Saturday, May 26, 2018

Iridocorneal Endothelial (ICE) Syndrome vs Axenfeld-Rieger Syndrome

Iris strands
Iris stroma
Ectropion uveae
100% cases
60% cases
20-30 years
Mostly females
Equal distribution
Autosomal dominant


Friday, May 18, 2018

Aerie Pharmaceuticals Submits New Drug Application to U.S. Food and Drug Administration for RoclatanTM (netarsudil/latanoprost ophthalmic solution) 0.02%/0.005%
DURHAM, N.C.--(BUSINESS WIRE)--May 15, 2018-- Aerie Pharmaceuticals, Inc.(NASDAQ:AERI), an ophthalmic pharmaceutical company focused on the discovery, development and commercialization of first-in-class therapies for the treatment of patients with open-angle glaucoma and other diseases of the eye, today announced the submission of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for RoclatanTM(netarsudil/latanoprost ophthalmic solution) 0.02%/0.005%. RoclatanTM is a once-daily eye drop designed to reduce intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. It is a fixed dose combination of Aerie’s Rhopressa®, which is currently available in the United States, and the widely-prescribed PGA (prostaglandin analog) latanoprost. RoclatanTM successfully achieved its primary efficacy endpoint in two Phase 3 registration trials, named Mercury 1 and Mercury 2, and also achieved successful 12-month safety and efficacy results in Mercury 1, the results of which are included in the NDA submission.
The expected FDA review period for RoclatanTM NDA is only ten months instead of twelve months because Aerie’s submission is filed under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, since RoclatanTM is a fixed dose combination of two previously approved drugs in the United States.
“The RoclatanTM NDA filing represents another significant achievement for Aerie this year, on top of our recent commercial launch of Rhopressa® in the United States. Since RoclatanTM is being filed through the 505(b)(2) regulatory pathway, in which both active ingredients, netarsudil and latanoprost, are already approved in the United States, we expect a ten-month FDA review. We believe, if approved, RoclatanTM has the potential to be the most efficacious therapy in the market for the reduction of IOP, which makes this submission all the more exciting for our valued employees, eye care professionals, and most importantly, patients who suffer from glaucoma or ocular hypertension,” said Vicente Anido, Jr., Ph.D., Chief Executive Officer and Chairman at Aerie.

Tuesday, May 15, 2018


Iridocorneal Endothelial Syndromes (ICE) are characterized by the following:

Common features of the three ICES:

1. Corneal endothelial dystrophy
2. Distorted pupil
3. Ectropion uveae
4. Goniosynechiae
5. Secondary synechial glaucoma

Characteristics which distinguish between the three ICES:

1. Iris naevus syndrome (Cogan-Reese)=
Multiple small or a few larger iris nodules.

2. Chandler’s Syndrome=
Corneal oedema at normal or mildly elevated IOP.

3. Essential iris atrophy=
Progressive iris atrophy with iris hole formation (opposite to the side of goniosynechiae). 

Wednesday, May 9, 2018


The Glaucoma Laser Trial (GLT) was conducted during 1984-87 to assess the effectiveness of Argon Laser Trabeculoplasty (ALT) in newly diagnosed primary open angle glaucoma patients. 

271 patients in the trial randomly underwent ALT in one eye and standard topical treatment in the other eye. The GLT-Followup Study (GLTFS) was a followup study of 203 of the 271 patients who had earlier been enrolled in the GLT. By the end of GLTFS, the patients had been under followup for a median duration of 7 years since the diagnosis of POAG. In GLT each half of the trabecular meshwork was treated with 45-55 laser burns in 2 sessions, 1 month apart. If the IOP was not controlled on followup the medications were changed in the treatment arm or added in the laser group. Further management including surgery was advised on further followup.

As compared with the treated eyes, those which underwent ALT had 1.2 mmHg greater reduction in IOP (P <0.001) and 0.6 dB greater improvement in visual fields (P <0.001). The C:D ratio also showed slightly more worsening [-0.01] (P=0.005) in the treatment group. 

In conclusion, ALT was atleast as efficacious as initial treatment with topical medication.

Saturday, May 5, 2018



A number of lasers have been used to target the anterior chamber angle and achieve reduction in IOP. This laser induced modification of the angle is known as Laser Trabeculoplasty (LTP). Some of the lasers which have been used for LTP include: the argon (peaks at 488 nm and 514 nm); krypton (647.1 or 568.2 nm); diode (810 nm); and the continuous wave, frequency doubled Nd:YAG (532 nm) laser. The Glaucoma Laser Trial and the Glaucoma Laser Trial-Follow-up Study showed that eyes initially treated with argon laser trabeculoplasty (ALT) had lower IOP and better visual field and optic disc status than their fellow eyes treated initially with topical treatment.


ALT was first described by Wise and Witter in 1979. Usually 50 spots over 1800 of 50 micron spot size, 0.1 second duration and an average power ranging from 400-600 mW are given.

The precise mechanism by which LTP works is not known. It has been suggested that the ALT scars induce tightening of the trabecular beams around the scar with widening of the spaces between them, thus enhancing outflow. In ALT, light energy enters the tissue faster than it can dissipate, resulting in a rise of temperature and thermal energy which spreads from the beam focus. ALT also destroys a viable area of the trabecular meshwork (TM), creates a crater in this tissue and causes depopulation of all normal structures. Studies have shown that ALT causes increased division of trabecular cells and remodeling of the juxtacanalicular extracellular matrix. However, over time the biological changes lead to the formation of a fibrocellular membrane over the trabecular meshwork, resulting in decreased aqueous outflow and failure of LTP. 

Previous LTP also increases the probability of bleb encapsulation following subsequent trabeculectomy. ALT produces significant tissue disruption and coagulative damage to the TM. This limits the reapplication of LTP again in an effective manner. Complications reported with ALT include: transient IOP spikes (6.3-54%), peripheral anterior synechiae (12-47%) and uveitis. 


In 1995 Latina and Park reported that a 532 nm, frequency-doubled Q-switched Nd:YAG laser could selectively cause cytotoxicity and cell death of TM cells without any apparent changes in the adjacent non-pigmented cells. This came to be known as Selective Laser Trabeculoplasty (SLT).

SLT is based on the principle of “selective thermolysis”, whereby only pigmented trabecular cells are targeted by the laser. There is no associated structural or coagulative damage to the TM. Selective thermolysis is effective as it targets intracellular chromophore (melanin) sparing the nonpigmented cells. Transmission electron microscopy following SLT demonstrated fracture of melanin granules, rupture of lysosomal membranes in pigmented cells and absence of ultrastructural damage in neighboring nonpigmented cells. In the areas where the SLT laser had struck, beams of TM were intact except for rare crack-like defects between preserved beams. There was total absence of coagulative damage. The endothelium was intact, with a few vacuolated cells. Many pigmented trabecular cells contained disrupted, fragmented intracytoplasmic pigment granules and others also had intact granules in their cytoplasm.

SLT delivers light energy in extremely short nanosecond pulses, 8 orders of magnitude shorter than that of ALT. Cooling from dissipation does not occur and temperature rise is very rapid. This causes disintegration of a small volume of tissue into a collection of ions and electrons called "plasma". Vaporization of water around melanosomes at temperatures around 1500C causes formation of small, short duration microbubbles which disintegrate cellular structures by micro-explosions in the region of pigmented TM cells.

SLT also causes increased secretion of cytokines by TM endothelial cells. This could theoretically be linked to the IOP lowering effect of SLT. Other mechanisms suggested for SLT include: proliferation of trabecular endothelial cells, release of cytokines, inflammation (recruitment of macrophages) and phagocytosis. SLT causes nuclear translocation of transcription factors and an induction of vasoactive agents (e.g. cytokines) followed by macrophage recruitment. IOP then decreases even as the repair process begins.

Following SLT there is also significant elevation in the aqueous concentration of lipid peroxide. Such free oxygen radicals can cause inflammation and prove to be a double edged sword during SLT.

SLT uses a 532 nm, frequency-doubled, Q-switched Nd:YAG laser with a 3 nanosecond pulse and 400µ  beam diameter. The size of the aiming beam is much larger than the typical 50µ size ALT beam. This allows the SLT beam to cover the entire width of the TM, thus accurate aiming is less critical. The TM is a strip of tissue approximately 44 mm long and 0.3 mm wide. The larger spot size is less harmful to ocular tissue because the energy is not concentrated in a small area. The low fluency of energy safely and effectively diffuses over a large area.

The energy density of a typical ALT pulse of 800 mW, 0.1 second and 50 micron spot size is roughly 4 million mJ/cm2. Contrarily, an SLT pulse of 0.8 mJ and 400 microns spot size delivers energy of 637 mJ/cm2. This shows that each SLT pulse delivers less than 0.1% total energy compared to ALT.

The procedure with the diode laser is similar: a 50–75-µm laser beam is focused through a goniolens with a power setting of 600–1000 mW and duration of 0.1 second.

The patient is pre-treated with an alpha-agonist to prevent post-laser spike in IOP. Topical anesthesia and a Goldmann 3-mirror or Latina SLT Lens is used. A low power beam is focused at the pigmented TM. Power is usually set at 0.8 mJ per pulse initially. In heavily pigmented eyes, it can be lowered further. About 50 non-overlapping spots are applied to 180 degrees of the angle circumference. Unlike ALT where blanching or large vaporization bubbles are produced, the endpoints of SLT are more subtle. Some authors increase the energy to obtain small “champagne bubbles” and then decrease power by 0.1 mJ without any subsequent visible changes. Others strive to achieve these tiny bubbles during 50% or more of applications. 

Post-laser anti-Glaucoma medications are continued until the IOP becomes stable. Topical steroids/NSAIDs are also added to control inflammation. However, some suggest that postlaser inflammation might help in lowering of IOP.

Some practitioners apply 100 shots over 3600. However, studies have shown that success rates do not differ significantly between 1800 and 3600 SLT. However, 900 of SLT is not as effective as 1800. Studies report latanoprost to be more effective than 1800 SLT.

Compared to ALT, SLT is better tolerated with less discomfort and post-laser inflammation.

However, Samples et al performed a meta analysis of 145 papers and concluded there is no evidence of superiority of any particular form of LTP.

Indications for SLT include:

1. In medically non-compliant patients.

2. Those who cannot tolerate medications.

3. As an adjuvant treatment to reduce the number of anti-Glaucoma medications.

4. Those with uncontrolled IOP despite previous ALT.

5. As a primary modality to treat OAG, pxg, pigmentary Glaucoma, NTG, OHT, juvenile glaucoma, aphakic/pseudophakic Glaucoma.

Side effects of SLT:

1. Post-laser IOP spike (0-27%)

2. Hyphema

3. Upto 50% pts show mild-moderate uveitis lasting for about 24 hours and managed with steroid/NSAID topically

4. Corneal edema (resolved with topical anti-inflammatory agents)

5. Transient corneal endothelial changes.


IOP reductions following SLT ranged from 2.1-10.6 mmHg with follow-up ranging from 4 weeks to 72 months. Reductions in IOPs ranging from 18-40% over a 6 to 12 month follow-up have been reported. Most of the IOP lowering effect has been reported in the first week with some additional effect during the next 4-6 weeks.

Success rates in African-American and white subjects were similar.

Baseline IOP was positively associated with better IOP reduction following SLT.

Patients with thinner corneas (<555m) also demonstrated better IOP control atleast for the first 30 months after SLT.

Pigmentation of the angle, type of Glaucoma, age, sex, past history of ocular surgery, phakic status, diabetes were not associated with effectiveness of the procedure.

Chen did report an early better reduction of IOP associated with pigmentation and pseudoexfoliation.

Cross-over effect of SLT:

SLT appears to have a statistically significant IOP lowering effect in the contralateral untreated eye. An, as yet known, biologic effect could be responsible.

In case IOP is lowered in the treated eye, it gives a probability of SLT being effective in the other eye too. However, these effects have not been studied well.

Retreatment of SLT:

Retreatment is defined as treatment over a previously treated area of TM. As the SLT laser beam bypasses surrounding tissue (since it targets pigmented cells only) leaving it undamaged, theoretically SLT can be repeated several times in eyes in which the IOP has risen to pretreatment levels or has not met the target IOP goal. Studies have found that repeat SLT treatment is associated with further IOP lowering and is safe and effective.

The "SLT/MED study" was conducted to compare SLT with medications.IOP reduction was similar in both arms after 9 to 12-months follow-up. More treatment steps were necessary to maintain target IOP in the medication group, although there was not a statistically significant difference between groups. These results support the option of SLT as a safe and effective initial therapy in open-angle glaucoma or ocular hypertension.


In this technique, 200 ms long bursts comprising of 100 micropulses are applied to 200 µm spots on the TM. There is an interval of 1.7 ms between each micropulse. About 70 spots are applied over 1800. With this procedure, an IOP lowering of more than 20% was achieved in 60% eyes after 1 year of follow up.


PLT is based on the PASCAL technology for retinal photocoagulation. The PASCAL system has an aiming beam of 633 nm and therapeutic laser of 532 nm. Continuous wave light laser is directed to the TM by the Latina gonio-lens. 10 ms pulses are used to produce blanching of the TM. The procedure is started from the inferior quadrant which has the maximum pigment. Subsequently the power is maintained but the pulse duration is reduced to half (5 ms from 10 ms). Ophthalmoscopically invisible spots are achieved at the TM with this reduced pulse energy. The pattern consists of several arcs composed of multiple laser spots. Each arc contains 3 rows of 22 spots (total:66 spots). Each arc covers around 22.50 so that 8 applications for 1800 or 16 applications for 3600 are used. Thus, more than 1000 spots of 100 micron diameter are applied over 3600. The IOP was lowered by an average of 24% over 6 months of follow up in 60% eyes.

The PASCAL Streamline 577 uses yellow wavelength of 577 nm. A study by Nozaki showed a 31% IOP reduction over 6 months of follow up.

Looking at almost similar results with PSLT and SLT, the only advantage of PSLT appears to be a faster delivery time.