
This article was reviewed by David F. Chang, MD

The first report associating use of the α1A antagonist tamsulosin with intraoperative floppy iris syndrome (IFIS) appeared in the literature in 2005. 

Subsequently, studies have examined the underlying mechanism for the complication and determined that it occurs in women as well as in men, with other α1-antagonists, when α1-antagonist treatment was stopped preoperatively, and in patients without a history of taking an α1-antagonist.



Challenges to topical drop adherence after cataract surgery

Furthermore, research shows that a significant proportion of physicians who prescribe α1-antagonists fail to consider or are even unaware of how these medications can cause complications during 

With this background in mind, cataract surgeons need to carefully review medication history as part of the preoperative evaluation so that they can identify at-risk patients and be knowledgeable about the strategies for IFIS management.



In a clinical update on IFIS during the 

American Academy of Ophthalmology’s 2020 virtual meeting

, David F. Chang, MD, reviewed the literature on these topics and provided some practical advice.

Chang is in private practice in Los Altos, California, and is a clinical professor of ophthalmology at the University of California, San Francisco. He coauthored the 2005 paper linking tamsulosin use with IFIS and has since been involved in research and education about this complication.



Good nutrition optimizes ocular surface in premium cataract patients


Chang presented information on the pharmacology and pharmacokinetics of drugs that block α1-adrenergic receptors to explain why, within this medication class, tamsulosin is associated with the greatest risk of IFIS. 

In addition, he discussed evidence showing that tamsulosin not only blocks the α1A receptor in the iris dilator muscle but also causes atrophy of the dilator muscle to explain why discontinuing treatment preoperatively does not eliminate IFIS risk.

There are potential factors to consider, and investigators have looked at these issues.

Chang reviewed studies that identified other possible risk factors for IFIS, including hypertension, and reports of IFIS in patients with no history of α1-antagonist use. 

Changing patient conversations around cataract surgery

Among the latter papers was a prospective study coauthored by Chang that documented that in the absence of any epinephrine in the irrigating bottle, severe IFIS occurred during cataract surgery in almost 5% of patients who had no history of α1-antagonist use. 

He added that the study was also among the first to provide evidence supporting a benefit for routinely adding epinephrine in the irrigation bottle to prevent mild to moderate IFIS.

“The commercially available fixed combination of phenylephrine 1%/ketorolac 0.3% (Omidria, Omeros Corp.) is approved for maintaining pupil mydriasis, but off-label use of epinephrine in the bottle is also very effective,” Chang said.



Drop-free prophylaxis regimen before cataract surgery lowers treatment burden with caveats


As an alternative to adding phenylephrine 1%/ketorolac or epinephrine in the irrigation bottle, Chang recommends considering direct intracameral injection of an α-agonist, such as epinephrine or phenylephrine, for patients with a history of α1A-antagonist use.

“Because of its low pH, epinephrine should be first diluted 1:4000 or 1:5000 with BSS [balanced salt solution] prior to off-label intracameral injection,” Chang said.

Epinephrine formulations containing chlorobutanol preservative or tartaric acid are not intended for intraocular use and should be avoided. Unpreserved epinephrine ampules may contain bisulfite 0.1% to slow oxidation, but corneal endothelial toxicity is avoided with the recommended dilution.


Intracameral injection of phenylephrine 1.5% offers an effective alternative to epinephrine for preventing IFIS, but this must be obtained from a compounding pharmacy in the United States. 



Minimize inflammation after cataract surgery


For any compounding of intraocular drugs, Chang recommended using a 503B outsourcing facility that is authorized to ship products nationally and is subject to stringent FDA regulations and inspection.


Chang cautioned against doing pupil stretching to manage IFIS or a small pupil in a patient at risk for IFIS, but said iris retractors and mechanical pupil expansion rings are very effective for maintaining an enlarged pupil.

“I use a pupil expander if there is any question about severe IFIS risk and also when there is a comorbidity, such as pseudoexfoliation, a dense lens, or perhaps a shallow chamber, as well as when the pupil is not dilating well, even with intraocular phenylephrine,” Chang said.

Strategies for preventing IFIS also include efforts to educate physicians who prescribe α1-antagonists to treat benign prostatic hyperplasia (BPH) about the risk.



Reducing burden on veterans undergoing cataract surgery

These prescribers should be counseled to ask patients if they have cataracts, consider advising patients with symptomatic cataracts to undergo cataract surgery prior to initiating nonemergent treatment with an α1-antagonist, or treat BPH with a medication other than tamsulosin that carries a lower risk of IFIS or no risk.


Chang said he recommends that prescribing physicians consider tadalafil used alone or in combination with dutasteride as a first-line treatment for BPH in their patients with cataracts. 

While it is better known as a treatment for erectile dysfunction, tadalafil is a phosphodiesterase-5 inhibitor that also can offer some benefits for patients with lower urinary tract BPH symptoms by improving bladder emptying.



Perioperative medications can eliminate postoperative drops after cataract surgery

According to Chang, dutasteride, a 5α-reductase inhibitor, decreases prostate size, and offers an option for patients. It can prove to be a vialble option for ophthalmologists.

When an α-antagonist is needed, Chang noted that alfuzosin carries a low risk of postural hypotension in patients and is less likely to cause severe IFIS than tamsulosin, according to a masked comparison study he and his colleagues published. 


This article is based on Chang’s presentation at the American Academy of Ophthalmology’s virtual 2020 annual meeting. Chang has no financial interest in any product mentioned.

Articles

Cataract surgeons must consider medication history as part of preoperative evaluation.

Expert on IFIS offers practical pearls for success

Research is finding key patient benefits to gene therapy as a promising treatment strategy for Leber's hereditary optic neuropathy (LHON). 

This article was reviewed by Patrick Yu-Wai-Man, FRCOphth, FRCPath, BMedSci, MBBS, PhD


	
	Data from two clinical studies of Leber’s hereditary optic neuropathy (LHON) showed substantial visual improvements in patients with both disease durations of less than six months and between six months and one year. The improvements resulted from a unilateral injection of a gene therapy vector (GS010) and remarkably, the viral vector seemed to be carried over to the untreated eye.  

The mechanism of action for these unexpected results need to be clarified with further experimental work. 
	
	

Research targets precision dosing for gene, cell therapy 

LHON is the most common cause of mitochondrial blindness with a minimal prevalence of one in 30,000 individuals in the population. It causes blindness mostly in young adult men with a peak age of onset in the third decade of life. It is invariably a bilateral disorder in which the fellow eye becomes affected within three to six months after disease onset in the first eye. 

Both eyes are affected simultaneously in about 25% of patients, according to Patrick Yu-Wai-Man, FRCOphth, FRCPath, BMedSci, MBBS, PhD, an academic neuro-ophthalmologist with faculty positions at the University of Cambridge, Moorfields Eye Hospital, and the UCL Institute of Ophthalmology, in the UK.

Three primary mutations within the mitochondrial genome cause about 90% of cases worldwide, namely, m.3460G>A, m.11778G>A and m.14484T>C, with m.11778G>A being the most common mutation by far, accounting for over 70% of those affected with LHON. Unfortunately, most affected patients remain legally blind with vision worse than 1.3 logarithm of the minimum angle of resolution (logMAR) or 3/60 in Snellen equivalent. 

Given the poor prognosis, there is an urgent clinical need to identify effective treatments for this blinding optic nerve disease.

LHON gene therapy: Deciphering phase III data


	“Gene therapy is obviously a very attractive treatment option, because the underlying pathophysiology is due to insufficient amount of the wild-type protein,” Dr. Yu-Wai-Man said. “Therefore, if the defective gene is replaced, we should be able to rescue the retinal ganglion cells, preserving function and improving the visual prognosis.”

He described the principles of allotopic gene expression that involves inserting the mitochondrial gene of interest, in this case 

, into the nuclear genome with a modified viral vector. The wild-type protein produced has a specific mitochondrial targeting sequence that directs it to be imported into the mitochondrial compartment.

The use of an intravitreal injection is a big advantage for this treatment approach as it is a relatively straightforward procedure that provides direct access to the inner retina. Previous preclinical work indicates that allotopic expression is able to rescue the retinal ganglion cells from the deleterious effects of the m.11778G>A mutation.
	
	

Gene therapy offering hope for retinal, corneal patients 


	RESCUE and REVERSE are two studies sponsored by GenSight Biologics. The RESCUE study included 39 subjects with the m.11778G>A mutation who have had the disease for 180 days or less. The REVERSE study included 37 subjects who had lost vision for 181 to 365 days. In both studies, one eye was treated with the gene therapy vector (GS010) and the contralateral eye received a sham treatment.  

The primary end point of the RESCUE study was the difference between the GS010-treated and sham-treated eyes at 48 weeks, with the hope of finding a difference between the eyes of 15 or more letters on the ETDRS chart. Other parameters of visual function were assessed, including optical coherence tomography imaging and patient-reported quality-of-life measures.  

Among the 39 patients (31 men) included in the RESCUE study, vision was lost for an average of 4 months and the average best-corrected visual acuity (BCVA) just before treatment was 1.29 logMAR. During the first 48 weeks, vision continued to decrease in both eyes of each patient to reach a nadir. The primary end point was not met.
	
	

Gene therapy focus of Schepens lectures at AAO 2019 

“Interestingly and unexpectedly, vision started to improve bilaterally from week 48 to week 96 in both the GS010- treated and sham-treated eyes,” Dr. Yu-Wai-Man said. “In fact, at week 48, vision had already begun recovering from the nadir.” By week 96, vision in the GS010-treated eyes improved by a mean of 26.3 letters from the nadir while in the sham eyes, vision improved by 22.8 letters.

A responder analysis was conducted, defined as an improvement of 10 or more letters if the patient’s BCVA was on-chart at its lowest point, or the ability to read a minimum of five letters or more if the VA was off-chart at its lowest point. Based on this definition, the responder rate was 63.2% in the RESCUE study. To put this into perspective, the responder rate was 27.9% in a retrospective natural history study of LHON.

In the REVERSE study, the same unexpected bilateral improvement in vision in the GS010-treated and sham-treated eyes was also observed as in the RESCUE study. Using the same responder analysis that had been conducted for the RESCUE study, 67.6% of patients recruited into the REVERSE study achieved a clinically relevant visual recovery in BCVA.

Optic atrophy in children: Taking aim at possible hereditary atrophies


	To help determine the basis for the unexpected bilateral response, a study with non-human primates was undertaken to evaluate the biodistribution of the GS010 gene therapy vector. A unilateral injection of GS010 was administered in Cynomolgus monkeys. A  quantitative polymerase chain reaction (qPCR) assay was performed at three months to detect and quantify the viral vector DNA in various parts of the eye and brain. 

Three animals were treated with an injection of GS010 in the right eye and one control animal received a placebo intravitreal injection in the right eye. In the treated animals, viral vector DNA was detected in all ocular tissues, but not in the tears of the injected eyes. In the fellow uninjected eyes, vector DNA was found in the anterior segment, optic nerve, retina, optic chiasm, optic tract, and the lateral geniculate nucleus, but not in the visual cortex.

There was, therefore, evidence pointing towards the transfer of the viral vector from the injected to the contralateral uninjected eyes. This observation needs to be confirmed and it remains to be determined whether there is a diffusion pathway via the optic chiasm. The possible transfer of the viral vector between eyes provides a plausible explanation for the unexpected bilateral improvement seen in both the RESCUE and REVERSE studies.

According to Dr. Yu-Wai-Man, the data from the GenSight trials showed a continuous bilateral improvement in BCVA from week 48 to week 96. 

“This improvement in BCVA was significant: GS010-treated eyes had a 26-letter average increase compared with the nadir in RESCUE and a 28-letter increase in REVERSE,” he concluded. “More than two-thirds of the combined number of participants in the RESCUE and REVERSE studies experienced a clinically relevant recovery from the lowest level of BCVA compared with 28% of patients in a retrospective natural history study.”
	
	

Patrick Yu-Wai-Man, FRCOphth, FRCPath, BMedSci, MBBS, PhD

This report was designated Best Paper in Session at the American Academy of Ophthalmology 2019 annual meeting. Dr. Yu-Wai-Man is a consulstant to GenSight Biologics. 

Studies target unilateral gene therapy injection 

A variety of approaches are commercially available or in development that allow refractive adjustments after cataract surgery, including changes in sphere, cylinder, asphericity, and multifocality

This article was reviewed by Burkhard Dick, MD

Available and emerging technologies are addressing the need for solutions to the persistent problem of refractive surprises after 

 (PreciSight, InfiniteVision Optics; Harmoni Modular IOL, ClarVista) and the light-adjustable lens (LAL, RxSight) are now on the market in some countries, and four companies are developing approaches for inducing refractive index changes using a femtosecond laser, said Dr. Dick, professor of ophthalmology, Ruhr University, and chairman, The University Eye Hospital Bochum, Bochum, Germany.

Simulator helps patients 'see' with multifocal IOLs before implantation 


	Sharing his personal perspectives on the light-adjustable lens, Dr. Dick noted that there is now more than 10 years of clinical experience with this technology, and an upgraded version is now available commercially in Europe that is showing great success. 

“A vast amount of experience underscores the value of this three-piece silicone lens whose refractive power can be changed within a few weeks after cataract surgery by specifically targeted UV irradiation,” he said. “I consider the light-adjustable lens a great option to improve refractive outcomes and advance patient care.”

The upgraded light-adjustable lens platform features added UV protection, is implanted with a proprietary injector that allows introduction through incisions ≤ (</=) 2.75 mm, and is adjusted with a new light delivery device. This offers improved ergonomics, a 10-fold reduction in retinal UV irradiance, and new optical patterns.

“The new platform allows for earlier noninvasive post-implantation adjustment and less lock-ins, and it can create an extended depth of focus pattern, induce negative asphericity, and be used to design individually adjustable mini-monovision,” Dr. Dick said.

The safety and performance of the new light-adjustable lens was investigated in a multicenter European study that enrolled 100 eyes of 50 patients with 0.5 to 3 D of preop keratometric astigmatism. The results demonstrated the safety and efficacy of the upgraded light-adjustable lens technology, Dr. Dick said.

“More than 70% of eyes achieved 20/20 or better UCVA, which represents a twofold improvement over the outcomes achieved with toric IOLs, and the accuracy to target refraction for spherical equivalent and cylinder was exceptionally high, matching LASIK outcomes,” he pointed out. 

“In addition, the incidence of both glare and halo were very low.”

Presbyopia-correcting IOLs: Expanding, improving last frontier 


	Refractive adjustment with multicomponent adjustable 

 is achieved by exchanging a front optic with a new component that corrects refractive error or better serves the patient’s vision goals. The two available technologies differ in design. 

 is a dual optic platform that is implanted into the capsular bag. In contrast, the Harmoni Modular IOL uses a scaffold that is implanted into the bag and a front exchangeable optic.

“My personal opinion is that because the multicomponent IOLs require a secondary procedure for power adjustment, they are best considered in situations where there is an increased likelihood of refractive change, such as in cases of pediatric cataract, progressive corneal pathology, or with vitreoretinal tamponade,” Dr. Dick said.

Advanced toric IOL calculator improves refractive outcomes 


	Laser-induced refractive index change (LIRIC) is caused by multiphoton absorption of ultrashort laser pulses and can be performed in silicone, hydrogel, or dye-doped polymers but also in the cornea.

Clerio Vision, one company developing LIRIC technology, is focusing on the development of a device for refractive index modification in the cornea that could supersede LASIK and is the first company to demonstrate LIRIC of a living human cornea. 

The company is also working on a bench top customization device for contact lenses and investigating modification of 

Perfect Lens is another company working in the LIRIC space. It focuses on developing a device for in vivo

Striving for perfection: Creating the perfect IOL

 power adjustment in live rabbit eyes and the feasibility of adding or canceling 

material optimized for modification by a femtosecond laser and a device for in vivo IOL modification. To date it has found a material suitable for refractive index shaping that is expected to have potential for relatively high power change. 

LicriEye (Merck) currently is developing polymers containing coumarin side groups to enable photo-induced adjustment of LIRIC. Its work is in an early stage of development.
	
	

Read more by Cheryl Guttman Krader, BS, Pharm

This article is based on Dr. Dick's presentation at the American Academy of Ophthalmology 2019 annual meeting. Dr. Dick is a consultant to RxSight. 

Improving outcomes of cataract surgery 

Attention to detail is key when reviewing optic coherence tomography (OCT) to get a real picture of what is occurring in the eye. 

This article was reviewed by Richard K. Lee, MD, PhD

scans to correlate structure with function of the optic nerve. Sounds simple enough.

For example, a patient with an inferior optic nerve head notch has a superior visual field defect that can then be correlated and quantified on the OCT scans and confirm that there really is loss of the nerve fiber layer, according to Richard K. Lee, MD, PhD, associate professor and the Walter G. Ross Distinguished Chair in Ophthalmology at the Bascom Palmer Eye Institute,  University of Miami Miller School of Medicine, Miami.

Clinicians should not be concerned only with structure to follow or identify glaucomatous disease. He noted that in the Ocular Hypertension Treatment Study (

 2006;113:1603-12), the optic nerve head (ONH) showed the first signs of disease progression in almost 60% of patients. In a third of patients the first sign of glaucoma development was visual field deterioration. Both should be followed. Optic nerve dysfunction with concomitant cupping of the ONH was observed in only 7% of patients. 

OCT finds niche in glaucoma diagnosis, management 


	No matter how much a perfect instrument is desired, 

“Clinicians can see ONH hemorrhages, pallor, edema, peripapillary crescents white, black, or grey, or other features of the optic nerve anatomy that cannot be observed in or identified by OCT,” Dr. Lee said. “There is no reliable information at all in eyes with high myopia where the OCT signal strength is so poor that no imaging is possible.”

 progression. If physicians rely only on the green color coding, and don’t look more closely, they can easily miss the fact that the nerve fiber layer (NFL) may be continuously becoming thinner and thinner. The 

 printout tells the clinician that the NFL thickness is in the normal range relative to the normative database, but the clinician may miss the thickness issue. 

Evaluation of the VF in such a patient may show continued progression of a glaucomatous VF defect that can happen despite aggressive medical therapy. 
	
	

Measuring RNFL with OCT detects subtle differences in glaucoma progression 

“This patient could be seen as normal, but functionally getting much worse,” Dr. Lee commented.

Physicians used to review all the data manually. 

 can provide all of this information with an automated comparison of current to prior OCTs to determine if there is change which, Dr. Lee believes, should be reviewed for all patients on a regular basis.

“The lesson here is that in some eyes no signal can be obtained, and the eye can be absent and a normal signal can be obtained,” he explained. “The caveat is that clinicians must look closely at their scans and correlated to the clinical examination. The fact that there were no OCT NFL scan results should tell the ophthalmologist that something is wrong.”
	
	

Macular OCT: A must for treating glaucoma patients 

A number of variables affect OCT instruments that are machine-, operator-, and patient-dependent. 

“We always obtain duplicate or triplicate OCT scans or more at the same sittings for comparisons of minute details among the scans,” Dr. Lee said. 

Clinicians should check the signal strength and segmentation, review the right and left eye and superior and inferior NFL density butterfly pattern and the average NFL thickness, and look for asymmetry and progression of the NFL loss. 
	
	

Dr. Lee has no financial interest in any aspect of this report. 

Ophthalmology Times: Feb. 1, 2020

Expert on IFIS offers practical pearls for success

Studies target unilateral gene therapy injection

Improving outcomes of cataract surgery

OCT artifacts and pitfalls: In the eye of the beholder