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Exfoliation Syndrome

Exfoliative Syndrome

Exfoliation syndrome is an ophthalmologic disease of unknown etiology that is associated with progressive accumulation of granular extracellular material in distinct ocular tissues and secondary glaucoma. This disease may also be referred to as exfoliation glaucoma, pseudoexfoliation syndrome and pseudoexfoliation glaucoma.


Presentation

ES patients may be asymptomatic. In these cases, accumulation of granular protein in the anterior chamber or other ocular tissues is a mere incidental finding of an ophthalmologic examination. If patients are symptomatic, complaints result from secondary complications of ES.

In case of glaucoma, patients often report visual field deficits. ES is more frequently associated with chronic open-angle glaucoma than acute and painful angle-closure glaucoma. However, ES-associated glaucoma progress faster than open-angle glaucoma triggered by other pathologies. A considerable increase in intraocular pressure is characteristic although not diagnostic. Those individuals that suffer from cataract will complain about diminished visual acuity. Lenticular opacity may be visible to the naked eye. If degeneration of zonule fibers causes lens dislocation, this may lead to monocular diplopia or glaucoma.

Despite its etiology, ES-related symptoms usually affect one eye only. However, patients may present with complaints regarding the other eye within a few years.

Hunting
  • Molecular Vision. 2013; 19: 1146-1152 14 Genome-wide association studies in the hunt for genes causing primary open-angle glaucoma: a review Kathryn P Burdon Clinical & Experimental Ophthalmology. 2012; 40(4): 358 15 Changes in lysyl oxidase (LOX) distribution[meajo.org]
  • Mathew CG , Palmer CN , Plomin R , Rautanen A , Sawcer SJ , Trembath RC , Viswanathan AC , Wood NW , Spencer CC , Band G , Bellenguez C , Freeman C , Hellenthal G , Giannoulatou E , Pirinen M , Pearson R , Strange A , Su Z , Vukcevic D , Langford C , Hunt[ncbi.nlm.nih.gov]
Severe Clinical Course
  • There is a significantly higher frequency and severity of optic nerve damage at the time of diagnosis, worse visual field damage, poorer response to medications, more severe clinical course, and more frequent necessity for surgical intervention.[glaucoma.net]
Anisocoria
  • Anisocoria, Physiologic (Anisocoria) Anisometropia Anisometropic Amblyopia (Amblyopia) Anophthalmia (Anophthalmos) Anophthalmos Anterior Ischemic Optic Neuropathy (Optic Neuropathy, Ischemic) Anterior Uveitides (Uveitis, Anterior) Anton Syndrome (Blindness[provisu.ch]
Retinal Pigmentation
  • pigment epithelium; SC, Schlemm's canal; ST, stroma; TM, trabecular meshwork; original magnification, 100.[ncbi.nlm.nih.gov]

Workup

Diagnosis of ES requires an ophthalmologic examination. As per definition, detection of fibrillar or granular material at the margin of the iris or in the anterior chamber are diagnostic for this disease. In the majority of cases, accumulated protein is easily during slit-lamp examination, and dilation of the pupil is not required. Rarely, precipitates are not visible during slit-lamp examination because they concentrate in ocular tissues that are not accessible by this technique. Of note, while glaucoma, cataract or lens dislocation are generally unilateral, accumulation of abnormal protein can often be detected in both eyes.

Diagnostic workup should also aim at evaluating the condition of distinct ocular tissues, e.g., lens, ciliary body and optic nerve. Simple lit-lamp examination does not suffice; gonioscopy is required to visualize the iridocorneal angle. Upon administration of mydriatic agents, protein precipitates may be raised and may float within the aqueous humor. The patient's intraocular pressure needs to be measured.

Besides an accumulation of abnormal protein, cataract and lens dislocation, the following conditions may be detected in an ES patient:

Every patient diagnosed with ES should undergo regular follow-ups in order to monitor their intraocular pressure.

White Matter Lesions
  • In many populations, significant associations between XFS and various systemic vascular diseases including elevated plasma homocysteine level, myocardial dysfunction, stroke, aortic aneurysm, and white matter lesions were found.[ncbi.nlm.nih.gov]

Treatment

Treatment of ES is symptomatic and needs to be adjusted to the symptoms of each individual patient.

If accumulated protein interferes with drainage of aqueous humor and an affected person develops glaucoma, standard techniques to improve fluid outflow are generally applied (e.g., application of miotics and/or diuretics). However, ES-related glaucoma is often resistant to medication and in most cases, sufficient reduction of the intraocular pressure cannot be achieved. Also, the risk of posterior synechiae formation needs to be considered. In intractable cases, argon laser trabeculoplasty or selective laser trabeculoplasty are indicated. Both are equally effective in patients suffering from glaucoma due to ES and short-term results are generally satisfying. If necessary, trabeculectomy may constitute an alternative therapeutic option. It has to be noted that recurrence of glaucoma is possible and patients should continue to undergo regular follow-ups.

Some patients may require cataract surgery or combined glaucoma and cataract treatment. Similar to the above described therapeutic approach to glaucoma, standard procedures are carried out to treat cataract. Post-surgically, close monitoring is required due to an increased risk of complications. This also applies if no anomalies were registered during surgery.

Prognosis

When compared with patients presenting with other types of glaucoma, the prognosis for ES is doubtful. In general, ES-associated glaucoma is related to higher intraocular pressure, responds poorly to medication therapy and recurs frequently. More sophisticated therapeutic regimes are usually required to lower intraocular pressure and to avoid progression of visual impairment. Moreover, ES patients who undergo cataract surgery have higher rates of complications [10].

Etiology

The etiology of ES is not entirely clear. The fact that the majority of ES patients are older than 70 years argues for degenerative mechanisms. However, deposition of granular protein is not a part of the physiological aging process and most people never show any signs of ES. Possibly, genetic factors predispose for those pathophysiological mechanisms that finally trigger the disease.

Recently, genetic variants of the LOXL1 (lysyl oxidase homolog 1) gene could be identified as risk factors for ES. The gene is located on chromosome 15 and encodes for a lysyl oxidase-like protein. In general, lysyl oxidases are enzymes that modify lysine side chains and thus alter the properties of the corresponding protein; they are of major importance for maturation and stabilization of connective tissue fibers. In detail, the LOXL1 protein seems to play an important role in tropoelastin cross-linking [4]. Distinct studies revealed several single-nucleotide polymorphisms (SNPs) that render carriers much more susceptible to ES. Two of these SNPs are located in the first exon of LOXL1 (rs1048661 / Arg141Leu and rs3825942 / Gly153Asp), a third one can be found in its first intron (rs2165241) [5]. A significant share of patients carries both intronic SNPs [6]. It has been estimated that the risk to develop ES is several hundredfold increased in patients who are homozygous for any of these SNPs. However, heterozygous individuals may also develop ES: According to current knowledge, the above mentioned gene defects are inherited with an autosomal dominant trait with incomplete penetrance.

Of note, the prevalence of the aforementioned SNPs by far exceeds the prevalence of ES. Thus, additional etiological factors have to be considered. So far, it can only be speculated that environmental conditions contribute to symptom onset, but reliable data are not yet available.

Epidemiology

ES is distributed throughout the whole world, but geographical variations have been reported. The disease is most frequently diagnosed in Caucasians, particularly in those of European descent. Prevalence rates among the elderly average 10% in Central Europe, while up to 25% of Northern Europeans aged 70 years and older show signs of ES [7]. In fact, ES is typically a disease of the elderly and the majority of patients are older than 70 years. As the world's population becomes older, incidence and prevalence of ES are expected to increase over the next years.

ES may account for about 10% of all cases of glaucoma; in turn, approximately 10% of patients who present with ES are also diagnosed with increased intraocular pressure. The life-time risk of glaucoma in ES patients probably exceeds 60% [8].

Sex distribution
Age distribution

Pathophysiology

As has been described above, genetic defects of the LOXL1 gene are considered major risk factors for ES. This gene encodes for an enzyme that is required for maturation and stabilization of elastic fibers. The main components of elastic fibers are elastin and microfibrils, whereby elastin is a network of tropoelastin molecules that are interconnected. Cross-linking of tropoelastin units occurs during elastogenesis and is mediated by the aforementioned enzyme. Disturbances of elastogenesis result in diseases like Marfan syndrome or cutis laxa.

Possibly, ES should be added to that list. This pathology is characterized by pathological accumulation of fibrillar protein in distinct ocular tissues, but protein deposits are mainly found in close proximity to the margin of the iris and in the anterior chamber. In order to understand the current hypothesis regarding ES pathogenesis, the following facts should be recalled: The aqueous humor is produced by the ciliary body, passes iris and pupil, and is finally drained through anterior chamber, trabecular meshwork and Schlemm's canal. While the aqueous humor is still in the posterior chamber, it is in direct contact with the zonular fibers whose main functions are to anchor the lens in its physiological position and to allow for changes of the lens' shape in order to focus.

Zonule fibers contain important amounts of elastin. Consequently, dysfunction of the protein encoded for by LOXL1 may cause structural alterations of those suspensory fibers, possibly resulting in granular precipitates. If sufficiently small, they may hauled along with the aqueous humor and end up in the anterior chamber or even in the trabecular meshwork. Here, they interfere with the outflow of aqueous humor and this condition leads to glaucoma. The fact that lens dislocation is observed in some ES patients supports this hypothesis.

According to another theory, deposited proteins are not carried away from their site of precipitation but accumulate directly in the anterior chamber. The fact that proteins may also be found in other ocular tissues and sometimes even in organs like heart, lung, liver, kidney and cerebral meninges [9]. Presumably, the zonule fibers are not the only source of abnormal protein, but accumulation within the anterior chamber is most likely a mechanic effect caused by aqueous humor flow and this condition is what causes glaucoma.

Prevention

Due to considerable knowledge gaps regarding disease etiology, no specific measures can be recommended to prevent ES.

The prevalence of ES-associated SNPs is high in populations of determined countries, but not all carriers develop the disease. Thus, it needs to be assumed that additional factors contribute to symptom onset - possibly environmental conditions. Future research may shed more light on the latter and then, prevention might become possible.

In order to avoid a late diagnosis of ES and possible optic nerve damage due to secondary glaucoma, annual ophthalmologic examinations are recommended to elder patients.

Summary

Exfoliation syndrome (ES) is an ophthalmologic disease characterized by progressive accumulation of fibrillar protein in distinct ocular tissues, mainly in close proximity to the iris and in the anterior chamber [1]. Presumably, ES may be classified as a degenerative disorder that affects genetically predisposed individuals. The pathogenetic mechanisms that provoke protein deposition are not yet known and because exfoliation may not be the cause of the disease, some physicians prefer to refer to it as pseudoexfoliation syndrome. Moreover, the latter term avoids confusion with true exfoliation of the lens capsule, a distinct entity [2].

Deposited material may interfere with the outflow of aqueous humor and thus cause an increase in intraocular pressure and glaucoma. Depending on the precise localization of drainage obstruction - fibrillar proteins may block the iridocorneal angle, the trabecular meshwork or Schlemm's canal - both open-angle glaucoma and angle-closure glaucoma may be provoked. Because glaucoma is the most characteristic symptom of ES, the terms exfoliation glaucoma and pseudoexfoliation glaucoma are used interchangeably with the aforementioned designations of the disease. However, if a patient undergoes an ophthalmologic examination for any other reason, ES may be diagnosed before any type of glaucoma develops. Additionally, granular protein deposits may also affect cornea, lens and other intraocular tissues, and patients who suffer from ES may present with cataract, lens dislocation or retinal vasculopathies [3].

ES is a very common cause of glaucoma, particularly in the elderly. Prevalence varies with geographical location and highest rates have been reported in Europe. If left untreated, ES and complications may cause severe visual impairment and blindness, but because of significant knowledge gaps regarding the etiology of the disease, causative treatment is not available. Consequently, glaucoma, cataract and other ES-associated pathologies are treated symptomatically.

Patient Information

Exfoliation syndrome, sometimes also referred to as exfoliation glaucoma, pseudoexfoliation syndrome and pseudoexfoliation glaucoma is an eye disease of unclear etiology. It is characterized by accumulation of fibrillar, abnormal protein in distinct ocular tissues, mainly in close proximity to the iris and in the anterior chamber. While these proteins are generally detected during an ophthalmologic examination, they may not cause any symptoms in years. However, most patients eventually develop increased intraocular pressure and glaucoma.

In order to understand why this happens, one needs to know about aqueous humor production and drainage. This fluid is secreted by the ciliary body, which is located behind the iris. It flows through the pupil into the anterior chamber and is absorbed within a trabecular meshwork at the bottom of that chamber. If protein precipitates accumulate here, the obstruct aqueous humor drainage and consequently, the intraocular pressure rises. This results in glaucoma, optic nerve damage and visual impairment.

Moreover, exfoliation syndrome may cause cataract or lens dislocation. Accordingly, affected individuals may also note diminished visual acuity, lenticular opacity or monocular diplopia.

Treatment is symptomatic, i.e., patients may receive therapy for glaucoma, cataract or lens dislocation. The ophthalmologist may try to relieve symptoms by means of drug therapy, but surgery is often inevitable. Due to relatively high rates of post-surgical complications and recurrence, regular follow-ups are strongly recommended even if no symptoms are perceived anymore.

References

Article

  1. Plateroti P, Plateroti AM, Abdolrahimzadeh S, Scuderi G. Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma: A Review of the Literature with Updates on Surgical Management. J Ophthalmol. 2015; 2015:370371.
  2. Ng AL, Marcet MM, Lai JS, Yeung JC. Age-Related True Exfoliation of the Lens Capsule: Phacoemulsification Surgery Results. Case Rep Ophthalmol. 2015; 6(3):401-407.
  3. Bhattacharjee H, Saxena RK, Medhi J. Bilateral spontaneous anterior dislocation of intraocular lens with the capsular bag in a patient with pseudoexfoliation. Indian J Ophthalmol. 2015; 63(10):796-798.
  4. Schlötzer-Schrehardt U, Pasutto F, Sommer P, et al. Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol. 2008; 173(6):1724-1735.
  5. Fan BJ, Pasquale L, Grosskreutz CL, et al. DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a U.S. clinic-based population with broad ethnic diversity. BMC Med Genet. 2008; 9:5.
  6. Pasutto F, Krumbiegel M, Mardin CY, et al. Association of LOXL1 common sequence variants in German and Italian patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci. 2008; 49(4):1459-1463.
  7. Mossböck G, Renner W, Faschinger C, Schmut O, Wedrich A, Weger M. Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population. Mol Vis. 2008; 14:857-861.
  8. Jeng SM, Karger RA, Hodge DO, Burke JP, Johnson DH, Good MS. The risk of glaucoma in pseudoexfoliation syndrome. J Glaucoma. 2007; 16(1):117-121.
  9. Tarkkanen A, Reunanen A, Kivela T. Frequency of systemic vascular diseases in patients with primary open-angle glaucoma and exfoliation glaucoma. Acta Ophthalmol. 2008; 86(6):598-602.
  10. Hemalatha BC, Shetty SB. Analysis of Intraoperative and Postoperative Complications in Pseudoexfoliation Eyes Undergoing Cataract Surgery. J Clin Diagn Res. 2016; 10(4):NC05-08.

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Last updated: 2019-07-11 21:03