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• W2146959773 abstract "A hundred years after its description in 1917 by John Lindberg, a Finnish ophthalmologist (Tarkkanen and Kivelä, 2002Tarkkanen A. Kivelä T. John G. Lindberg and the discovery of exfoliation syndrome.Acta Ophthalmol. Scand. 2002; 80: 151-154Crossref PubMed Scopus (50) Google Scholar) pseudoexfoliation syndrome (PES) — an eye abnormality estimated to affect 80 million people and to be associated with a significantly increased risk of cataract and secondary open-angle glaucoma, both of which may compromise vision — continues to be shrouded in mysteries (Ritch, 2014Ritch R. Ocular and systemic manifestations of exfoliation syndrome.J. Glaucoma. 2014; 23: S1-S8Crossref PubMed Scopus (56) Google Scholar, Anastasopoulos et al., 2015Anastasopoulos E. Founti P. Topouzis F. Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.Curr. Opin. Ophthalmol. 2015; 26: 82-89Crossref PubMed Scopus (62) Google Scholar). Why is PES so often unilateral? Why does not everyone with PES develop secondary glaucoma? Why do lysyl oxidase like-1 gene polymorphisms that are strongly associated with PES (Thorleifsson et al., 2007Thorleifsson G. Magnusson K.P. Sulem P. Walters G.B. Gudbjartsson D.F. Stefansson H. Jonsson T. Jonasdottir A. Jonasdottir A. Stefansdottir G. Masson G. Hardarson G.A. Petursson H. Arnarsson A. Motallebipour M. Wallerman O. Wadelius C. Gulcher J.R. Thorsteinsdottir U. Kong A. Jonasson F. Stefansson K. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.Science. 2007; 317: 1397-1400Crossref PubMed Scopus (585) Google Scholar) vary in different populations (Ji et al., 2015Ji Q.S. Qi B. Wen Y.C. Liu L. Guo X.L. Yu G.C. Zhong J.X. The association of LOXL1 polymorphisms with exfoliation syndrome/glaucoma: meta-analysis.Int. J. Ophthalmol. 2015; 8: 148-156PubMed Google Scholar)? What actually is the pseudoexfoliation material, visible in the eye by biomicroscopy and elsewhere in the body by electron microscopy? Is it identical inside and outside of the eye (Vesti and Kivelä, 2000Vesti E. Kivelä T. Exfoliation syndrome and exfoliation glaucoma.Prog. Retin. Eye Res. 2000; 19: 345-368Crossref PubMed Scopus (130) Google Scholar)? Finally, and perhaps most importantly, is PES a systemic disease that shortens life expectancy? This is what Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar from Norway, a country with a long tradition of PES research, address in this issue of EBioMedicine. The authors conducted in 1985–1986 an epidemiological survey covering 1888 of the 2109 inhabitants older than 64 years in three Norwegian municipalities and determined by biomicroscopy whether they were PES-positive (Ringvold et al., 1988Ringvold A. Blika S. Elsås T. Guldahl J. Brevik T. Hesstvedt P. Johnsen H. Hoff K. Høisen H. Kjørsvik S. Rossvoll I. The Middle-Norway eye-screening study. I. Epidemiology of the pseudo-exfoliation syndrome.Acta Ophthalmol. (Copenh). 1988; 66: 652-658Crossref PubMed Scopus (66) Google Scholar). They returned to this cohort in 2014 by which time 99% of their subjects had died, and requested their dates of death (Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar). The authors found no difference in all-cause mortality: the relative risk of death for PES-positive subjects, adjusting for gender and age, was 1.01 and the median life spans of PES-positive and PES-negative subjects were similar in all age groups studied. These long-term, population-based data corroborate half a dozen cohort studies conducted previously albeit typically with shorter, less mature follow-up — the Act 1 of addressing the potentially different life spans of PES-positive subjects (for references see Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar). As the authors point out, their results are also inconsistent with studies that have reported impaired circulation in vital organs such as the aorta, heart and brain as well as potentially deleterious hyperhomocystinemia in PES-positive subjects (for references see Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar). Such claims have independently been challenged by data from other centers, which also has spoken against a clinically significant, true association between PES, vascular disease and, indirectly, excess mortality (Tarkkanen, 2008Tarkkanen A. Is exfoliation syndrome a sign of systemic vascular disease?.Acta Ophthalmol. 2008; 86: 832-836Crossref PubMed Scopus (37) Google Scholar, Anastasopoulos et al., 2015Anastasopoulos E. Founti P. Topouzis F. Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.Curr. Opin. Ophthalmol. 2015; 26: 82-89Crossref PubMed Scopus (62) Google Scholar). Although one tends to agree with the main conclusion of Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar in that PES is unlikely to be a life threatening condition — an important message to millions of people — one has to address potential bias in their statistics. A notable confounding factor that the authors mention — and one that they cannot adjust for — is that although several PES-negative subjects most likely later converted to PES-positive ones they were still all counted as PES-negative. One can roughly estimate the magnitude of this bias as follows. First, the prevalence of PES by age group given in Table 1 of Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar can be plotted to provide prevalence estimates for other ages (Fig. 1). Second, the eventual median age of PES-negative subjects by age group can be read from Fig. 1 of Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar. One can then read the corresponding predicted prevalence of PES from the plot (Fig. 1) and calculate the number of PES-positive subjects at the end of the study for each age group. For example, the eventual median age for the 65–69 years old is 85 years, prevalence of PES 28.5%, and number of PES-positive subjects 143 (as compared to 67 years, 11.0% and 55 at baseline — an increase of 88 subjects). Repeating this across all age groups returns a total number of 575 rather than 319 PES-positive subjects. If those who converted to PES-positive had similar survival than those who were PES-positive at baseline, the median life length of the PES-negative subjects would have been somewhat higher, but not much; for example, the estimated median life span for those 65–69 years old would be 4 months longer. This bias is unlikely to change the main results. However, another source of bias that the authors acknowledge, namely analyzing only all-cause mortality, cannot be dismissed as potentially hiding clinically meaningful differences in cause-specific mortality. PES has only been suspected of increasing cardio- and cerebrovascular mortality (Anastasopoulos et al., 2015Anastasopoulos E. Founti P. Topouzis F. Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.Curr. Opin. Ophthalmol. 2015; 26: 82-89Crossref PubMed Scopus (62) Google Scholar). It has not been implicated in cancer, another major cause of death. Moreover, PES has often been less common among diabetic patients (for references see Tarkkanen et al., 2008Tarkkanen A. Reunanen A. Kivelä T. Frequency of systemic vascular diseases in patients with primary open-angle glaucoma and exfoliation glaucoma.Acta Ophthalmol. 2008; 86: 598-602Crossref PubMed Scopus (56) Google Scholar). Because cardiovascular complications of diabetes shorten survival, this diminishes chances of detecting any mortality excess from PES. Luckily, this bias can still be addressed by Slettedal et al., 2015Slettedal J.K. Sandvik L. Ringvold A. Ocular pseudoexfoliation syndrome and life span.EBio. Med. 2015; 2 (http://www.sciencedirect.com/science/article/pii/S235239641530027X): 763-767Summary Full Text Full Text PDF Scopus (17) Google Scholar, because causes of death are generally obtainable for valid research purposes. There is, consequently, scope for Act 3 before excluding shortened life spans in a subset of PES-positive subjects. I declare that I have no conflict of interest. Ocular pseudoexfoliation syndrome and life spanTo compare life span of persons with and without ocular pseudoexfoliation syndrome (PES). Full-Text PDF Open Access" @default.
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• W2146959773 date "2015-07-01" @default.
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• W2146959773 title "Ocular Pseudoexfoliation Syndrome and Life Span: Act 2" @default.
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