1. Home
  2. Issue 13-2
  3. Glaucoma Opinion

advertisement

WGA Rescources

Glaucoma Opinion IGR 13-2

Exfoliation Syndrome

Robert Ritch, MDDaniel Hayes, MD

Exfoliation syndrome (XFS) is an age-related, generalized disorder of the extracellular matrix (ECM) characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues and is the most common identifiable cause of open-angle glaucoma worldwide.1 It is the most common identifiable cause of open-angle glaucoma worldwide, affecting an estimated 60 to 70 million people.2,3

Exfoliation syndrome is the most common identifiable cause of open-angle glaucoma worldwide

  Exfoliative glaucoma (XFG) is more severe than primary open-angle glaucoma (POAG) and carries a worse prognosis. Patients with XFS are twice as likely to convert from ocular hypertension to glaucoma4 and are more likely to develop glaucoma at all intraocular pressures (IOP).5 Patients with XFG have a greater mean IOP, greater diurnal IOP fluctuation, more visual field loss and optic disc damage at diagnosis, poorer response to medications, and greater need for surgical intervention, more rapid progression and greater proportion of blindness.1

Exfoliative glaucoma is not a form' or type' of glaucoma, but rather an ocular manifestation of a systemic disease. Other ocular manifestations include dry eye, cataract, lens (and intraocular lens) sub-luxation, angle closure, retinal vein occlusion and zonular dialysis, capsular rupture and vitreous loss at the time of cataract surgery. Marked rises in IOP after dilation mandate examination of the anterior chamber for pigment and measurement of IOP after pupillary dilation.6 Exfoliation material (XFM) has been found in heart, lung, liver, kidney, gall bladder and meninges of patients with ocular XFS.7,8 XFS has been reported to be a risk factor for coronary artery disease9-11 and has been associated with transient ischemic attacks, hypertension, angina, myocardial infarction, Alzheimer's disease and hearing loss.12-17 Patients with XFS and XFG have reduced cerebral blood flow velocity,18 ocular perfusion pressure,19 peripheral vascular disease,20 and more white matter hyperintensities (WMH) on magnetic resonance imaging than controls, demonstrating a potential link between XFS and ischemic brain lesions.21

In XFS, a fibrillogranular material accumulates throughout the anterior segment, whether through excess production and/or insufficient breakdown, and is pathognomonic for the disease. Streeten et al.22 first described the elastic microfibril theory of pathogenesis, based on similarities between XFM and zonular fibers, and explained XFS as a type of elastosis affecting elastic microfibrils. These fibrils are composed of microfibrillar subunits surrounded by an amorphous matrix comprising various glycoconjugates, and contain predominantly epitopes of elastic fibers such as elastin, tropoelastin, amyloid P, vitronectin and components of elastic microfibrils.

The XFS-specific tissue alterations are caused by a generalized fibrotic matrix process, which has been characterized as a stress-induced elastosis associated with the excessive production and abnormal cross-linking of elastic microfibrils into fibrillar XFS aggregates.23 The genetic cause of XFS lies within the lysyl-oxidase-like 1 (LOXL1) gene on chromosome.15 Two single nucleotide polymorphisms (SNPs) in the coding region account for 99% of XFS in several populations.24-27 However, not everyone with these SNPs develops XFS, some develop XFS unilaterally and some bilaterally, some never develop the clinical manifestations in the fellow eye, some show rapid, and others slow, progression, all suggesting that other factors are involved. Recently, LOXL1 promotor haplotypes have been associated with XFS and XFG, suggesting that promotor region SNPs can influence LOXL1 gene expression and predispose to disease.28 A combination of genetics, epigenetics, and environmental conditions may eventually be found.

Growing evidence implicates oxidative stress and inflammation in XFS pathogenesis.

Growing evidence implicates oxidative stress and inflammation in exfoliation syndrome pathogenesis

Decreased concentrations of aqueous humor ascorbic acid29 and increased malondialdehyde30 and 8-iso-prostaglandin F2α31 point to a role for free radicals and oxidative damage in the disease process. There is a significant increase in serum total oxidant status (TOS) and decrease in serum total antioxidant capacity (TAC) in patients with XFS.32 Increased aqueous humor levels of interleukins IL-6 and IL-8 are seen in the early stages of XFS,33 and IL-6 induces the expression of transforming growth factor-ß1 (TGFβ1) and elastic fiber proteins. Inflammation and oxidative stress may be a modifiable risk factor in the management of patients with XFS and XFG.34 Aqueous humor in patients with XFG contains significantly greater levels of tumor necrosis factor-alpha,35 and connective tissue growth factor.36,37 Elevated levels of CTGF, TIMP-1 and TIMP-2 may promote the abnormal ECM accumulation and may be involved in the pathogenesis of XFG.36,38,39 Alterations in matrix metalloproteins and their tissue inhibitors suggest dysregulation of ECM synthesis.

Patients with XFS have elevated homocysteine levels in blood, aqueous humor, and tears.40-46 Hyperhomocysteinemia is a risk factor cardiovascular disease and is associated with many of the systemic abnormalities seen with XFS. It is another potentially modifiable risk factor in XFS, and is inversely associated with intake of vitamins B2, B6 and B12.47 Treatment with folic acid, B6 and B12 reduces homocysteine levels.48

The ultimate goal in the management of XFS and XFG is to identify etiologic factors and modifiable risk factors that can be manipulated to prevent its development and progression. Increased understanding of the genetics of the disease, the associated conditions, and the role of inflammation and oxidative stress, will be important steps in that direction. Future management of XFS and XFG may directly target XFM by preventing its formation and/or by depolymerizing it once it has formed.

Alzheimer's disease is a neurological disorder with production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of this so called protein conformational disease'.49 Alzheimer's disease and cardiovascular disease are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation.50 Curcumin inhibits many transcription factors, inflammatory cytokines, protects against cellular stress responses, and has broad anti-oxidant and neuroprotective activity.51 It has been reported to disrupt existing plaques, and partially restore distorted neurites in an Alzheimer mouse model.52 Possible approaches in XFS include finding a means to prevent it from aggregating initially, prevent it from cross-linking, disaggregating the fibrils, and depolymerizing the micro-fibrils. We remain hopeful that multidisciplinary approaches will help us achieve the goal of making XFS the first cause of glaucoma to be preventable or even cured. Eliminating XFS could not only prevent glaucoma, but also many serious disorders related to elastic tissue within the body. Much more research is needed on this ubiquitous and fascinating disease, which may represent a fundamental aspect of aging.

References

  1. Ritch R. The management of exfoliative glaucoma. Prog Brain Res 2008; 173: 211-224.
  2. Ritch R. Exfoliation syndrome: The most common identifiable cause of open-angle glaucoma. J Glaucoma 1994; 3: 176-178.
  3. Ritch R, Schlötzer-Schrehardt U, Konstas AGP. Why is glaucoma associated with exfoliation syndrome? Prog Retinal Eye Res 2003; 22: 253-275.
  4. Leske MC, Heijl A, Hussein M, et al. Factors for glaucoma progression and the effect of treatment. The Early Manifest Glaucoma Trial. Arch Ophthalmol 2003; 121: 48-56.
  5. Teus MA. Increased likelihood of glaucoma at the same intraocular pressure in subjects with pseudoexfoliation. Am J Ophthalmol 2009; 148: 606-613.
  6. Jewelewicz DA, Radcliffe NM, Liebmann J, Ritch R. Temporal evolution of intraocular pressure elevation after pupillary dilation in pigment dispersion syndrome. J Glaucoma 2009; 18: 184-185.
  7. Schlötzer-Schrehardt U, Koca MR, Naumann GOH, Volkholz H. Pseudoexfoliation syndrome. Ocular manifestation of a systemic disorder? Arch Ophthalmol 1992; 110: 1752-1756.
  8. Streeten BW, Li ZY, Wallace RN, Eagle RCJ, Keshgegian AA. Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992; 110: 1757-1762.
  9. Andrikopoulos GK, Mela EK, Georgakopoulos CD, et al. Pseudoexfoliation syndrome prevalence in Greek patients with cataract and its association to glaucoma and coronary artery disease. Eye 2009; 23: 442-447.
  10. Citirik M, Acaroglu G, Batman C, Yildiran L, Zilelioglu O. A possible link between the pseudoexfoliation syndrome and coronary artery disease. Eye 2007; 21: 11-15.
  11. Sekeroglu MA, Bozkurt B, Irkec M, et al. Systemic associations and prevalence of exfoliation syndrome in patients scheduled for cataract surgery. Eur J Ophthalmol 2008; 18: 551-555.
  12. Hagadus RJ, Wandel T, Ritch R, et al. Pseudoexfoliation in patients with Alzheimer's disease. Invest Ophthalmol Vis Sci 1989; 30(Suppl): 27.
  13. Repo LP, Suhonen MT, Teräsvirta ME, Koivisto JK. Color Doppler imaging of the ophthalmic artery blood flow spectra of patients who have had a transient ischemic attack. Correlations with generalized iris transluminance and pseudoexfoliation syndrome. Ophthalmology 1995; 102: 1199-1205.
  14. Mitchell P, Wang JJ, Smith W. Association of pseudoexfoliation with increased vascular risk. Am J Ophthalmol 1997; 124: 685-687.
  15. Linnér E, Popovic V, Gottfries CG, et al. The exfoliation syndrome in cognitive impairment of cerebrovascular or Alzheimer's type. Acta Ophthalmol Scand 2001; 79: 283-285.
  16. Cahill M, Early A, Stack S, Blayney AW, Eustace P. Pseudoexfoliation and sensorineural hearing loss. Eye 2002; 16: 261-266.
  17. Shaban RI, Asfour WM. Ocular pseudoexfoliation associated with hearing loss. Saudi Med J 2004; 25: 1254-1257.
  18. Akarsu C, Unal B. Cerebral haemodynamics in patients with pseudoexfoliation glaucoma. Eye 2005; 19: 1297-1300.
  19. Galassi F, Giambene B, Menchini U. Ocular perfusion pressure and retrobulbar haemodynamics in pseudoexfoliative glaucoma. Graefe's Arch Clin Exp Ophthalmol 2008; 246: 411-416.
  20. Praveen MR, Shah SK, Vasavada AR, et al. Pseudoexfoliation as a risk factor for peripheral vascular disease: a case-control study. Eye 2011; 25: 174-179.
  21. Yüksel N, Anik Y, Altintas O, Onur I, Caglar Y, Demirci A. Magnetic resonance imaging of the brain in patients with pseudoexfoliation syndrome and glaucoma. Ophthalmologica 2006; 220: 125-130.
  22. Streeten BW, Gibson SA, Dark AJ. Pseudoexfoliative material contains an elastic microfibrillar-associated glycoprotein. Trans Am Ophthalmol Soc 1986; 84: 304-320.
  23. Schlötzer-Schrehardt U. Genetics and genomics of pseudoexfoliation syndrome/glaucoma. Middle East Afr J Ophthalmol 2011; 18: 30-36.
  24. Thorliefsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007; 317: 1397-1400.
  25. Fingert JH, Alward WL, Kwon YH, Wang K, Streb LM, Sheffield VC, et al. LOXL1 mutations are associated with exfoliation syndrome in patients from the Midwestern United States. Am J Ophthalmol 2007.
  26. Hewitt AW, et al. Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people. Hum Mol Genet 2007; Nov. 23 (Epub ahead of print).
  27. Hayashi H, Gotoh N, Ueda Y, et al. Lysyl Oxidase-like 1 Polymorphisms and Exfoliation Syndrome in the Japanese Population. Am J Ophthalmol 2008; Jan 15 (Epub ahead of print).
  28. Fan B, Pasquale LR, Rhee D, Li T, Haines JL, Wiggs JL. LOXL1 promoter haplotypes are associated with exfoliation syndrome in a U.S. Caucasian population. Invest Ophthalmol Vis Sci 2011; 52: 2372-2378.
  29. Koliakos GG, Konstas AGP, Schlötzer-Schrehardt U, et al. Ascorbic acid concentration is reduced in the aqueous humor of patients with exfoliation syndrome. Am J Ophthalmol 2002; 134: 879-883.
  30. Yilmaz A, Adiguzel U, Tamer L, et al. Serum oxidant/antioxidant balance in exfoliation syndrome. Clin Experiment Ophthalmol 2005; 33: 63-66.
  31. Koliakos GG, Konstas AGP, Schlötzer-Schrehardt U, et al. 8-Isoprostaglandin F2a and ascorbic acid concentration in the aqueous humour of patients with exfoliation syndrome. Br J Ophthalmol 2003; 87: 353-356.
  32. Cumurcu T, Gunduz A, Ozyurt H, Nurcin H, Atis O, Egri M. Increased oxidative stress in patients with pseudoexfoliation syndrome. Ophthalmic Res 2010; 43: 169-172.
  33. Zenkel M, Lewczuk P, Junemann A, Kruse FE, Naumann GO, Schlotzer-Schrehardt U. Proinflammatory cytokines are involved in the initiation of the abnormal matrix process in pseudoexfoliation syndrome/glaucoma. Am J Pathol 2010; 176: 2868-2879.
  34. Schlotzer-Schrehardt U. Oxidative stress and pseudoexfoliation glaucoma. Klin Monatsbl Augenheilkd 2010; 227: 108-113.
  35. Sawada H, Fukuchi T, Tanaka T, Abe HT. Tumor necrosis factor-alpha concentrations in the aqueous humor of patients with glaucoma. Invest Ophthalmol Vis Sci 2010; 51: 903-906.
  36. Ghanem AA, Arafa LF, El-Baz A. Connective tissue growth factor and tissue Inhibitor of matrix metalloproteinase-2 in patients with exfoliative glaucoma. Curr Eye Res 2011; 36: 540-545.
  37. Browne JG, Ho SL, Kane R, et al. Connective tissue growth factor is increased in pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci 2011; Feb. 17 (Epub ahead of print).
  38. Ho SL, Dogar GF, Wang J, et al. Elevated aqueous humour tissue inhibitor of matrix metalloproteinase-1 and connective tissue growth factor in pseudoexfoliation syndrome. Br J Ophthalmol 2005; 89: 169-173.
  39. Määttä M, Tervahartiala T, Harju M, et al. Matrix metalloproteinases and their tissue inhibitors in aqueous humor of patients with POAG, XFS, and exfoliation glaucoma. J Glaucoma 2005; 14: 64-69.
  40. Leibovitch I, Kurtz S, Shemesh G, et al. Hyperhomocystinemia in pseudoexfoliation glaucoma. J Glaucoma 2003; 12: 36-39.
  41. Vessani RM, Liebmann JM, Jofe M, Ritch R. Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol 2003; 136: 41-46.
  42. Bleich S, Roedl J, Von Ahsen N, Schlötzer-Schrehardt U, Reulbach U, Beck G, et al. Elevated homocysteine levels in aqueous humor of patients with pseudoexfoliation glaucoma. Am J Ophthalmol 2004; 138: 162-164.
  43. Roedl JB, Bleich S, Reulbach U, et al. Homocysteine in tear fluid of patients with pseudoexfoliation glaucoma. J Glaucoma 2007; 16: 234-239.
  44. Roedl JB, Bleich S, Reulbach U, et al. Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma. J Neural Transm 2007; 114: 571-575.
  45. Puustjärvi T, Blomster H, Kontkanen M, et al. Plasma and aqueous humour levels of homocysteine in exfoliation syndrome. Graefe's Arch Clin Exp Ophthalmol 2004; 242: 749-754.
  46. Altintas O, Maral H, Yuksel N, Karabas VL, Dillioglugil MO, Caglar Y. Homocysteine and nitric oxide levels in plasma of patients with pseudoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 2005; 243: 677-683.
  47. Zee RY, Mora S, et al. Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C>T polymorphism, nutrient intake, and incident cardiovascular disease in 24,968 initially healthy women. Clin Chem 2007; 53: 845-851.
  48. Lobo A, Naso A, Arheart K, et al. Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. Am J Cardiol 1999; 83: 821-825.
  49. Calabrese V, Cornelius C, Mancuso C, et al. Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem Res 2008; 33: 2444-2471.
  50. Cole GM, Lim GP, Yang F, et al. Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol Aging 2005; 26 (Suppl 1): 133-136.
  51. Ritch R, Araie M, Leung D. Non-pharmaceutical therapy for glaucoma. In: Weinreb RN, et al. (Eds.), Medical treatment of glaucoma. Consensus Series 7. Amsterdam: Kugler Publications; 2010.
  52. Garcia-Alloza M, Borrelli LA, Rozkalne A, et al. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 2007; 102: 1095-1104.

Issue 13-2

Table of Contents Editor's Selection

Change Issue

advertisement

Oculus