Cowboys, duels, swinging-door saloons and damsels in distress (often, and inexplicably) tied to railroads… these are the tales of the Wild West as told by Hollywood — even though history does paint a somewhat tamer version.
In vitreoretina practice, there was also a time when things were, let’s just say it — wild. For example, until medical retina rode onto the scene, doctors’ hands were tied (similar to the aforementioned damsels) with regard to treating diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR) and diabetic macular edema (DME). Indeed, new pharmaceuticals, as well as innovations in surgical techniques and diagnostics, have helped tame this particular frontier. This “Gold Rush” changed treatment paradigms — and spurred some of ophthalmology’s greatest “duels” as doctors took aim at the target of improved outcomes.
And the ophthalmic gold rush isn’t over yet. Certainly, newfound innovations have not only helped to conquer previous frontiers… they will help uncover new ones. So, strap a saddle onto that metaphorical horse and grab the reins — we’re ridin’ into the “Wild West” of vitreoretinal practice. (Yee-haw!)
Mapping the Frontier in Vitreoretina
During the Wild West, the frontier was the boundary between the known and unknown, the civilized and the untamed. In ophthalmology, there is a similar frontier — the before and after of practice-changing medical therapies, surgical techniques, imaging devices and diagnostic equipment. And when compared to the specialty’s history, these trails were only recently blazed…
Medical retina’s “ace-in-the-hole”
On frontier-changing innovations in medical retina, the response was unanimous: anti-VEGF is (and was) the ace-in-the-hole.
“Definitely, the development of anti-VEGF drugs for the management of neovascular macular degeneration (nAMD) and diabetic macular edema changed posterior segment practice forever,” said Professor Anat Loewenstein from Tel Aviv University and the Tel Aviv Medical Center, Israel.
Dr. Judy Kim, from The Eye Institute at the Medical College of Wisconsin, Milwaukee, USA, agreed: “In the realm of medical retina, there is no question: anti-VEGF. These intravitreal agents have not only stabilized, but also improved vision, in patients with various retinal-vascular diseases.”
This was echoed by Dr. Vaibhav Sethi in India, as well as Dr. Andrew Chang in Australia, who added that anti-VEGF is not only a sight-saving therapy for conditions like nAMD, DME and RVO (retinal vein occlusion), its development has led to a paradigm shift.
Before anti-VEGF reared its “vascular endothelial growth factor-head,” the only available treatments were thermal laser and PDT, neither of which were necessarily ideal. This is because thermal laser is destructive to neural tissue with resulting loss of vision and scotoma — and there’s a high recurrence rate. Meanwhile, PDT is not very effective in improving vision and needs repeat treatment,” explained Dr. Chang from Sydney Retina Clinic and Sydney Eye Hospital.
To add to laser’s woes, using it for macular degeneration was only proven effective in decreasing loss of vision in very specific lesions; later, PDT gave stabilization of vision, but only in a subset of patients, said Prof. Loewenstein. “And for diabetic macular edema, we only had laser which was not beneficial enough.”
Dr. Kim also had a yarn on laser: “Prior to anti-VEGF, laser was the treatment of choice for DME, PDR and macular edema from branch retinal vein occlusion (BRVO) — even thermal laser was used at one time for wet AMD based on the Macular Photocoagulation Study.”
She explained that they used to draw out the location of the choroidal neovascular membrane (CNV) based on fluorescein angiogram and then treat with laser. Using this procedure, Dr. Kim said: “Juxtafoveal CNV patients may do well, albeit with paracentral scotoma, as long as there is no enlargement of the laser scar over time.”
However, those with subfoveal lesions experienced an immediate decline in vision — with the hope that this result would be better compared to no treatment years down the line. “I remember getting a sick feeling in my stomach after treating a patient with subfoveal CNV with laser, knowing well that her vision would be worse the next day, and wondering if this is the best we can do for these patients.”
Dr. Kim continued: “I am old enough to have done submacular surgery to remove CNV, as well as limited macular translocation to move the fovea away from the CNV — and, don’t forget radiation treatment for wet AMD. Now those were truly the wild, wild times!”
These insights beg the question: Back then, what was worse: the disease or the treatment?
Thankfully, when anti-VEGF entered the scene, it changed everything. “We moved from a situation where everyone lost vision, to a situation where (almost) no one loses vision and has stable vision for a long time,” said Prof. Loewenstein.
That’s like going from a lame horse to a steam locomotive — full speed ahead. However, like the railroad in its expansion of the west, anti-VEGF has also encountered some challenges. While these hurdles aren’t masked bandits with explosives, they can still cause derailments. “There are new challenges in patient compliance and the burden associated with intensive treatment regimes,” shared Dr. Chang. “Clinics, physicians and stakeholders have had to adapt workflows to manage this.”
These “derailments” will hopefully be managed with drugs with longer durability and port delivery systems, which are on the horizon, he added.
Frontiers evolve in surgical retina
Of course, not all conditions can be placated with the “magic bullet” of an anti-VEGF injection — some will inevitably require surgical management. Thus, the surgical frontier is in flux as new techniques evolve.
A big shift occurred with the introduction and evolution of pars plana vitrectomy (PPV), shared Dr. Sherman Valero from The Makati Medical Center, The Medical City and The American Eye Center, Philippines. “Pars plana vitrectomy has allowed us to manage more and more cases — from the simplest vitreous hemorrhage to complicated retinal detachment surgery, to the most delicate ILM (internal limiting membrane) peeling.”
“Without PPV as a surgical modality, many eyes would still be going blind,” added Dr. Kim. “Since its development, much has changed over the years, such as the cut speed, improved fluidics, and smaller gauge instruments. However, these are all tweaks to the fundamental system.”
According to Dr. Chang, one of these “tweaks” was the procedure’s evolution to transconjunctival sutureless vitrectomy (TSV) which is more surgically efficient, improves patient outcomes and allows for a more rapid recovery.
“This technology has paralleled improvements in cutter and instrumentation technology… higher speed cutters, smaller gauge instruments, brighter and safer light sources, improved visualization with microscope viewing systems including 3D vitrectomy (i.e., NGENUITY 3D Visualization, Alcon, Geneva, Switzerland; and ZEISS ARTEVO 800, Carl Zeiss Meditec, Jena, Germany) and intraoperative OCT,” said Dr. Chang.
He continued: “Prior to this, we had conjunctival peritomy, which required suturing, larger gauge instrumentation and had higher risk of complications, including retina and vitreous incarceration. Plus, older visualization techniques provided less surgical control.”
Another pre-vitrectomy procedure was scleral buckling, added Dr. Kim. However, this procedure is limited in usage, as many eyes cannot be fixed with scleral buckling alone.
In addition to vitrectomy, the development of perfluorocarbon (PFC) liquid has also been crucial to increased success in complex cases. “Prior to this development, the surgical bed was turned upside down and air was used intraoperatively to flatten the retina and surgeons worked from below! Imagine the neck and back pain for the surgeons and the assistants!” shared Dr. Kim, adding that innovation in tamponading agents, such as various intraocular gases and silicone have also contributed greatly.
Dr. Sethi from Arunodaya Deseret Eye Hospital, Gurugram, and Dr. Sethi’s Eye Centre, Delhi, India, said that wide angle viewing systems have forever impacted the way surgeons operate in the posterior segment. “This has changed the way we treat vitreoretinal disorders, both medically and surgically,” he explained, adding that previous treatments resulted in variable outcomes and associated collateral damage, like field of vision loss.
Can’t fix what you can’t see
Further, enhancements in imaging have helped to lift the proverbial blindfold in vitreoretinal practice.
“OCT (optical coherence tomography) has changed the way we practice retina — allowing us to visualize, diagnose, manage and follow-up on retinal diseases to a degree that was unimaginable before,” Dr. Valero pointed out.
Dr. Kim agreed. She shared that in her lifetime, along with anti-VEGF, OCT has revolutionized how retina patients are treated.
This was echoed by Prof. Loewenstein. She explained that prior to OCT, there was only fluorescein angiography, which showed the retina in a much lower detail than OCT. “So, from the diagnostic point of view, definitely it was OCT that changed our lives forever — now, we’re able to see the retina extremely meticulously with great detail.”
Great Duels in Vitreoretina
Bang, bang… we’ve got a stand-off. Like in the great duels of the Wild West, we asked our cutter-wielding surgeons to take 10 steps and shoot… their recommendations for treating diabetic retinopathy and retinal detachment, that is. Will anti-VEGF hit first? Will laser find some footing? And how does the feud between scleral buckling and vitrectomy end?
Duel #1: Anti-VEGF vs. laser in diabetic retinopathy
In the duel between laser and anti-VEGF for DR, it was more of a tip-of-the-hat and a handshake than a duel — in fact, most of the interviewed cowboys and cowgirls (of the doctor variety) agreed on the first-line treatment. Shots (not) fired!
For DR patients, Dr. Valero said that before any treatment considerations, he begins with a discussion about the need for better sugar control and regular follow-up. Dr. Kim also takes this route: “If the patient has less than PDR and no DME, I monitor and educate on the importance of glycemic control and follow-up at various intervals, depending on the DR stage.”
PRP and PRP-anti-VEGF combos lead in PDR
In cases of PDR without DME, or eyes with PDR and DME that achieve resolution of DME, Dr. Kim addresses the risks, benefits and alternatives of pan retinal photocoagulation (PRP) versus anti-VEGF therapy, and then together with the patient, the most appropriate treatment is determined.
“Often, in a compliant patient, we start with anti-VEGF injections followed by PRP for extending the durability of treatment and reducing the treatment burden,” she said, noting that in DRCR Retina Network Protocol S, there was less difference in visual field loss between PRP treated eyes and anti-VEGF-treated eyes at five years than at two years — and further, continuous anti-VEGF treatment for more than five years is a huge treatment burden. “I worry about patients getting sick and missing treatment visits along the way — and some patients worry about the copay at each visit. Therefore, minimizing the number of visits while maximizing the care is the goal.”
In her patients with PDR, Dr. Loewenstein said she also uses both PRP and anti-VEGF, depending on the patient: “I recommend either PRP or monthly injections, provided that the patient commits to being followed-up and treated monthly for a few months.”
For patients with clinically significant disease like PDR, Dr. Valero said he usually offers PRP as the first-line treatment. “In the very few patients for whom the side effects of PRP are unacceptable, I offer anti-VEGF injections — but only after an exhaustive conversation about possible adverse events, the need for very regular treatment and follow-up, and the possibility of recurrence,” he said. This is because if PDR patients treated solely with anti-VEGF interrupt their treatment, they are at a high risk of developing irreversible blindness* — and that’s a gamble many aren’t willing to take.
“I find that when anti-VEGF treatments are discontinued, neovascularization often recurs. This does not happen as often after good PRP,” explained Dr. Kim. She said that if the patient seems likes they will not follow up with recommended visits (e.g., due to health or transportation issues, in young patients with a history of noncompliance in diabetic care, or those already monocular from poor eye care, etc.) she will recommend PRP on the same day of the visit — not only for eyes with PDR but also with severe NPDR (nonproliferative diabetic retinopathy). “If at all possible, I do not want to lose the opportunity to treat and stabilize.”
Dr. Chang also recommended laser for non-center involving PDR, as well as DME: “This is an effective therapy which requires less rigorous intervention in the long-term,” he explained.
This rigorous intervention, like the treatment burden of monthly injections, was also noted by Dr. Sethi as a reason to treat PDR with PRP. “I prefer to treat PDR with PRP as most patients I come across are from far away places and cannot afford to get monthly anti-VEGF injections,” he explained.
“If the patient is educated, willing to attend monthly follow-ups and can afford it, then I would advise anti-VEGF therapy for PDR — and only in cases that don’t have significant traction or fibrovascular proliferation,” continued Dr. Sethi. In severe cases, he would also consider early vitrectomy, “as the visual outcome tends to get worse as we delay the surgical intervention.”
Anti-VEGF wins in DME
What about DME? Here, anti-VEGF was the clear winner: When treated intensively with anti-VEGF drugs, about one-third of eyes with DME experience an improvement in their DR severity scale.1 However, steroids were also considered in some instances.
“First-line treatment for diabetic macular edema? That would be an intravitreal anti-VEGF injection,” said Dr. Sethi.
In patients with any DR and DME, Dr. Kim also begins anti-VEGF therapy — usually with Avastin (bevacizumab; Genentech, California, USA) as the drug costs less than other agents, and insurance pre-authorization is usually not necessary. “However, if the baseline visual acuity is less than 20/50 and/or there is significant central subfield thickness on OCT, I will switch to Eylea (aflibercept; Regeneron Pharmaceuticals, New York, USA) early based on DRCR Retina Network Protocol T findings,” explained Dr. Kim.
In the Philippines, Dr. Valero also said anti-VEGF is his first line treatment, although the choice of which agent to use is cost-dependent, as he uses a self-pay system. For patients with recent cardiovascular or cerebrovascular events, as well as for those who have difficulty making monthly injection appointments, he would instead offer a steroid implant.
In cases of DR with DME, Dr. Loewenstein also prefers anti-VEGF — this is because it’s shown to provide the best results. “In Israel we are obliged to start with bevacizumab. If after three injections there is not a good enough response, I switch to either ranibizumab or aflibercept,” she explained. Like Dr. Valero, Dr. Loewenstein would only deviate from using anti-VEGF if the patient could not commit to multiple visits and injections, or if there was a history of stroke or heart attack. “In these cases, I sometimes start with steroids as the first line treatment.”
Dr. Chang added: “Anti-VEGF therapy has revolutionized treatment of center-involving DME — it’s established and proven effective to restore and maintain sight.” However, he said that this comes with challenges of a demanding treatment regime and often, DME patients are working to support themselves and their families, and therefore could miss appointments. Plus, diabetic patients frequently suffer from related complications and see multiple doctors for diabetes and diabetes-associated conditions, he explained.
Duel #2: Vitrectomy vs. Scleral Buckle in Retinal Detachment
Our second duel puts scleral buckle against vitrectomy to correct retinal detachment (RD). In this stand-off, vitrectomy hit the target for most doctors — however, there is still room for scleral buckle and other techniques, in certain patients and detachments.
“Vitrectomy approach to RD repair is increasingly trending as the first-line [treatment] compared to scleral buckle,” said Dr. Chang. “This has arisen from technology improvements in cutters, machines, illumination, instrumentation and visualization systems that allow safe and effective surgery. Patient postoperative recovery also is potentially improved following vitrectomy versus buckle.”
According to Dr. Kim, PPV is also the first-line therapy for older patients with posterior vitreous detachment, pseudophakic patients, or patients with cataract who understand that cataract surgery may be needed following RD repair. “For those with significant cataract, we do a combined surgery of PPV with cataract extraction at the same time. Even for eyes with RD-associated with giant retinal tear, PPV alone has been successful,” she explained.
“For a great majority of my patients, I usually offer a primary PPV with gas and laser,” said Dr. Valero. “The introduction of small gauge sutureless vitrectomy has somewhat skewed my preference to this method — this likely because a vitrectomy affords me greater confidence in visualizing and treating all the breaks.
“It also allows me to clean the vitreous as much as possible and manage any existing PVR (proliferative vitreoretinopathy) more definitively. When you combine this with the ease of the newer system, it makes for an attractive choice for management of RD,” said Dr. Valero, adding that he would also offer pneumatic retinopexy for those who met the criteria, as well as segmental buckle for younger patients.
These recommendations from Dr. Valero were in line with Dr. Loewenstein’s approach: “In most cases, I do a vitrectomy as it’s the fastest and very safe. If it’s a young patient with a tear that is relatively anterior and phakic, I may recommend a scleral buckle — or I will recommend pneumatic retinopexy if it meets the criteria,” she shared.
Pneumatic retinopexy is certainly an option for localized retinal detachment with superior retinal tear, agreed Dr. Kim, adding that “it requires understanding and the compliance of the patient who is willing to position.”
“In a young, phakic patient with clear media who refuses pneumatic, or if the tear(s) are not amenable to pneumatic retinopexy (e.g., multiple tears, inferior tears, extensive lattice or atrophic holes, etc.), scleral buckling is my first-line treatment,” continued Dr. Kim.
Dr. Chang recommends scleral buckle in RD without posterior vitreous detachment, such as in younger patients with atrophic holes causing the RD or in retinal dialysis. He also considers this approach in patients who may not be able to cooperate with care or posture postoperatively.
Dr. Sethi would also prefer taking the alternative approach of scleral buckling in young patients who have a clear lens and treatable peripheral retinal breaks, or lesions with or without PVR changes. In other instances, he primarily manages RD with micro-incision vitreoretinal surgery (MIVS) using 23-, 25- or 27-gauge instrumentation as per the case.
“In uncomplicated cases without PVR, I prefer to leave gas in the eye as tamponade, preferable SF6 or C3F8,” said Dr. Sethi. “In cases of traumatic retinal detachment or in cases of RD with PVR, I use silicone oil as a tamponade agent.”
And for more complicated detachments, Dr. Kim combines scleral buckling with PPV. “These include eyes with recurrent RD, proliferative vitreoretinopathy or trauma. While I usually use gas as a tamponading agent, in these more complex cases, silicone oil has come in handy, but does require another surgery to remove the oil.”
The “Gold Rush” in Innovation
In the era of the Wild West, settlers were driven west for a variety of reasons. One of which was gold — as in “there’s gold in them hills.” Now, in ophthalmology, we aren’t necessarily seeking golden nuggets, but rather “golden” innovations.
So, what will ophthalmology pan for next?
According to Dr. Kim, the next “gold rush” will be decreasing the treatment burden, improving early detection, and finding treatments for currently untreatable diseases.
For decreasing treatment burden, longer effective drug duration in a consistent manner for as many patients as possible will be needed: “This is currently being approached in several different ways, including various drug delivery methods and drug design. Gene therapy will play a big role here, with the possibility of long-term drug delivery,” said Dr. Kim.
Dr. Valero added: “Now that we have seen the success of drugs to treat a variety of retinal conditions such as DME, AMD, etc., it’s exciting to see development of drug delivery systems that will allow for a more sustained dosing and better compliance to these medications — and hopefully translating to better outcomes.”
“Port delivery systems combined with home monitoring holds promise for less interventions and personalized care in the treatment of conditions such as neovascular AMD or DME,” agreed Dr. Chang. “In vitreoretinal surgery, intraoperative OCT and heads-up 3D vitrectomy will be increasingly adopted as the cost falls and the machines become smaller and more ergonomic. This is an important foundation for virtual and robotic surgeries in the future.”
Along those lines, Prof. Loewenstein shared, “The next ‘gold rush’ in vitreoretina practice will be longer acting drugs or devices, home monitoring by home OCT, and the use of virtual reality in vitreoretinal surgery.
“AI, of course, is touted to be the next big thing in ophthalmology,” she continued. “Hopefully it will allow us to predict disease progression and give us a chance to improve patient outcomes.”
In addition to its ability to predict, AI could also help improve early disease detection by capturing fluid recurrence sooner via home monitoring — this could incorporate data evaluation using AI, which allows for more frequent and accurate monitoring, said Dr. Kim. However, current models need infrastructure, reimbursement, and patient self-motivation to be effective. That said, she believes that this type of monitoring will become more important with the rise of longer durability treatments.
“To me, AI incorporation in diagnostics will be the next big thing as it will change the way we practice vitreoretina. It will improve the diagnostic accuracy many folds and will be able to pick out details that a human observer might miss or overlook,” said Dr. Sethi. “It will also help in defining the management protocol customized to the particular eye. This will help the clinician to take the right step at the right time to get the best outcome for the patient.”
Dr. Chang also concluded that AI will assist the clinician in individualizing patient care and predicting what treatment a patient may require.
And one final wish? “I wish someone could design a compact, portable, wide-field, inexpensive multimodal imaging system that captured great images. This could be used by the public with immediate AI interpretation to help screen more people around the world and to attack vision problems, such as diabetic retinopathy. Am I asking for too much?” [Editor’s Note: We don’t think that’s asking for too much at all… but we’re writers, not amazing device designers.]
Making the West Less “Wild”
Thanks to these frontier-shifting therapies, surgical techniques, and other ophthalmic innovations, vitreoretinal practice is certainly looking less “wild” than it may have 20 years ago. In fact, the dust from what were once great duels for treatment preference seems to have settled… and perhaps will only reignite with further development in instrumentation and techniques.
However, a number of untreatable conditions or conditions remain that need to be better managed, including dry AMD, central retinal artery occlusion (CRVO), and inherited retinal degeneration, said Dr. Kim. She predicts both dry and wet AMD will attract more research: “Developments in complement inhibitors and cell therapies are being investigated — and this is a wide open frontier for someone to conquer!”
So, as we saddle up to ride off into the sunset, we’re left to ponder the next frontier — and gold rush — in vitreoretinal practice: the rise of technologies like AI, improvement to existing therapies and delivery systems, and more. Certainly, these will have a profound impact in ophthalmology and treatment paradigms. Yee-haw, indeed.
*Wu L, Acón D, Wu A, Wu M. Vascular endothelial growth factor inhibition and proliferative diabetic retinopathy, a changing treatment paradigm?. Taiwan J Ophthalmol. 2019;9(4):216-223.