SECONDARY GLAUCOMA
| EXFOLIATION SYNDROME AND EXFOLIATIVE GLAUCOMA —Robert Ritch, MD, Surgeon and Chief of Glaucoma
Service, New York Eye and Ear Infirmary, New York City
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| Background: exfoliation syndrome (XFS) most common identifiable cause of glaucoma; worldwide, XFS thought to afflict
60 to 70 million people; ocular manifestation of systemic disease; prevalence increases with age; racial and ethnic variations;
often misdiagnosed as primary open-angle glaucoma (POAG)
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 | Reasons for misdiagnosis: failure to dilate pupil or to examine lens after dilation; low index of suspicion; inability to
recognize condition; underestimating importance of accurate diagnosis
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| Epidemiology: Eskimos only ethnic group that does not develop XFS; syndrome common in POAG patients in Greece,
throughout Middle East, Ireland, and Scandinavia; found throughout Asia; rare to nonexistent in subSaharan Africa
(recently reported in Gambia and seen in Zulus); seen in Spain (found in 45% of Basque glaucoma patients); prevalence
high among people of Celtic or Scandinavian descent; highest documented prevalence seen in Russian Jewish
immigrants in New York
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| XFS vs POAG: XFS associated with worse prognosis, higher mean intraocular pressure (IOP), and more IOP fluctuation;
rate of conversion of ocular hypertension to glaucoma higher among patients with XFS; more disc and visual-field damage
at presentation; patients with exfoliation fail medical therapy and undergo surgery more often than those with POAG,
and more eventually go blind
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| Clinical appearance: central disc composed of microfibrils believed to be deposited from aqueous; surrounded by intermediate
clear zone and peripheral granular zone; exfoliation material (thought to be from iris) deposited in clear zone;
when material in clear zone becomes too thick, iris develops clefts over it; granular zone develops and may present as
2 or 3 layers
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| Pregranular appearance: sometimes develops before intermediate zone laid down; more common in certain populations;
characterized by fine striations of exfoliation material coming off temporally; best visible with lights down and wide slit
beam angled at 45o toward eye and patient looking temporally (can see it ≈3 mm from center of pupil; also may see it on
pupillary border); sometimes resembles uveitis due to rubbing off of exfoliation material; material also may appear in
vitreous and on intraocular lenses (IOLs); has affinity for surfaces
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| Other disease characteristics: frequently described as unilateral, but really asymmetric (one eye may be afflicted more severely,
but disease occurs in both); according to recent study, about two thirds of cases “unilateral” (clinically meaningful
in only one eye); disease progression varies among patients; could be 2 different disease processes, or perhaps
disease in one eye elicits immune suppression in other eye (raises possibility of inflammatory component that, combined
with immune suppression, produces unilateral presentation); in one study, 15 yr after initial diagnosis, 50% of
patients developed XFS in other eye
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| Pigment dispersion: exfoliation material rubs and diffuses into iris pigment epithelium; check for pigment in anterior
chamber after dilation (in patients with XFS, also check IOP after dilation, as it can rise 2-3 hr afterward due to pigment
in anterior chamber); pigment usually rubbed off near sphincter; pigment sticky and may adhere to cornea or
iris surface; pigment also may accumulate in angle and on Schwabe’s line; eyes with glaucoma have more pigment
than uninvolved eyes, and amount of pigment in angle correlates with severity of glaucomatous damage; in eyes
without XFS, pigment signs may indicate increased risk (exfoliation material found on conjunctival biopsy in some
patients)
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| Exfoliation material: strongly periodic acid-Schiff (PAS)-positive; stains with colloidal iron, but not form of amyloid;
made of repeating subunits ≈55 nm in diameter; mature fibers composed of fibrils (17 nm in diameter) that are, in turn,
composed of microfibrils (3-7 nm in diameter); microfibrils deposited in central disc, while granular zone contains mature
fibrils; microfibrils aggregate into mature fibrils as material extruded from cell
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| Mechanism of open-angle glaucoma: not known; exfoliation material or pigment may block trabecular meshwork (both
entities now thought to be involved); pigment sticks to exfoliation material, blocking intertrabecular spaces; trabecular
cell dysfunction may contribute; in some patients, concurrence of exfoliation and POAG may be coincidental; pathophysiology
unknown
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| Angle closure: once believed rare, but some reports of high incidence of narrow angles among patients with XFS; in speaker’s
study of patients with appositional closure or occluded angles, 28% had XFS
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| Predisposing factors: zonular weakness, allowing lens to thicken and come forward; iris rigid and thick, due to exfoliation material
in stroma; pupil sluggish and does not dilate normally; posterior synechiae and cataracts develop (cataracts etiologically
related to XFS; when each unilateral, they “almost invariably occur in the same eye”); XFS associated with deeper
anterior chambers than in patients without XFS; eyes with acute angle closure often more myopic than those without
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| Other ocular associations: posterior synechiae, especially in patients with history of prolonged treatment with miotics;
zonular destruction; tear film disturbance; decreased goblet cells; increased incidence of dry eye; retinal vein occlusion;
vascular ischemic disease; microneovascularization may extend into posterior synechiae, sometimes leading to
triple hyphema formation
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| Relationship between XFS and cataracts: eyes with both conditions have markedly reduced concentration of ascorbate,
compared to eyes with cararacts only; aqueous level of 8-isoprostaglandin F2a (marker of oxidative damage) significantly
decreased in eyes with XFS; in Italian study, patients with POAG also had increased oxidative damage in trabecular
meshwork, which correlated with IOP and visual field damage
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| Blood-aqueous barrier: damaged in eyes with XFS; total aqueous concentrations of protein, IgG, and albumin increased;
hyaluronan also higher (associated with abnormal metabolism of glycosaminoglycans)
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| Risks of cataract surgery in eyes with XFS: complication rate declined since advent of phacoemulsification, but still higher
than in eyes without XFS; due largely to problems associated with zonular dehiscence; risk for late sequelae still high;
associated with chronic breakdown of blood-aqueous barrier; speaker recommends lifelong prednisone tid, 3 days per
week; incidence of posterior capsule opacification also increased, as well as protein deposition on IOL
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| Other late sequelae: capsular contraction; IOL decentration syndrome; subluxation; complications associated with brittle,
broken zonules; ultrasound biomicroscopy can show degree of zonular involvement
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| Ways to avoid complications of cataract surgery: use trypan blue on patients with XFS who undergo capsulorrhexis;
place iris hooks at 3, 6, 9, and 12 o’clock; some surgeons also use anterior capsule hooks; capsular tension rings help;
vertical chopping through dense lenses with exfoliation
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| Retinal vein occlusion: in study of 36 patients with central retinal vein occlusion (CRVO), those with exfoliation material
on slit-lamp examination underwent conjunctival biopsies; 22 patients (61%) positive for XFS
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| Protein deposits on IOL: resolve with steroids
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| Systemic problems associated with XFS: accumulation of exfoliation-like fibrils in many organs, including heart, lung,
meninges, skin, and liver, mostly in connective tissue; increased risk for transient ischemic attack, chronic cerebrovascular
disease, aortic aneurysm (findings mixed), Alzheimer’s disease, sensorineural hearing loss, blood flow abnormalities,
and hyperhomocysteinemia; no increased risk for myocardial infarction or stroke found; no correlation between
XFS and diabetes
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| Alzheimer’s disease: iris and ciliary epithelium types of neuroepithelium, so association with Alzhemier’s disease perhaps
not surprising; common link may be abnormal ubiquitination, although not found in XFS; Alzheimer’s protein A ⓵-42
found in aqueous humor of patients with XFS
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| Hyperhomocysteinemia: associated mainly with vascular diseases, including myocardial infarction, stroke, Alzheimer’s
disease, and retinal vein occlusion; causes abnormalities in homeostasis of extracellular matrix, dysfunction of vascular
endothelium, decreased nitric oxide levels, and proliferation of vascular muscle cells (all seen also in XFS); homocysteine
levels elevated in patients with XFS and those with exfoliative glaucoma; may play role in disease genesis;
if so, vitamins B6 , B12 , and folic acid may slow development
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| Development of XFS: thought to be related to conformational disorder involving fibrillin abnormality (explains zonular
damage); HNK1 epitope appears on many glycoproteins related to cell adhesion; marker of ocular exfoliation material,
but not found outside eye; significance unknown
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| Protein components: many basement membrane proteins and components of elastic fibril system involved; latent transforming
growth factor (TGF)- β binding proteins (LTBPs) 1 and 2 reported in intraocular and extraocular exfoliation
material; LTBP structural element in extracellular microfibrils, especially those containing fibrillin; activated complement
H also found, although implications unknown
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| XFS triggers: some evidence of genetic component; correlation with various blood groups reported, but nothing substantiated;
antinuclear antibodies found in aqueous of affected eyes in one study (never repeated); few patients developed
XFS years after iris surgery (possible relationship to trauma); some reports of possible correlation with exposure to ultraviolet
light, but findings contradictory; vascular nature of disorder unquestionable; inflammatory component possible;
may also be conformational disorder of fibrillin
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| Evidence of infectious etiology: study of married couples showed incidence of XFS to be higher than would be expected
by chance; Helicobacter pylori infection higher than average among people with XFS and exfoliative glaucoma, compared
to people with anemia; in one study, 14% of eyes with XFS had herpes simplex titers, compared to 2% of controls;
taken together, findings suggest infectious etiology, inflammatory component, and vascular complications
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| Prions: suggested as possible etiology
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| Treatment: 2% pilocarpine at bedtime prevents pigment epithelium and exfoliation material from rubbing off
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| International Exfoliation Syndrome Treatment Study: now comparing treatment with timolol or timolol and dorzolamide
to pilocarpine and latanoprost; 275 patients in 11 countries participating
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| Argon laser trabeculoplasty: initial response good, but late increases in IOP occur, possibly due to pigment overwhelming
trabecular meshwork; maintain on 2% pilocarpine
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| Surgery: good results reported with trabeculotomy or trabecular aspiraton
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| NEOVASCULAR GLAUCOMA —Steven R. Sarkisian, Jr., MD, Assistant Professor, Glaucoma Service, The Hamilton
Eye Institute at the University of Tennessee Health Science Center, Memphis
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| Causes: diabetes most common, followed by CRVO (usually occurs within 90 days of event; 20% of patients have preexisting
POAG or ocular hypertension); carotid occlusive disease next (ocular hypotension occurs first; restored perfusion increases
aqueous production, which raises IOP; visual prognosis poor because of extent of hypoxia); central retinal artery
occlusion rarer, but possible cause; uveitis (related to chronic inflammation; watch iris at pupillary margin; perform periodic
gonioscopic examinations); retinal disease (23% of patients with retinal detachment develop neovascularization of
iris [NVI]); malignant melanoma (related to size of tumor necrosis and extent of retinal detachment); retinoblastoma (depends
on posterior pole involvement)
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| Pathophysiology: symptom onset rapid; includes red, painful eye, possible nausea or vomiting, increased IOP; NVI usually
visible at pupillary margin (crosses iris to angle later; appearance of any NVI indicates gonioscopy)
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| Disease stages: first (preglaucoma)—characterized by normal IOP, open angle; NVI visible; second—NVI more florid;
inflammatory characteristics in aqueous; angle still open, but fibrovascular membrane growing and IOP rising; peripheral
anterior synechiae form and start covering angle; third (angle closure)—iris stroma flattens, appears smooth and
glistening; peripheral anterior synechiae worsen and close
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| Management: goals are to lower IOP and to eliminate cause of NVI (consult patient’s internist and obtain carotid ultrasonography
when necessary); apply laser as soon as possible (often solves problem by itself); refer for carotid endarterectomy
if necessary
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| Medications: steroids and atropine relieve inflammation and promote uveoscleral outflow; pilocarpine contraindicated
(decreases uveoscleral outflow)
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| Surgery: delay 1 to 4 wk until NVI reduced; if high IOP persists as NVI regresses, consider filter with antimetabolite; if IOP
>60 mm Hg, consider intravenous mannitol followed by drainage tube (treat as soon as possible); drainage implant preferred
if active inflammation and NVI present; if visual potential poor, consider transscleral cyclophotocoagulation;
retrobulbar alcohol another possibility
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| Surgical issues: trabeculectomy has higher rate of failure in these patients, especially if NVI active; filtering surgery almost
certain to fail unless antimetabolite used; consider using longer application or higher concentration of mitomycin
C; consider larger flap or block excision to ensure adequate postsurgical flow; consider anterior chamber washout if
blood clot occludes drainage tube; warn patient “it’s going to be a long haul”; use 5-fluorouracil if blebs form; perform
early laser suture lysis and follow closely; make judicious use of digital pressure or massage if bleb fails or IOP rises
(but beware of complications, including hyphema, iris incarceration in sclerostomy, or bleb rupture)
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Educational Objectives
| The goal of this program is to review the causes and treatment of exfoliation syndrome and neovascular glaucoma. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Identify the people most likely to develop exfoliation syndrome or exfoliative glaucoma.
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| 2. Compare the prognosis and diagnosis of exfoliative and primary open-angle glaucoma.
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| 3. Explain why exfoliation syndrome is considered a systemic disease.
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| 4. Name some of the risks of cataract surgery inherent in patients with exfoliative glaucoma.
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| 5. List the major causes and treatments of neovascular glaucoma.
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Discussed on This Program
Atropine sulfate [Atropine Sulfate Ophthalmic, Atropine Care, Atropine-1, Atropisol, Isopto Atropine, Sal-Tropine]
Dorzolamide [Trusopt]
Dorzolamide HCl and timolol maleate [Cosopt]
Fluorouracil (5-fluorouracil, 5-FU) [Adrucil, Carac, Efudex, Fluoroplex]
Latanoprost [Xalatan]
Mannitol [Osmitrol, Resectisol]
Mitomycin (mitomycin-C; MTC) [Mutamycin]
Pilocarpine HCL (many preparations and trade names)
Prednisone (many preparations and trade names)
Timolol maleate [Betimol, Blocadren, Istalol, Timoptic, Timoptic-XE]
Trypan blue dye [VisionBlue]
Suggested Reading
Battaglia Parodi M, Iacono P: Photodynamic therapy for neovascular glaucoma. Ophthalmology 112:1844, 2005; Harju M:
Intraocular pressure and progression in exfoliative eyes with ocular hypertension or glaucoma. Acta Ophthalmol Scand
78:699, 2000; Hayreh SS: Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res
24:493, 2005; Konstas AG et al: Latanoprost therapy reduces the levels of TGF beta 1 and gelatinases in the aqueous humor
of patients with exfoliative glaucoma. Exp Eye Res Aug 20, 2005 [epub ahead of print]; Kuang TM et al: Clinical experience
in the management of neovascular glaucoma. J Chin Med Assoc 67:131, 2004; Leszczynski R et al: Transscleral cyclophotocoagulatioin
in the treatment of secondary glaucoma. Med Sci Monit 10:CR542, 2004; Orr AC et al: Exfoliation syndrome:
clinical and genetic features. Ophthalmic Genet 22:171, 2001; Puska P, Tarkkanen A: Changes in visual acuity and refraction
in the exfoliation syndrome. A five-year follow-up study. Eur J Ophthalmol 11:245, 2001; Puska P, Tarkkanen A: Exfoliation
syndrome as a risk factor for cataract development: five-year follow-up of lens opacities in exfoliation syndrome.
J Cataract Refract Surg 27:1992, 2001; Puska PM: Unilateral exfoliation syndrome: conversion to bilateral exfoliation and
to glaucoma: a prospective 10-year follow-up study. J Glaucoma 11:517, 2002; Puustjarvi T et al: Plasma and aqueous humor
levels of homocysteine in exfoliation syndrome. Graefes Arch Clin Exp Ophthalmol 242:749, 2004; Ritland JS et al: Exfoliative
glaucoma and primary open-angle glaucoma: associations with death causes and comorbidity. Acta Ophthalmol
Scand 82:401, 2004; Vessani RM et al: Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol
136:41, 2003; Yamamot K et al: Neovascular glaucoma after branch retinal artery occlusion. Jpn J Ophthalmol
49:388, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Ritch spoke at Ophthalmology 2006: New Directions in Ocular Therapies, held December 1-2, 2005, in San Francisco,
and sponsored by the University of California, San Francisco, Beckman Vision Center, Department of Ophthalmology.
Dr. Sarkisian was recorded at the Annual Clinical Update for the Comprehensive Ophthalmologist, held December 3,
2005, in Memphis, and sponsored by the University of Tennessee Health Science Center, Department of Opthalmology,
Memphis. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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