each exfoliation phenotype or population were tabulated separately and tested for deviation from the Hardy-Weinberg equilibrium (HWE) using a standard Chi(2) test. There were no HWE deviations and no significant genotypic differences between these subcategories for the three studied SNPs. For the combined exfoliation cohort, homozygote genotypes of G/G (rs1048661), G/G (rs3825942), and T/T (rs2165241) were significantly overrepresented. Likewise, case-control allelic association for rs1048661 (p=7.74x10(-9)), rs3825942 (p=3.10x10(-17)), and rs2165241 (p=4.85x10(-24)) were highly significant. The corresponding two-locus haplotype frequencies of GG for rs1048661-rs3825942 (p=1.47x10(-27)), GT for rs1048661-rs2165241 (p=1.29x10(-24)), and GT for rs3825942-rs2165241 (p=2.02x10(-24)) were highly associated with exfoliation phenotypes. The combined effect of these three SNPs revealed that the GGT haplotype is overrepresented by 66% in exfoliation cases, and this deviation from controls is highly significant (p=1.93x10(-24)). This haplotype constituted a major risk factor for development of exfoliation in both XFS and XFG. By contrast, the GAC haplotype was significantly underrepresented (p=4.99x10(-18)) in exfoliation cases by 83% and may potentially have a protective effect for this condition with an estimated attributable risk percent reduction of 457%. The only other haplotype that was significantly different between cases and controls was TGC (p=5.82x10(-9)). No observation was made for the GAT haplotype. The combined three haplotypes of GGT, GAC, and TGC were associated with 91% of the exfoliation syndrome cases in the studied populations. Seven coding exons of LOXL1 were also sequenced in 95 affected cases. In addition to the three above-mentioned SNPs, 12 other variations were also observed in these patients (G240G, D292D, A320A, V385V, rs2304719, IVS3+23C>T, IVS3-155G>A, IVS3-101G>A, IVS4+49G>A, rs2304721, IVS5-121C>T, and rs2304722). None were considered a disease-causing mutation. CONCLUSIONS: We confirmed a strong association with LOXL1 variants in our patients. For the LOXL1 gene, individual alleles of rs1048661 (G), rs3825942 (G), and rs2165241 (T) are highly associated with XFS and XFG in American and European populations. The GGT haplotype constitutes a major risk haplotype for exfoliation, and GAC may have a protective role. DNA sequencing of 95 affected patients did not show any mutations in this gene. The LOXL1 SNPs are located in the 15q24.1 band and within a genetic locus (GLC1N) that is associated with primary open-angle glaucoma (POAG). However, the LOXL1 genetic predisposition is only limited to exfoliation with or without glaucoma and does not include the POAG phenotype.

Frequency of systemic vascular diseases in patients with primary open-angle glaucoma and exfoliation glaucoma.

PURPOSE: Abnormal fibrils can be identified by electron microscopy in the heart, lung, liver, kidney, cerebral meninges and other tissues of patients with exfoliation syndrome (ES). However, a clinical association of ES with arterial hypertension (HT), ischaemic heart disease (IHD), cerebrovascular accidents and aneurysm of the abdominal aorta is debated. We conducted a national registry-based survey to further assess the first two of these associations. METHODS: We reviewed the records of 519 consecutive patients to whom the Social Insurance Institution of Finland had granted free medication for glaucoma according to national common criteria. The glaucoma was classified either as primary open-angle glaucoma (POAG) or exfoliation glaucoma (EG), masked to any systemic diseases; 20 patients with other types of glaucoma were excluded from the survey. Masked to the type of glaucoma, the registry provided data on free medication similarly granted for HT, IHD and diabetes mellitus (DM), a known modifier of risk for cardiovascular disease. Data were analysed by logistic regression, modelling age, gender and DM as confounders. RESULTS: The control group of 344 patients with POAG was comparable as regards gender with the study group of 155 patients with EG, but patients with POAG were both younger (mean 69 versus 73 years; P < 0.0001) and had DM twice as often (10% versus 5%; P = 0.05) compared to those with EG. Adjusting for age, gender and presence of DM, no difference in frequency of HT [odds ratio (OR) 0.80 for presence of EG; 95% confidence interval (CI) 0.52-1.23, P = 0.31] or IHD (OR 0.86 for presence of EG; 95% CI 0.49-1.13, P = 0.66) was detected between the two groups. CONCLUSION: In this population-based registry survey, no difference in frequency of HT or IHD was noted between patients with POAG and EG who had been granted free medication for these chronic diseases according to national common criteria. The frequency of DM was lower among patients with EG, in line with several previous reports.

Nordic research in ophthalmology.

Nordic ophthalmologists and vision scientists are active in many fields of eye research. This is most evident at the biannual Nordic Congress of Ophthalmology, most recently held in Malmö in June 2004. The authors here review some of the research in vision and ophthalmology presented at this meeting or published recently by Nordic scientists. This paper does not represent a comprehensive review of all Nordic research in the field, but attempts to give an overview of some of the activities underway in eye research in this part of the world.

Cumulative incidence of converting from clinically unilateral to bilateral exfoliation syndrome.

PURPOSE: To obtain long-term cumulative incidence estimates of time to conversion of clinically unilateral to bilateral exfoliation syndrome (ES). METHODS: A retrospective, longitudinal cohort study of 35 patients with clinically unilateral ES from the private office of one author. Diagnosis of ES was made between 1968 and 1998. On return visits a careful search for ES in the nonexfoliative fellow eye was made by the same author in a semidark room using a slit lamp and maximal pupillary dilatation. Cumulative incidence of converting to bilateral ES was calculated, taking death into account as a competing risk. RESULTS: Cumulative incidence of conversion to bilateral ES was 0.11 (95% CI, 0.03-0.25) at 5 years, 0.36 (95% CI, 0.15-0.57) at 10 years, and 0.52 (95% CI, 0.27-0.93) at 15 years when the day of examination was taken to be the day of conversion, and 0.14 (95% CI, 0.04-0.29) at 5 years and 0.52 (95% CI, 0.26-0.73) at 10 years when analysis was based on conversion taking place at the midpoint between the last two visits. The median age at conversion was 72 years (range, 66-86), and the median age of patients remaining clinically unilateral was 77 years (range, 57-90). Factors associated with time to conversion depended on the strategy of the analysis and included higher age at first visit and larger IOP difference between the involved and uninvolved eye. CONCLUSION: A large proportion of patients with clinically unilateral ES will not convert to bilateral involvement in long-term follow-up. Immunohistochemical studies suggest that local factors must either expedite ES or slow it down in one eye to explain the frequently longstanding asymmetric involvement, and a difference in initial aqueous outflow facility might be examined as one candidate.

Fungal endophthalmitis caused by Paecilomyces variotii following cataract surgery: a presumed operating room air-conditioning system contamination.

PURPOSE: To report a case of delayed fungal endophthalmitis by Paecilomyces variotii following uncomplicated cataract surgery. To our knowledge this is the first reported case of postoperative endophthalmitis by this species. METHODS: We report the longterm clinical follow-up of an 83-year-old female who underwent uncomplicated sutureless, small-incision cataract surgery. She developed recurring uveitis 4 months after surgery. Vitreous tap and finally complete vitrectomy with removal of the capsular bag including the intraocular lens were performed. Fungi were studied by histopathology and culture. RESULTS: At histopathological examination, the fungi were found to be closely related with the capsular bag. A few mononuclear inflammatory cells were encountered. At culture, Paecilomyces variotii, a common ubiquitous non-pathogenic saprophyte, was identified. Despite systemic, intravitreal and topical antifungal therapy after vitrectomy the uveitis recurred several times, but no fungal organisms were isolated from the repeat intraocular specimen. At 18 months postoperatively the subject's visual acuity was finger counting at 2 metres. At the time of surgery the operating room air-conditioning system was undergoing repairs. Cases of fungal endophthalmitis after contamination from air-conditioning ventilation systems have been reported before, but none of the cases reported have been caused by P. variotii. CONCLUSION: P. variotii, a non-pathogenic environmental saprophyte, may be disastrous if introduced into the eye. International recommendations on the environmental control of the operating room air-conditioning ventilation system should be strictly followed. No intraoperative surgery should be undertaken while the air-conditioning system is undergoing repairs or service.

Iodine brachytherapy as an alternative to enucleation for large uveal melanomas.

PURPOSE: To evaluate the safety and efficacy of iodine 125 plaque brachytherapy (IBT) for large uveal melanomas. DESIGN: Retrospective, nonrandomized comparative trial (historical control). PARTICIPANTS: One hundred twenty-one consecutive patients with a large uveal melanoma according to the Collaborative Ocular Melanoma Study (COMS) criteria who attended a national ocular oncology service. METHODS: Ninety-seven patients (80%) underwent primary IBT (mean dose to tumor apex, 87 Gy) with noncollimated 20- to 25-mm plaques. Assessment of metastatic disease at death and visual outcome followed COMS guidelines. Time to low vision (20/70 or worse) and blindness (loss of 20/400 vision) in the study eye were modeled by Cox proportional hazards regression, based on both single- and repeated-failure data sets. Person-years of retained vision were calculated. MAIN OUTCOME MEASURES: All-cause and melanoma-specific survival, local and distant recurrence, and preservation of vision and cosmesis. RESULTS: Median tumor height was 10.7 mm (range, 4.5-16.8 mm), and largest basal tumor diameter was 16.1 mm (range, 7.3-25.0 mm). The Kaplan-Meier estimate for all-cause and melanoma-specific survival was 62% (95% confidence interval [CI], 49%-72%) and 65% (95% CI, 52%-75%) at 5 years. The corresponding estimate for local tumor recurrence was 6% (95% CI, 2%-14%) and for major cosmetic abnormality was 38% (95% CI, 26%-52%). The median visual acuity in the study eye was 20/100 at baseline and 20/1600 at 2 years after treatment. The Kaplan-Meier estimate for avoiding low vision and blindness was 11% (95% CI, 4%-24%) and 26% (95% CI, 16%-37%) at 2 years, respectively. Tumor height and location entirely posterior to the ora serrata were the most robust predictors of visual loss. In this series, 49 person-years without low vision (median, 0.6 years; range, 0.04-8.2 years) and 111 person-years without blindness (median, 1.0 years; range, 0.03-8.6 years) in the treated eye were conserved. CONCLUSIONS: Iodine 125 plaque brachytherapy seems to be a safe and effective alternative to enucleation with regard to survival and local tumor control. It provides a fair chance of preserving the eye with acceptable cosmesis and a reasonable chance of conserving useful vision for 1 to 2 years.

Evaluation of the clinical association between exfoliation syndrome and abdominal aortic aneurysm.

PURPOSE: To assess the validity of the suggested association between intraocular exfoliation syndrome and aneurysm of the abdominal aorta. METHODS: A total of 77 patients recently operated for abdominal aortic aneurysm underwent biomicroscopy under pupillary dilatation to detect the presence of manifest and suspect deposits of exfoliation material. RESULTS: The mean age of the 71 (92%) male and six female subjects was 73 years (range: 59-88 years). Manifest exfoliation was detected in 11 patients (14%; 95% CI 7-24), five of whom were aged 60-69 years and six of whom were aged 70-79 years. In addition, four patients (5%; 95% CI 1-13) had suspect exfoliation. CONCLUSIONS: The prevalence of exfoliation syndrome in patients operated for abdominal aortic aneurysm was similar to that in the general population of the same age in Finland. This finding does not support the proposed connection between exfoliation syndrome and abdominal aortic aneurysm.