Pigment Dispersion Syndrome

Etiology

The proposed etiological mechanism for PDS is the concave iris configuration, which results in rubbing the iris's posterior surface against the zonular fibers anteriorly during pupil dilatation and constriction.[7] This results in the release of iris pigments granules through pigment epithelial membrane disruption of iris and deposition in anterior segment structures. The pigments granules are deposited in the trabecular meshwork and cause intraocular pressure elevation by reducing the trabecular meshwork outflow. The trabecular meshwork endothelial cells and collagen beams undergo chronic pathological changes with time.[8] This results in resistance to aqueous outflow, causing  IOP elevation and secondary glaucoma.[9] Aptel et al., in their analysis, concluded that patients with PDS or PG have a 15 times higher concentration of pigments in the anterior chamber as compared to normals.[10]

The pigments are released with pupillary movement, and irido-zonular contact is necessary for the same. The maximum irido-zonular contact is noticeable during blinking. It has been hypothesized that with blinking, aqueous humor is shunted from the posterior chamber to the anterior chamber, thus increasing the pressure in the anterior chamber.[11] The increased anterior chamber pressure compared to the posterior chamber causes posterior iris bowing (concave iris configuration), resulting in the reverse pupillary block. This pupillary block can be reduced with suppression of blinking.[12]

With the ciliary muscle contraction during accommodation, the irido-lenticular contact increases as the lens surface move forward. The concave iris configuration has been documented more in myopic eyes without any evidence of pigment dispersion and even in normal eyes.[13] This infers that pigment dispersion in PDS is an inherent property of iris in addition to other factors. The pigment dispersion, as already described, is also linked with pupillary movement. In some patients, IOP elevation is noted after vigorous exercise or workouts due to the release of pigments. Pigment release has also been noticed after trauma and rubbing IOL to the iris's posterior surface.[14]

Risk Factors for Pigment Dispersion Syndrome

• Male gender -Previous literature has reported a male to female ratio between 2 and 5 to 1 for PG, but for PDS, the male predominance is slightly less 1 to 1.[15]
• Age - PDS, and PG are more common in young males in the third decade, and females are typically older in their 40s. PDS has also been reported in young patients in the second decade. In young patients, the lens is not thick, and accommodation is very active; hence concave iris configuration is usually not seen. In contrast, the reverse is applicable for more incidence of PDS and PG in later age groups. In Caucasians, PG is reported in the age group of 40 to 50 years compared to African Americans, where it is reported in younger males.[16]
• Refractive error - PDS and PG is more common in myopes with a mean spherical equivalent of -3 to -4 D.[15]
• Race - PDS, and PG are more common in African American ancestry. These patients of African ancestry have thick iris, and thus it becomes challenging to identify the transillumination defects.[17]
• Corneal configuration - PDS and PG are more common in flat corneas. The excessive gush of aqueous humor from the posterior chamber to the anterior chamber.[18]
• Iris configuration - PDS and PG patients have posterior iris insertion and concave iris configuration, which leads to more irido-lenticular contact and more pigment dispersion.[19]
• Family history - PDS and PG can run in families. These patients have an autosomal dominant mode of inheritance with incomplete penetrance. The disease can run in multiple generations.[20]

Risk Factors for Progression to Pigmentary Glaucoma

• Trabecular meshwork pigmentation - More pigmentation is more excellent than the severity of PDS, especially in bilateral cases.
• Iridolenticular contact - More the irido-lenticular contact more severe is the PD and PG.[21]
• Intraocular pressure - An intraocular pressure of more than 21 mmHg is a high-risk factor for progression from PDS to PG.[22]

Epidemiology

The epidemiology of PDS is variable. Many cases are misdiagnosed due to the asymptomatic nature of the disease.[23] PDS affects 2-4 % of the patient from the 2-4 decades. Approximately 15 % of the patients with PDS develop PG after nearly 15 years of age. A prevalence of 15 per 10,0000 cases has been reported in African ancestry. Doane et al. reported a prevalence of 25.9% of PDS in patients attending the clinic for refractive surgery, probably due to a high number of myopic patients seeking refractive surgery.[24] 

Goyeneche et al. reported a prevalence of 37.5% of PG in Latin American patients.[22] Ritch et al., in their analysis of the white US population, reported a prevalence of  PDS to be 2.45%.[25] In his case series of PDS patients, Speakman reported that 20% has ocular hypertension and 25.60% has PG.[26] Various studies have reported a risk of 35-50% of PDS patients developing glaucoma.[13]

In another retrospective study by Mastropasqua et al., 20 % of patients with PDS developed  PG. They also reported that 85% of patients converted to PG within the first ten years. Apart from this, major studies have reported that the conversion rate of PDS to PG is approximately 50%.[15][27]

Pathophysiology

Genetic Factors

A large number of recent studies have indicated that PDS has genetic characteristics, and the majority of cases are inherited in which sporadic cases predominate. Various genetic loci play an essential role in the inheritance of PDS, such as 7q35-q366 and 18q11-q21.5,6,93. A single gene does not cause PDS. Instead, it results from a combination of genetic mutations. Tandon et al. in their analysis, reported that most PDS cases are sporadic, and only 10.1% of the first-degree relatives developed PDS.

Another proposed theory is that congenital mesodermal abnormalities and degenerative iris changes are related to PDS, accounting for the higher incidence of lattice degeneration and breaks in myopic patients with PDS.[28]

Mechanical Factors

Pigment dispersion from the iris and ciliary body occurs due to mechanical contact of lens or IOL with the iris, rubbing of iris against zonules, reverse pupillary block, hypoplastic iris, and hypoperfusion. The pigment release has been linked to idiopathic atrophy of the iris pigment epithelium. The other mechanical factors related to PDS are mechanical movement and bowing of the iris posteriorly, deep anterior chamber, and myopia. Karickhoff hypothesized that a higher aqueous pressure causes backward push to the iris and collapse of the posterior chamber.[29]

Physiological Factors

Lid movement, accommodation, movements of eyes, and exercise are linked with reverse pupillary block. In PDS, there is more iris and lens contact, resulting in elevated aqueous humor pressure. The rise in pressure results in pigment dispersion syndrome. Iris shape and change in axial length are responsible for the resolution of PG.[14]

Histopathology

Richardson analyzed that trabecular meshwork endothelial cells engulf pigments that are produced due to changes in aqueous humor dynamics.[30]

History and Physical

The patients with PDS present can be completely asymptomatic or present with pain, redness, photophobia, glare, and halos. Most of these patients are myopic patients detected on routine retinoscopic examination. A history of trauma, exercise, complicated cataract surgery should be ruled out in PDS.[6]

The condition can be bilateral, and both eyes should be examined in detail. The patients may present with field loss or defective vision due to glaucomatous optic atrophy and corneal edema. A detailed history, meticulous anterior segment, posterior segment examination, applanation tonometry, gonioscopy, and Humphrey field analysis are necessary in each case to reach a conclusive diagnosis. A history of excessive blinking and hormonal changes should be ruled out.[31]

Cornea

The pigment deposition is seen in the inferior corneal endothelium due to an aqueous current known as the Krukenberg spindle, which is not pathognomic of PDS. In the early stage, there may be diffuse pigment deposition at the back of the cornea.

Anterior Chamber

PDS patients have a deep anterior chamber, and there may be pigment deposition in the anterior chamber admixed with aqueous. Melanin granules can also be observed in the anterior chamber.[32]

Anterior Chamber Angle

The pigment deposition is seen more in the inferior angle on the gonioscopy. Usually, all the quadrants are densely pigmented, with a circumferential homogenous band of pigment is seen on the posterior meshwork. A dense line of pigmentation may be seen anterior to Schwalbe's line, known as Sampaolesi's line. A reduction in pigmentation of angle is seen with growing age.[33]

Iris

Iris's findings are a hallmark of PDS. These patients present with characteristic iris transillumination defects, radial spoke-like defects, melanin deposition on the surface of the iris. They may be atrophic patches or loss of pupillary ruff. There may be heterochromia, the iris with pigment deposition will be darker. There is the concave configuration of the iris mid-peripheral on the gonioscopy, and the iris is bowed backward.[34]

Lens

The pigment may be deposited on the anterior lens surface. The pigment deposition has a typical pattern, such as a line (Scheie stripe) or a pigment ring (Zentmayer ring) around the equatorial lens surface and zonular apparatus.[35]

Fundus

The fundus should be assessed for peripheral retinal depigmentation, myopic disc, tessellated background, myopic macular degeneration, lattice degeneration, holes, tears, and retinal detachment. There can be glaucomatous optic atrophy in cases of PG. The cupping can be asymmetrical, with one eye having advanced glaucomatous changes and mild changes in the other.[24]

Evaluation

The diagnosis of PDS and PG is based on clinical evaluation and imaging.

Visual Acuity

Snellen's uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) should be documented in each case. Visual acuity can be reduced due to corneal edema, associated cataract, or retinal detachment.[27]

Intraocular Pressure

Intraocular pressure assessment by noncontact tonometry (NCT) should be reconfirmed with gold standard applanation tonometry (GAT), which gives an idea about ocular hypertension and PG. The IOP changes can be volatile; some patients will show wider variations in IOP than primary open-angle glaucoma patients. When pigment dispersion reduces with time in PDS patients, the IOP will also come to normal. Some patients can be wrongly misdiagnosed as NTG when the pressure has come to normal and signs of PDS have resolved.[36]

Gonioscopy

Gonioscopy is a crucial tool to diagnose PDS. PDS is a type of open-angle glaucoma. The majority of angles are wide open, there is concavity in the mid-peripheral iris, and the iris is bowed backward. There is heavy trabecular meshwork pigmentation in all quadrants, and a dense circular homogenous posterior band is seen. There may be a line of pigmentation anterior to the Schwalbe line called Sampaolesi's line. The pigmentation in angles reduces with age and can also be seen after trauma to the eye.

Visual Field Analysis

Standard automated perimetry is a valuable tool to assess the extent of glaucomatous damage in PDS and PG cases. In PG, the temporal field damage is less as compared to POAG. The nasal optic disc damage is less damaged in cases of PG. The possible reasons for this could be young patients in PDS and myopia as a risk factor.[37]

Anterior Segment Optical Coherence Tomography

Anterior Segment Optical Coherence Tomography (AS-OCT) is a vital tool to assess anterior chamber depth, width, the volume of iris, and iris concavity in patients with PDS. Aptel et al., in their analysis using Visante OCT, compared PDS and PG eyes and showed that PDS eyes had a larger anterior chamber volume and irido-lenticular contact area and larger iris volume to length ratio than the healthy subjects. They also assessed the angle opening distance (AOD) and trabecular iris space area (TISA) at 500mm and 750mm and showed that indices were also more in eyes with PDS and PG patients than normals.[38]

Optic Nerve Head Optical Coherence Tomography

This is an essential tool to assess the optic nerve head (ONH), retinal nerve fiber layer (RNFL), cupping, and ganglion cell complex (GCC) morphology. The OCT used is either spectral-domain or swept-source to classify the disease as either PDS or PG. OCT is also helpful in assessing the progression of glaucoma pathology or therapeutic response to glaucoma treatment.[39]

Retinal nerve fiber and macular thickness are surrogate measures of glaucomatous structural defect. Various studies have documented that at least 40% of ganglion cell damage should ensue before any detectable glaucomatous field defect. Arifoglu et al., in their analysis, found that PDS and PG patients had lower superior and inferior RNFL thickness and ganglion cell layer thickness as compared to normal.[40] 

Therefore, OCT is a valuable tool in documenting disease progression and differentiating the types of glaucoma. Another hypothesis is intermittent IOP spikes may result in lower RNFL thickness in PDS patients. In preperimetric glaucoma, the RNFL and GCC assessment with OCY help pick up disc suspects and patients with ocular hypertension. The OCT parameters analysis may also help monitor the later progression of advanced disease.[41]

Optical Coherence Tomography Angiography (OCTA)

OCT angiography is a valuable tool for assessing the retinal and optic nerve blood flow. The advantage of OCTA is that it is non-invasive. OCTA can scan superficial peripapillary retinal plexus and macula also. But optic nerve imaging poses challenges like artifacts and interpreting anatomical landmarks.[42]

OCTA depicts reduced vascular density, an excellent diagnostic predictor of glaucoma. OCTA is a sensitive marker for diagnosing, progressing, and monitoring glaucoma with visual field changes. A good diagnostic OCTA is possible only with a good quality scan when factors like cataract, corneal opacity, eye blinking, and other artifacts are eliminated. A good signal strength and scan centration are other factors influencing the results.[43]

Ultrasound Biomicroscopy (UBM)

UBM is a helpful tool to assess the detailed anatomy of angle structures and factors that predispose to irido-zonular and irido-lenticular contact. In PDS, UBM is a valuable tool to see the relationship between peripheral iris and zonular structures during accommodation and after exercise and scleral indentation. The anatomical details that UBM in PDS and PG patients can assess are concave iris configuration, increased iris and lens contact, increased lenticular thickness, increased distance from scleral spur to iris insertion, increased posterior bowing of iris, anterior chamber depth, irido-zonular contact, and Schwalbe's line to iris root distance.

Treatment / Management

The management of PDS and PG is governed by various factors like stage of the disease, amount of pigment dispersion, IOP value, and presence or absence of glaucomatous optic neuropathy. The first stage of PDS is characterized by diffuse pigment dispersion in the early second to the third decade and is usually asymptomatic.[16](B2)

After some time, the pigments block the trabecular meshwork, resulting in raised IOP and OHT, which leads to the second stage of the disease and may result in optic nerve damage. In the third stage, the pigment accumulation reduces, and IOP is normalized and characterized by iris transillumination defects. In the third stage, the "pigment reversal sign" is seen in which a dark and dense pigment is seen in the upper quadrant and less dark in the lower quadrant. The patients with PDS should be followed up annually to rule out the development of OHT and optic nerve damage. In the case of advanced glaucoma, the patient should be followed up every 4 to 6 months, and these patients can have rapid vision loss associated with risk factors like myopia and PDS.[44]

Lifestyle Measures

As vigorous physical activity and excessive exercise have been linked with PDS, the patients should be counseled regarding exercise behaviors if PDS or PG sets in.

Medical Management.

The medical management of PDS is on similar lines to POAG.[45]

Miotics

Pilocarpine is considered helpful in limiting pigment dispersion. It reduces irido-zonular contact and improves aqueous outflow. Pilocarpine 2% three times a day is deemed safe in these patients. Long-term use can exacerbate side effects like myopia, ocular surface disease progression, and retinal detachment in these patients. Pilocarpine is also poorly tolerated by young patients.

Selective Alpha-Adrenergic Antagonist

Topical thymoxamine can induce pupillary constriction without affecting the accommodation. It has the side effect of excessive irritation.

Other Antiglaucoma Medications

Prostaglandin analogs, beta-adrenergic blockers, and alpha agonists are considered safe in PG. Mastropasqua, in their randomized trial, showed that latanoprost is more effective than timolol in controlling IOP in PG patients. But prostaglandins don't affect pigment liberation. A combination of medical management and a laser is beneficial in many cases. After prostaglandins, the following drugs are b-adrenergic antagonists, carbonic anhydrase inhibitors, and alpha-adrenergic drugs.[46](A1)

Laser Trabeculoplasty

Laser trabeculoplasty is vital for treating the eye with heavy pigment dispersion. It is advisable to treat two quadrants simultaneously and with lower power settings to reduce the IOP spike.[47](A1)

Laser Peripheral Iridotomy

Laser peripheral iridotomy (LPI) helps to reduce pigment release by reversing the iris concavity and decreasing the irido-zonular contact. It also helps reduce the IOP spikes but may not reduce the development of glaucoma. LPI maintains the pressure between the anterior and posterior chamber, thus minimizing the iris and zonular friction. It has been estimated that LPI reduces approximately 65% pigment release into the anterior chamber.[48](A1)

Previous studies have concluded that LPI  will reverse iris concavity and reduce trabecular meshwork pigmentation, but the evidence is lacking that it prevents progression of visual field defect or prevent the conversion of PDS to PG. Selective laser trabeculoplasty is useful for PG as it has good repeatability and safety and lowers IOP in comparable numbers with medical therapy. The mechanism proposed for SLT is the stimulation effect on the trabecular meshwork.

One study reported a 20% reduction in IOP for 85% of eyes at one year to follow up and later dropped to 1% at two years of follow up. The majority of cases require additional topical antiglaucoma medication for IOP control. The most common side effects of SLT are inflammation and IOP spikes. The factors responsible for IOP spike post SLT are intense TM pigmentation, multiple drug use, and previous application of argon laser trabeculoplasty. In high-risk cases, SLT may precipitate the need for filtration surgery. Post SLT application, 0.5% ketorolac or 1% prednisolone is given four times per day to reduce inflammation. The least energy, 0.4 mJ per spot, is preferred for SLT.

Filtration Surgery

The indication for filtration surgery is inadequate to control IOP despite maximum medical therapy and visual field progression. Trabeculectomy with mitomycin C is indicated in advanced glaucoma and non-resolving cases. The antifibrotic agents prevent bleb scarring, control shallowing of the anterior chamber, vitreous and retinal traction. Hypotony and suprachoroidal hemorrhage are essential complications of filtration surgery in young myopic patients.[49]

Glaucoma Drainage Devices

Ahmed Glaucoma Valve (AGV) or Aurolab Aqueous Drainage Device (AADD) is indicated for failed filtration surgery cases.[50]

Minimal Invasive Glaucoma Surgery

The advantage of minimally invasive glaucoma surgery (MIGS) is that it doesn't require a bleb creation, and the aqueous is shunted from trabecular meshwork in the Schlemm canal.[51]

Trabectome

Trabectome was the first MIGS approved in 2004. This is a type of ab interno trabeculectomy employing a handheld electrode. A study reported similar IOP reduction with trabectome and antiglaucoma medications in PG and POAG eyes. There was a 20% IOP reduction from baseline in 92 % PG eyes and 86% POAG eyes.[52](B2)

Goniotomy

This is performed with a Kahook dual blade by removing the trabecular meshwork. A multicentric study on PAOG eyes with goniotomy and phacoemulsification reported a mean IOP alleviation of 26.2% and 50% reduction in antiglaucoma medications. The most common side effects were pain, capsular opacification, and IOP spike.[53](B3)

iStent

This is another procedure to bypass the trabecular meshwork. This device is indicated for POAG management with cataract surgery. There are no current studies for iStent in PG. The second-generation iStent is available as a preloaded device that can be injected perpendicularly in the trabecular meshwork.[54]

Canaloplasty

This is a surgical procedure to restore the normal aqueous drainage. In this technique, sodium hyaluronate is injected into the Schlemm's canal with the help of a microcatheter. A 10-0 prolene suture is inserted into the Schlemm's canal to ensure the 360-degree dilatation effect, which increases the aqueous outflow. This can be a potent treatment option for pigmentary glaucoma in young patients having mild to moderate visual field defects with a lower target IOP.[55] 

Differential Diagnosis

• Pseudoexfoliation syndrome
• Bilateral acute iris transillumination (BAIT)
• Bilateral acute depigmentation of the iris (BADI)
• Vogt-Koyanagi-Harada syndrome
• Sympathetic ophthalmia
• Acute autoimmune uveitis
• Posner-Schlossman syndrome
• Viral uveitis (herpetic)
• Fuch uveitic syndrome
• Traumatic uveitis
• Horner syndrome
• Acute angle-closure glaucoma
• Iris melanoma

Staging

Grades of Pigment Dispersion Syndrome[5]

Prognosis

The prognosis of PDS and PG is dependent on the level of IOP-associated risk factors like myopia and optic nerve damage. If the IOP is well controlled, the prognosis in the majority of cases is favorable. Permanent blindness is rare in these cases. The prognosis is also dependent on disease progression as the condition usually progresses very fast. Approximately 10% progress to PG after five years of PDS onset, and 15% progress to PG after ten years of the disease process. PDS patients with normal IOP and normal aqueous humor dynamics usually have a low risk for developing PG and have a favorable prognosis.[56]

Complications

Medical Complications

• Corneal edema
• Non-resolving uveitis
• Angle-closure glaucoma
• Iris atrophy
• Iridoplegia
• Relative afferent pupillary defect
• Intractable glaucoma
• Post SLT IOP elevation 

Surgical Complications

• Wound leak
• Late bleb leak
• Blebitis
• IOP spike
• Pupillary block
• Malignant glaucoma
• Over filtration
• Flat bleb
• Vascularized bleb (episcleral fibrosis)
• Encapsulated bleb (Tenon cyst)
• Hypotony
• Macular snuff out
• Endophthalmitis
• Panophthalmitis
• Blindness