Pigmentary Glaucoma and Pigment Dispersion Syndrome

Article initiated by: Pradeep Ramulu, M.D.

All authors and Sarwat Salim MD, FACS, Ahmad A. Aref, MD, MBA, Koushik Tripathy, MD (AIIMS), FRCS (Glasgow), Dr John Davis Akkara
contributors: (MBBS, MS, FAEH, FMRF), Dr. Kabir Hossain, Bharat Gurnani MBBS,DNB,FCRS,FICO(UK), MRCS (Ed), MNAMS, Pradeep
Ramulu, M.D.

Assigned editor: Ahmad A. Aref, MD, MBA

Review: Assigned status Up to Date

by Ahmad A. Aref, MD, MBA on December 25, 2022.

Pigmentary Glaucoma and Pigment Dispersion Syndrome

ICD (http://en.wikipe H (http://en.wikipedia.org/wiki/ICD-10_Chapter_VII:_Diseases_of_the_eye,_adnexa)40.1 (http://apps.who.int/classifications/icd10/

dia.org/wiki/Internat browse/2010/en#/H40.1)
ional_Statistical_Clas
sification_of_Disease
s_and_Related_Healt
h_Problems)-10 (http
://en.wikipedia.org/w
iki/ICD-10)

OMIM (http://en.wiki 600510 (http://omim.org/entry/600510)

pedia.org/wiki/OMI
M)

MeSH (http://en.wiki D005902 (https://meshb.nlm.nih.gov/record/ui?ui=D005902)

pedia.org/wiki/Medi
cal_Subject_Heading
s)
:
Pigment is deposited on the endothelium in a vertical spindle shape

Contents
1 Summary
2 Disease Entity
2.1 Disease
2.2 Etiology
2.3 Risk Factors
2.4 General Pathology
2.5 Pathophysiology
2.6 Primary prevention
3 Diagnosis
3.1 History
3.2 Physical examination
3.3 Signs
3.4 Symptoms
3.5 Clinical diagnosis
3.6 Diagnostic procedures
3.7 Laboratory test
3.8 Differential diagnosis
4 Management
4.1 General treatment
4.2 Medical therapy
4.3 Medical follow up
4.4 Surgery
4.5 Surgical follow up
4.6 Complications
4.7 Prognosis
5 Additional Resources
6 References
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 Summary
Disease Entity
Pigmentary glaucoma (PG) and pigment dispersion syndrome (PDS).

Disease
Pigmentary glaucoma is a type of secondary open-angle glaucoma characterized by heavy homogenous pigmentation of the trabecular meshwork, iris
transillumination defects, and pigment along the corneal endothelium (Krukenberg spindle). Individuals with these same findings who do not demonstrate optic
nerve damage and/or visual field loss are classified as having PDS, even if the IOP is elevated. The prevalence of PDS and PG in the general population is poorly
defined. After a period of about 15 years, approximately 15% of the patients with PDS will manifest raised IOP or develop glaucoma. It is an autosomal
dominant condition with variable penetrance having a wide variety of genetic loci. Screening of New York City employees reported that 2.5% had at least one
slit lamp finding consistent with PDS,[1] while a retrospective review of charts from a glaucoma practice demonstrated that roughly 1 in 25 patients (4%) was
followed for either PDS or PG.[2] In Olmstead County, Minnesota, the annual incidence of diagnosed PDS and PG was 4.8/100,000 and 1.4/100,000,
respectively.[3] True incidences are likely substantially higher, as many people with PDS and PG may have had the undiagnosed disease.

Etiology
The underlying mechanism responsible for PDS and PG is the presence of a concave iris contour which causes rubbing of the posterior iris surface against the
anterior lens zonules bundles during physiological pupil movement, leading to disruption of the iris pigment epithelial cell membrane and release of pigment
granules.[4][5] Pigment granules can produce temporary elevation of IOP by overwhelming the trabecular meshwork and reducing outflow.[6][7][8] Over time,
pathological changes in the trabecular endothelial cells and collagen beams can lead to increased resistance to aqueous outflow with chronic elevation of IOP
and secondary glaucoma.[5][9] Patients with PDS or PG have a 15-fold higher concentration of aqueous pigment granules in their anterior chamber compared to
normal controls.[7]

Pigment release requires irido-zonular contact and pupillary movement. Risk factors for irido-zonular contact based on ocular anatomy are discussed below.
Irido-zonular contact has been demonstrated to increase with blinking in eyes with PDS or PG.[10][11] Blinking has been hypothesized to burp fluid from the
posterior chamber to the anterior chamber in these eyes, resulting in a higher pressure in the anterior chamber as compared to the posterior chamber.[12] The
resulting pressure gradient results in a posterior-bowing (concave) iris with greater than normal iridolenticular contact (also referred to as reverse pupillary
block) which has been shown to be reduced with suppression of blinking.[10][11] The similar sounding Inverse Pupillary Block refers to blocking of pupil by
crystalline lens with large anteroposterior diameter in Microspherophakia. Such inverse pupillary block in microspherophakia aggravates with the use of
pilocarpine.

Greater iridolenticular contact also occurs with accommodation, in which the anterior lens surface moves anteriorly with contraction of the ciliary ring.[10]
[13][14] Increase in iris concavity secondary to accommodation has also been reported in myopic eyes without PDS and normal eyes. This suggests that irides in
eyes with PDS and PG may have inherent susceptibility to pigment liberation and factors other than iris shape and size may be at play.[15] Pupillary movement
produced by pharmacologic dilation has been observed to produce pigment release and increased IOP in some patients with PG or PDS.[6][7][16] Likewise,
physiological changes in pupil size resulting from lighting changes or accommodation, as previously mentioned, may also produce pigment release in individuals
with iridozonular contact.[17] In some patients with PG or PDS, significant pigment release accompanied by IOP elevation has been observed after strenuous
exercise.[17][18] However, systematic observation of IOP in patients with PDS or PG suggests that most patients do not have pigment release or IOP elevation
after exercise.[7][17] Pigment release producing elevated IOP and glaucoma has also been observed with sulcus placement of certain intraocular lens designs
after cataract surgery.[19][20][21] The terms PDS and PG are not applied to this secondary form of glaucoma, despite some underlying mechanistic similarities.

Risk Factors
1. Male gender- Pigmentary glaucoma has a strong male predominance, with all case series showing a male to female ratio of between 2:1 and 5:1. Much less
of a male predominance is noted for PDS, with case series describing male to female ratios between 1:1 and 2:1.[2][3][16][22][23]
2. Age- Male patients with PG and PDS most often present in their 30s, whereas female patients typically present roughly a decade later in
life.[3][16][22][24][25] Cases of PDS have been identified in patients as young as 12-15 years of age.[26][27][28] Disease may be more frequent in middle age
when the lens has enlarged and the iris is flexible enough to form a concave position.[4]
3. Myopia- The most common refractive error noted in eyes with PDS and PG is moderate myopia, with mean spherical equivalents typically in the range of
-3 to -4 D. A broad range of refractive errors is typically found, though hyperopia is relatively rare, usually accounting for only 5-10% of patients in most
case series.[2][16][22][29]
4. Race- Both pigment dispersion syndrome and PG occur infrequently (<5% of patients identified in case series) in persons of African ancestry.[2][16]
However, the actual prevalence may be higher than reported as persons of African ancestry have thick brown irides making detection of iris
transillumination defects more difficult.[30]
5. Concave iris and posterior iris insertion- Patients with PDS and PG have greater iridolenticular contact than individuals without the disease. Increased
iridolenticular contact results from a combination of a concave iris and a more posterior iris insertion, both of which are more common in patients with PDS
or PG.[11][13][31]
6. Flat corneas- Patients with PDS and PG have significantly flatter corneas than control subjects of similar age and refractive error.[29][32] A flat cornea might
be more likely to result in burping of aqueous humor from the posterior chamber to the anterior chamber with blinking, resulting in increased iridozonular
contact.[32]
7. Family history- Direct examination of a small set of family members of PDS patients showed that disease was present in 2/19 (12%).[33] A second
examination of family members reported signs of PDS in 36% of subjects’ parents and 50% of siblings, but no children, suggesting a possible autosomal
dominant inheritance pattern with incomplete penetrance.[34]Families with PG have also been described across multiple generations.[35][36] Roughly 50%
of family members in the described families had PDS or PG, reinforcing the idea of an autosomal dominant inheritance pattern.

Risk factors for progression of stage of disease or disease progression include:

1. Intraocular pressure- A retrospective study from Olmstead County Minnesota found IOP > 21 to be the only risk factor for progression from PDS to PG.
Age, refractive error and family history were not associated with conversion to PG.[3]
2. Degree of iridolenticular contact in patients with asymmetric disease- The more affected eye was noted to have more iris-lens contact than the less
affected eye. Features associated with greater iridolenticular contact (greater iris concavity, more posterior iris insertion) were also more common in
patients with PDS or PG.[31]
3. Greater trabecular meshwork pigmentation- In eyes with bilateral PDS, worse disease is typically found in the eye with more severe trabecular meshwork
pigmentation.[2]

General Pathology
Autopsy specimens of eyes with PG demonstrate disruption of the iris pigment epithelium cell membrane with extrusion of pigment granules.[5] The trabecular
meshwork in these eyes reveals collapse of trabecular sheets, free pigment granules and cellular debris clogging the intertrabecular spaces, and macrophages
and degenerated trabecular endothelial cells filled with pigment.[5][9][37]

Pathophysiology
Uveal pigment has been demonstrated to increase resistance to aqueous outflow in experimental studies,[38][39] and to result in increased IOP in vivo.[6]
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Primary prevention
No methods have been established for prevention of PDS or PG. In young patients with iris concavity and active release of pigment, a laser iridotomy has been
suggested to be of benefit by equalizing pressures in the anterior and posterior chambers and pulling the iris away from the zonules, although no definitive
benefit has been demonstrated. Older patients with glaucoma are less likely to benefit from iridotomy due to permanent changes in the trabecular meshwork
architecture. One large study reported that the risk of conversion from PDS to PG is approximately 10% at 5 years and 15% at 15 years.[3] This suggests that
treatment of all patients with iridotomy is not advisable. The decision to perform a laser should be individualized depending on the patient’s IOP and amount of
pigment liberation.

Diagnosis
Pigment dispersion syndrome is diagnosed clinically based on the presence of iris transillumination defects in the mid-peripheral iris, pigment on the corneal
endothelium (Krukenberg spindle, vertically oriented due to convection currents), and heavy pigmentation of the trabecular meshwork. The presence of all
three of these findings in the absence of another cause (i.e. history of trauma or posterior chamber IOL) suggests definite disease. No formal criteria have been
set forth in defining whether disease exists in eyes with 1 or 2 of the above findings. Disease is likely present when 2 of the above 3 findings are present,
particularly if other exam findings consistent with PDS or PG (i.e. elevated IOP, zonular pigment, posterior capsular pigment) are present. Pigmentary glaucoma
is present when the criteria for PDS are accompanied by optic nerve cupping and/or visual field loss.[40] PDS can occur with normal or elevated IOP.

History
Patients should be asked about a history of previous trauma, surgery, or eye disease. The presence of family members with glaucoma (and the type of
glaucoma) should be queried. Visual symptoms are unusual except in patients with visual field loss. Some patients may describe episodes of haloes and blurry
vision resulting from intermittent IOP elevation. Patients with such symptoms should be asked if they are brought about by exercise or dark exposure, which
have been previously described in patients with PDS or PG.

Physical examination
Careful slit lamp examination is critical to identification of PDS. Findings are typically bilateral, but can be markedly asymmetric on occasion.

1. The posterior surface of the central cornea should be carefully examined for the presence of pigment.
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 Krukenberg Spindle (Photo Courtesy of Sarwat Salim, MD, University of Tennessee)
Pigment is often arranged in a the shape of a Krukenberg spindle, narrow or rounded oval of brown pigment, usually 0.5 to 2.5 mm wide, and 2-6 mm in
length. Pigment is typically densest at the center, thinning out at the edges in the shape of a spindle.[41] Krukenberg spindles are present in roughly 90% of
patients with PDS or PG. Whether a dense Krukenberg spindle or very fine granules of pigment are present, visual acuity is not reported to be affected.
Corneas of patients with PDS or PG have not been demonstrated to be thicker or to have decreased endothelial cell counts.[42]
2. The anterior chamber should be examined for the presence of pigment granules and depth. On slit-lamp, pigments are brown and are smaller than anterior
chamber cells as seen in uveitis. Examination should be performed prior to and after pupillary dilation.
3. The iris should be examined with retroillumination to look for iris transillumination defects.

Iris transillumination defects in Pigmentary Glaucoma (Photo Courtesy of Sarwat Salim, MD, University of Tennessee)
Transillumination defects are most common in the mid-peripheral iris, where contact between iris pigment epithelium and anterior lens zonules is maximal.
Transillumination defects appear in a spoke-like configuration, and are most common or most prominent inferiorly or inferonasally.[12][26] Roughly 90% of
PDS/PG patients demonstrate iris transillumination defects in at least 1 eye,[16] though transillumination defects may be absent in patients with thick, dark
irides.[23][30] In asymmetric cases, frank iris heterochromia with increased iris pigmentation in the eye with greater pigmentation can be noted in the more
affected eye.[16][23] The eye with greater pigment loss can also have a larger pupil resulting in clinical anisocoria, possibly secondary to iris dilator
hypertrophy.[43][44][45]
4. The lens should be examined for the presence of pigment on the anterior surface, along the zonules, and along the posterior surface. Zonular pigment is
best noted after pupillary dilation with the patient gazing upwards to bring the inferior zonules into view.[46] Rarely, pigment can migrate posteriorly,
where it can be found trapped between the posterior lens capsule and anterior hyaloid.[47][48]
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 Densely pigmented TM in Pigmentary Glaucoma (Photo Courtesy of Sarwat Salim, MD, University of Tennessee)
5. Gonioscopy should be completed prior to dilation to evaluate the extent of trabecular pigmentation. The angle is typically widely open and the trabecular
meshwork typically shows dense, homogenous pigmentation.[23]Pigment deposition may be noted on Schwalbe’s line. The peripheral concavity of the iris
may be more prominently appreciated on gonioscopy. Pigment deposition along the zonular attachment at the posterior capsule of lens may be noted
(Schie line or Zentmayer line). This can give rise to a pigmented round line at the posterior capsule just internal to the equator of the lens.
6. Intraocular pressure should be measured. In a community based retrospective study, IOP at time of diagnosis for a population of patients with PG and PDS
was 29 mm Hg and 24 mm Hg, respectively.[3] Other studies confirm that patients presenting with PG typically have higher pressures.[22][49]

Signs
Mydriatic provocative testing has limited utility in diagnosing or predicting the course of PDS or PG. In one case series, roughly 1/3 of patients demonstrated
extensive anterior chamber pigment after phenylephrine administration, and only a fraction of these (20%) had an associated IOP rise.[17]

Symptoms
See discussion above in history section.

Clinical diagnosis
See diagnosis section above.

Diagnostic procedures
Patients with suspected PDS or PG should undergo gonioscopy to document the extent of trabecular pigmentation. In older patients, the only sign of PDS may
be the “pigment reversal sign,” where the trabecular meshwork is found to be darker in the superior quadrant when compared with the inferior quadrant. This
finding helps to differentiate patients with “burned out” PG from other types of glaucomas. Iris concavity and the extent of iridolenticular contact can also be
examined using ultrasound biomicroscopy (UBM) or anterior segment optical coherence tomography (AS-OCT). However, neither test is necessary for
diagnosis.

Laboratory test
No laboratory testing is recommended.

Differential diagnosis
Krukenberg spindles have been described in conditions other than PDS and PG, including uveitis and trauma. Trauma, previous ocular surgery, and
pseudoexfoliation can also produce heavy trabecular pigmentation. Exfoliation syndrome presents in older age group and clinical signs include peri-pupillary
transillumination defects, exfoliative material on the anterior lens capsule, and more uneven pigment distribution in the angle. However, it is important to
remember that the exfoliation syndrome is more common in PDS/PG than in the general population. Some patients may have both, an entity described as
“overlap syndrome”. Sulcus intraocular lens placement and iris melanoma can also produce a PG.

Management
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General treatment
Treatment for PG and PDS is similar to the treatment of primary open angle glaucoma, though laser iridotomy may be considered as a prophylactic treatment.
Men and persons of African descent often present with advanced disease, and may require more aggressive therapy.[49] In one case series, patients with PDS or
PG were more likely to require surgery than a control group with POAG.

Medical therapy
Pilocarpine has been demonstrated to reduce iris concavity and has been shown to block the exercise-induced elevation of IOP found in some
patients.[18][27][50] However, pilocarpine treatment can induce additional myopia and accommodative spasms. Peripheral retina should be carefully examined
before the initiation of miotics since lattice degeneration is present in up to 20% of these eyes, and the incidence of retinal detachment in patients with PDS
and PG is higher than in general population.[12]Therefore, treatment with pilocarpine has largely been replaced by newer medical agents including topical
prostaglandins, beta-blockers, carbonic anhydrase inhibitors, and alpha-adrenergic agonists. Prostaglandin analogues may be preferred over aqueous
suppressants as treatment with aqueous suppressants slows down the clearance of pigment from the trabecular meshwork.

Medical follow up
Patients treated medically should be followed up periodically every 3-6 months to ensure adequate control of intraocular pressure and to confirm that the
glaucoma has not progressed through examination, visual field testing, and/or imaging of the optic nerve head and nerve fiber layer.

Surgery
Given that PDS or PG results from a pressure differential across the iris (from the anterior to posterior chambers), it has been suggested that the underlying
mechanism of disease might be eliminated by treatment with laser iridotomy. Indeed, reports have demonstrated that laser iridotomy can eliminate iris
concavity and reduce iridolenticular contact in eyes with PDS.[51][52][53][54] However, some eyes may retain a concave iris configuration even after laser
treatment,[55] and this intervention may not always prevent exercise-induced pigment release and IOP elevation.[50][56] Limited data is available regarding
whether laser iridotomy is effective in controlling IOP in patients with PDS or PG. A small randomized controlled trial of 21 patients demonstrated a lower rate
of IOP elevation over 2 years of follow up in eyes treated with laser as compared to eyes not receiving laser (52% vs. 5%),[57] while a retrospective study of 60
patients did not suggest any benefit for laser iridotomy with regards to the future IOP course.[58] Given the heavy trabecular pigmentation in PDS and PG,
argon laser trabeculoplasty (ALT) may be an effective treatment option.[59][60][61][62][63] However, long-term control of IOP is unlikely, and 1/3 of eyes or more
may require trabeculectomy.[63] Younger patients are more likely to have long-term IOP lowering after ALT.[63]The effects of Selective Laser Trabeculoplasty
(SLT) as a treatment in PDS and PG has not been well studied. With either ALT or SLT, lower energy settings should be used to avoid release of pigment and IOP
spikes.

Patients demonstrating disease progression despite treatment with medicines and/or trabeculoplasty should be considered for trabeculectomy or other
incisional surgery. Long term results of trabeculectomy for PG have not been reported. The use of newer surgical modalities in the treatment of PG has not
been well described.

Surgical follow up
This page was last edited on April 3, 2023, at 16:22.
Follow-up after laser iridotomy is similar to the follow-up for iridotomy performed for angle closure. Follow-up after ALT and SLT is similar for the follow-up
This page has been accessed 319,473 times.
schedule used for ALT/SLT with primary open angle glaucoma.

Complications
Rise in intraocular pressure after iridotomy is greater in PDS and PG patients than in patients with occludable angles. To avoid this, lower energy levels should
be used, alpha adrenergic agonists should be administered before and after the laser treatment, and argon laser should be used, as it is less disruptive than a
YAG laser in terms of pigment liberation and inflammation.[64]

Prognosis
Blindness from PG is rare. In a community based study of 113 PDS and PG patients followed for a median of 6 years, 1 patient went unilaterally blind while a
second went bilaterally blind.[3] In the same study, 10% of PDS patients progressed to PG at 5 years, while 15% progressed at 10 years, though 23% of patients
were noted to have PG at diagnosis.[3] Forty-four percent of patients with PG had worsening of visual fields over a mean follow-up period of 6 years. Similar
rates of blindness were found in a group of patients followed in a glaucoma clinic, but higher rates of progression from PDS to PG were observed (35% over a
median follow-up at 15 years) and roughly 40% of PG patients were observed to have worsening of optic nerve damage.[25]No risk factor for progression has
been identified other than elevated intraocular pressure.[3][25] In some cases, PG may regress over time. Both TM pigmentation and iris transillumination
defects have been observed to normalize over time.[8][23][28] Even elevated IOP has been observed to normalize, suggesting return of normal TM function.[65]
Additionally, older patients with diagnosis of normal tension glaucoma have been identified with iris transillumination defects and dense TM pigmentation
suggesting they may have had PG with subsequent normalization of IOP due to cessation of pigment release.[66] In such patients, presence of “pigment reversal
sign” helps to distinguish between different types of glaucomas.

Additional Resources
References
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