Early-Onset Exfoliation Syndrome: A Literature Synthesis.

PRECIS
We conducted a literature review of younger patients with exfoliation syndrome in an attempt to identify case similarities and better understand disease etiology.


PURPOSE
Exfoliation syndrome (XFS), which predisposes to secondary glaucoma is a strongly age-related condition. We performed a literature review of XFS and exfoliation glaucoma (XFG) in patients aged ≤40 years to examine potential common characteristics and gain clues to its etiology.


METHODS
We conducted a broad literature search with appropriate keywords and manually extracted key demographic and ocular features on younger XFS and XFG cases. Articles that did not provide past ocular history on early-onset XFS/XFG were excluded.


RESULTS
We identified 12 cases of XFS and XFG in patients from 13-40 years old (8 females; 11 White; 5 from Iran). All had past ocular history remarkable for intraocular surgery for other glaucoma conditions (7 cases), other ocular diseases (3 cases), or ocular trauma (2 cases).


CONCLUSION
All reported early-onset XFS and XFG cases arise in the setting of events that produced significant disruption of the blood aqueous barrier. Understanding the metabolic alterations of aqueous humor from such cases could provide clues regarding how exfoliation material forms.

(J Glaucoma 2021;30:e164-e168) E xfoliation syndrome (XFS) was first discovered by Dr John Lindberg in 1917 when examining iris changes in eyes of older patients. 1 He described the presence of grayish flakes at the pupillary border and anterior lens capsule in 50% of patients with glaucoma. Lindberg's observed associations between XFS, age, and glaucoma remain robust; however, although great strides in the elucidation of this disease have been made in the last decade, 2 the genetic and mechanistic causes of XFS and exfoliation glaucoma (XFG) remain largely unknown.
XFS/XFG primarily affect older individuals. In a US-based study of incident disease, the risk of suspected or definite XFG was 46-fold greater in patients over 75 years of age compared with patients aged 40 to 55 years. 3 The purpose of this study is to examine the characteristics of XFS/XFG in younger patients, which are uncommon, to provide disease insights.

METHODS
We performed a literature search of the National Library of Medicine's PubMed Database in February 2020 using the following keywords "exfoliative," "exfoliation," "pseudoexfoliation," "syndrome," "glaucoma," "early-onset," and "premature." We manually extracted demographic and ocular features. Articles that did not provide past ocular history on early-onset XFS/ G were excluded.

RESULTS
In total, 12 cases of XFS in patients age 40 and under were identified. The small sample size precluded statistical analysis. These cases were described between 1967 and 2019 (Table 1). Patients ranged from 13 to 40 years of age. Eight patients were female; 11 patients were White and 1 patient was Asian. Five were from Iran, 3 from the United States, 1 from Germany, 1 from India, 1 from Turkey, and 1 from Greece/Georgia (of Greek ethnicity who was born and raised in Georgia and later moved to Greece at age 16 years).
All cases were unilateral. No case developed exfoliation material (XFM) de novo; all patients had prior intraocular surgery. The mean number of surgeries was 2 (range, 1 to 7). Seven patients had intraocular surgery for pre-existing glaucoma, 4,6-8,11 2 had penetrating keratoplasty (PKP) for keratoconus, 9,11 1 had extracapsular cataract extraction for childhood cataract, 5 and 2 patients had repair of limbal laceration with excision of prolapsed uveal tissue after ocular trauma. 7,10 Ten of the 12 cases involved iris surgery. The remaining 2 cases had PKP, which were performed in 1953 and 1974. At that time, PKPs were routinely completed with a peripheral iridectomy. As a result, it is likely that all 12 cases involved the manipulation of iris tissue. Of the 7 patients with pre-existing glaucoma, 4 had congenital glaucoma, 2 had juvenile open-angle glaucoma, 1 had primary open-angle glaucoma. It was not specified whether any patient had a family history of XFS/XFG. Two patients had a family history of any glaucoma, but the family history of only 6 patients was mentioned.

DISCUSSION
Although XFS is the most common identifiable cause of open-angle glaucoma, 12 the pathogenesis leading to its development is unclear. Several risk factors have been identified including environmental, most notably climatic, 3,13-15 and genetic factors, most notably, harboring-specific LOXL1 alleles. 16 We undertook an analysis on the basis of early chronological age to gain further insights into XFS. All cases present convincing clinical evidence for the presence of XFM and in 1 case, conjunctival biopsy provided ultrastructural confirmation of the disease. 8 All patients with early-onset XFS had a significant past ocular history of prior ocular surgery. There is insufficient evidence that a family history of glaucoma could play a role in these cases. Certainly, there is no mention of genetics in the XFS/XFG cases summarized here. Our sample is too small to draw inferences regarding geographic or other environmental predisposition to the disease. During our   17 Pakistan, 18 Australia, 19 Saudi Arabia, 20 Greece, 21 South Africa, 22 Iceland, 23 Russia, 24 India, 25 and Ethiopia. 26 Patients' ocular findings at the time of diagnosis and ocular histories are unknown. As a result, these patients were excluded from our study. In 2 cases, PKP for keratoconus preceded the development of XFS. 9,11 XFM was noted 6 to 11 years after corneal grafting. Küchle and Naumann 9 reported on a 46-year-old patient with keratoconus who developed XFS in both eyes 6 years after bilateral corneal grafts from an 81-year-old patient without a known history of XFS. There was an additional report of XFS after PKP in the literature, which suggests PKP may predispose XFS. 27 We also find no association between keratoconus and XFS. Küchle and Naumann suggest that the grafts somehow transmitted the disease to these patients, possibly through an infectious agent. The concept that XFS is caused by a microbial agent has been entertained previously. There is 1 study suggesting that prior herpes simplex I might be causative. 28 There are a few reports exploring a possible role for Helicobacter pylori, but these results are contradictory. [29][30][31] Others have proposed that prions contribute to the development of XFS. 32,33 In the cases analyzed, there was a history of multiple prior surgeries for glaucoma, cataract surgery, PKP with peripheral iridectomy, or repair of a limbal laceration with excision of prolapsed iris. Collectively, all these early-onset cases had incisional surgery of the iris. Reports have proposed that iris injury may contribute to the development of XFS in younger individuals. 7,8,34 Although the exact pathophysiology is unknown, it is likely that iris vasculature damage causes disruption of the blood-aqueous barrier, production of inflammatory cytokines and growth factors, and formation of XFM. 4,5,35 The ciliary epithelium is the primary site of the bloodaqueous barrier 36 and it is also the prime site for XFM formation. 37 Interestingly, patients with XFS demonstrate other findings consistent with a disrupted blood-aqueous barrier such as pseudouveitis, early capsular contraction syndrome after uncomplicated cataract surgery, and more prolonged aqueous humor flare after trabeculectomy when compared with primary open-angle glaucoma patients. 38 XFS likely develops when chronic low-grade insults cause matrix remodeling. Cellular stress leads to the formation of elastin stress microfibers, which are expulsed from cellular surfaces when ciliary epithelia generate profibrotic aqueous humor. Glycosaminoglycans (electronegative at physiological pH) then neutralize elastin stress fibers (electropositive at physiological pH). Elastin stress microfibers and glycosaminoglycans are likely crosslinked by LOXL1, resulting in XFM formation. 39 Although the mechanism relating surgery to elastin stress microfiber formation is unclear, aqueous humor composition may provide a clue. Aqueous humor formed by the ciliary processes demonstrates profoundly altered biochemical profiles in XFS. Tens of biochemicals are found in increased quantities in patients with XFS compared with controls. These include biochemicals implicated in (1) fibrosis, including connective tissue growth factor (CTGF), [40][41][42] tissue inhibitor of matrix metalloproteinase, 40,42 and basic fibroblast growth factor 43 : (2) inflammation, including interleukin-6, 35,44 interleukin-8, 35,44 complement factor 3, 45 and kininogen-1 45 : and (3) angiogenesis, including vascular endothelial growth factor 46 and endothelin-1. 47 Repeated studies have identified transforming growth factor-β1 44,48,49 and CTGF [40][41][42] as biomarkers of XFS. These 2 biochemicals have also been implicated in senescence, [50][51][52][53] which may relate to the high incidence of XFS in older individuals. It is possible that a major traumatic insult in a young individual causes excessive secretion of transforming growth factor-β1 and CTGF into the aqueous humor, leading to the formation of XFM.
Ideally, future research would compare the biochemical composition of aqueous humor in XFS, early-onset XFS, young controls, and older controls. However, this approach may prove impossible on the basis of how rare early-onset XFS seems to be. Instead, a prospective study of younger patients with a history of trauma and/or intraocular surgery could be conducted. The study could include thorough clinical examination and documentation of XFS findings, as well as ultrastructural analysis and aqueous humor biochemical profiles. Future research could also compare the XFM in early-onset XFS with the XFM of older patients with XFS. Previous research has suggested that early-onset XFM aggregates may be smaller and less compact than aggregates of older XFS patients. 8 Konstas et al 8 inferred that this finding could be caused by decreased aggregate accumulation time. However, additional ultrastructural analyses with biopsies performed at diagnosis and periodically thereafter are needed to confirm this hypothesis.
We studied the characteristics of patients with earlyonset XFS as an age-based phenotype analysis to better understand the pathogenesis of XFS. All patients with earlyonset XFS had prior intraocular surgery. Although any conclusion should be taken with caution, the present literature suggests that surgical trauma in younger patients may trigger XFS in some cases. Although the exact mechanism by which surgery causes early-onset XFS is unknown, an aqueous humor biochemical profile may provide disease insights.