The Secondary Glaucomas:Prevalence of and Consequence of their Malignancy

Marlene R. Moster, MD

Prof. of Clinical Ophthalmology
Thomas Jefferson Medical School
Wills Eye Hospital

It is convenient to first considerthe glaucomas in two arbitrary divisions:primary and secondary.

The Primary Glaucomas

• Primary open angle
• Primary angle closure
• Primary congenital glaucoma
• Not associated with other ocular or systemic diseases

The Secondary Glaucomas

Include all other forms of glaucoma that would not occur as distinct entities were it not for some underlying predisposing disorder
The list of secondary glaucomas are long and complex

The focus:

• Pseudoexfoliation
• Pigmentary dispersion
• Lens induced glaucoma

Pseudoexfoliation

• The commonest identifiable cause of OAG world wide
• Potentially aggressive form of secondary open angle glaucoma characterized by the deposition of whitish fibrillar material within the structures of the anterior segment and angle

Associated features

• Iris transillumination defects in the peripupillary region
• Reduced pharmacologic dilation
• Weakened zonular attachments
• Reduced blood aqueous barrier
• Evidence of pseudoexfoliative changes in other parts of the body, making this a systemic disorder with clinical relevance limited to the eye

Streeten BW et al.Pseudoexfoliative
Fibrillopathy in visceral organs with PSXF
Arch Ophthalmol. 1992;110:1757-62

How common is it?

• First reported by Lindberg in 1917 in Scandinavia
• Since then found in most populations throughout the world
• Females>males
• Prevalence:

  0.6% age 52 to 64

  5% age 75 to 85

LiebowitzHM ,KruegerDE, Maunder LR
The Framingham Eye Study Monograph
Surv Ophthalmol.1980.24:supp: 335-610

How common is it?

• PSXF accounts for 15-20% of cases of open angle glaucoma
• 40-50% present unilaterally
• 25% with unilateral PSXF develop the disease in the fellow eye within 10 years

Henry CJ,et al. Long-term follow-up
of PSXF and the development of elevated IOP
1987;94:545-52.

Is PSXF inherited?

Nearly all the pedigrees in the literature suggest maternal transmission raising the possibility of

• mitochondrial inheritance
• X linked inheritance
• Autosomal inheritance with genomic imprinting

Damji KF, et al. Is pseudoexfoliation syndrome inherited?
Ophthalmic Genetic. 1998 Dec;19(4):175-185.

How is the glaucoma secondary?

Chronic exposure to PSXF material and pigment overwhelms the T.M. resulting in:

• Increased resistance to flow
• Damage to the juxtacanalicular region and Schlemm’s canal
• Subsequent rise in IOP

PSXF within the T.M. results from deposition from the aqueous and local production by the cells in the outer T.M.

Morrison JC, Green WR. Light microscopy of the exfoliation
Syndrome.Acta Ophthalmol.1988;66:5-27.

Understanding the Malignancy of this disease

• The patients commonly present with IOP’s of 30-60mmHg in one or both eyes
• The “Uninvolved” eye often has subclinical PSXF
• Visual field and optic nerve are usually far advanced by the time of diagnosis

Ritch R.Perspectives on exfoliation syndrome
J Glaucoma. 2001 Oct;(5 supp 1) :s33-5

Understanding the Malignancy of this disease

Because of zonular laxity, anterior displacement of the lens diaphragm occurs with greater tendency toward angle closure

Schrehardt US,Naumann GO
A Histopathologic study of zonular instability
In PSXF, Am J Ophthalmol.1994;118:730-43

Understanding the Malignancy of this disease

Greater chance of complications during cataract surgery since zonular attachments may be weakened

Samuelson TW. Management of coincident glaucoma and cataract
Curr Opinion Ophthalmol.1995,6:1;14-21.

Understanding the Malignancy of this disease

• Greater chance of having the lens sublux or dislocate during the patients lifetime
• Mean time from IOL implantation to dislocation was 7 years 1 month

Jehan FS, Mamalis N, Crandall AS Spontaneous late dislocation
Of IOL within the capsular bag in PSXF.
Ophthalmology 2002 Nov;109(11):1951-2

Understanding the Malignancy of this disease

• Patients need to be educated that over time, zonular laxity can cause the IOL to slowly sink causing visual disturbances
• Viable options?
• Try pilocarpine to decrease the pupillary diameter
• Fix it with an IOL exchange, vitrectomy, trabeculectomy if needed

Treatment of PSXF

• Medications with varied success
• Laser therapy with either SLT or ALT
• If IOP is not controlled with medical or laser treatment, a surgical filtration procedure is indicated
• There is no added risk with just filtration surgery compared to other types of glaucoma

Glaucoma and Mortality: a connection?

Lee and coworkers found a modest but significant increase in mortality in patients with glaucoma from all causes, as well as cardiovascular causes with inconsistent results for cancer mortality

Lee DJ et al, Glaucoma and Survival.

Ophthalmology 2003;110:1476-1483

The relationship between homocysteine and cardiovascular disease

• JAMA: “The overall risk of cardiovascular disease was 2.2 times higher in those people whose blood plasma had total homocysteine levels in the top fifth of what is now considered the normal range”
• NEJM: “In pts. With coronary heart disease, the risk of death 4 to 5 yrs. after diagnosis was proportional to the total amount of homocysteine in the blood plasma”

Plasma homocysteine is elevated in patients with PSXF syndrome

• Vessani RM, Ritch R, et al. AJO 2003; 136:41-46.
• “Elevated plasma homocysteine, a risk factor for c.v. disease, is more common in exfoliation syndrome and exfoliative glaucoma pts than normal controls. Patients may benefit from measurement of homocysteine levels.”

Alerting the Pseudoexfoliation patients

• When the homocysteine levels are high, folic acid (foltx) 1-2 per day is the recommended treatment
• Although lowering homocysteine level may ultimately lower the cardiovascular risk, there are as yet no long term studies to prove this

Pigmentary Glaucoma

Secondary Open Angle Glaucoma associated with deposition of pigment within the corneal endothelium (Krukenberg Spindle)

Clinical Findings

• Pigment on the posterior lens capsule (Zentmayer sign or Sheie Line)
• Transillumination defects
• Excess pigment within the angle

Pigmentary Glaucoma (PG) Time Line

• 1949 Sugar and Barbour discovered PG
• 1979 Campbell presented evidence that the zonules rubbed against the neuroepithelium of the iris
• 1993 Karickhoff postulated the mechanism of “Reverse pupillary block”

Sugar HS, Barbour FA. AJO 1949:32;90-2
Campbell DG. Arch Opthalmol 1979;97:1667-72
Karickhoff JR. Ophthalmic Surg. 1993;115:707-10

Prevalence of Pigmentary Dispersion

• 25,000-220,000 affected individuals in the U.S.
• Associated with an autosomal dominant form of glaucoma
• Prevalence may be grossly underestimated

Anderson JS, Praelea AM,DelBono EA et al. A gene responsible
for the pigment dispersion syndrome maps to chromo. 7q35-q36
Arch Ophthalml. 1997;115:384-8

Ritch R. Going forward to work backward. Arch Ophthalmol
115:404-6

How common is it?

• More common in caucasions
• Rare in blacks and asians
• Male:female 3:1
• Younger males(35yo):older females(46yo)
• Approximately 25 to 50% of pigmentary dispersion syndrome patients eventually go on to manifest as pigmentary glaucoma

Sugar HS. AJO. 1966:62:499-507
Ritch R, Steinberger D,Liebmann JM. AJO 1993;115:707-10
Richter CU, Richardson TM, Grant WM. Arch Ophthalmol 1986:104:211-15

Who is at Risk of Developing Pigmentary Glaucoma?

• Risk of conversion from PDS to be 10% at 5 years
• Risk of conversion from PDS to be 15% at 15 years

Siddiqui YT et al. What is the risk of developing pigmentary glaucoma from pigmentary dispersion syndrome? Am J Ophthalmol 135:794 2003

Understanding the malignancyof pigmentary glaucoma

• Controversy of yag pi to reverse the pupillary block
• Pros
• Cons
• Treatment strategies
• Blindness and visual loss in young adults