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Laser eye surgery and chronic pain

An extra from In the blink of an eye (below)

Lingering questions about LASIK’s long-term effects

The offers began arriving by email in January: a chance at clearer vision for the special price of US$299 per eye. Over the next four months, I received 20 ads from the same company – each offering the same deal for the “safe, FDA approved” surgery.

“Individual results will vary,” each ad said in the fine print. None mentioned that those variable results could include seven categories of vision-threatening complications or 17 types of non-vision-threatening side-effects, such as “increased sensitivity to light”, “eye irritation related to drying of the corneal surface”, “pain or a foreign body sensation”, or increased susceptibility “to trauma from impact”. (Bargain offers notwithstanding, average all-in costs also exceed US$2,000 per eye.)

All surgeries carry risk, and the risks associated with laser in-situ keratomileusis, or LASIK, are listed on the standard consent form that all patients must sign. For many, the rapid procedure goes off without a hitch and leaves no residual effects. Scrupulous centres also turn away the roughly one-fifth of patients who are not good candidates.

But a quarter of a century after the first ‘flap and zap’ vision-correcting surgery, controversy continues to rage over whether regulatory authorities and industry officials have repeatedly downplayed or ignored the prevalence of dry eye disease, chronic pain and other potentially serious side-effects. Has the public, in other words, been told enough to make an informed decision about an elective surgery that can’t be undone?

In response to mounting pressure from patient advocates who say they haven’t, the US Food and Drug Administration co-sponsored a quality-of-life study to help quell the debate. The recently released preliminary results of that study, however, appear to be doing exactly the opposite.

Early procedures

How did it get to this point? Excimer lasers, as they’re known, were first used to perform a precursor method called photorefractive keratectomy (or PRK) in the late 1980s. During the procedure, a doctor removes the thin outer layer of corneal tissue and then uses the laser to create a precise vision-correcting divot on the surface. The painful method can mean several weeks of recovery time per eye, but it doesn’t cut through the corneal nerves like LASIK does.

Surgeons soon began gravitating toward the faster LASIK method, which cuts a hinged flap in the cornea to alter its light-refracting properties. From 1996 until his retirement in 2000, Morris Waxler was chief of the Diagnostic and Surgical Devices Branch that regulated corneal resurfacing lasers within the FDA’s Division of Ophthalmic Devices. He was at the helm when the FDA branch gave the green light to the first LASIK laser in July 1998.

The approval, Waxler said, was intended in part to stem major compliance problems and bring some order to the increasingly chaotic industry while reasserting the FDA’s regulatory authority. In the process, he alleged, the agency wasn’t as attentive as it should have been to the surgery’s long-term risks, including chronic eye pain.

“We were hard-pressed to know what to do about these problems,” Waxler said. The assumption was that the pain would persist for a few months, maybe, or a year. “So we figured we would handle it in the labelling and that ‘caveat emptor’ – ‘buyer beware’ – would rule the day, and we assumed that refractive surgeons and clinics would be honest and tell their patients ‘You’re going to have pain’, and that’s turned out not to be correct.”

Carlos Belmonte, founder of the Institute of Neurosciences in Alicante, Spain, and a pioneer in studying the physiological basis of eye pain, explains that corneal nerves don’t completely regenerate after LASIK surgery. “The main risk is that in a very small percentage of cases, this regeneration is pathological, and then you get this neuropathic pain and that is a disaster,” he said. “But this is a risk that happens in surgery.”

In 2007, Belmonte published a study that suggested a form of dry eye pain called ‘phantom’ cornea could occur after LASIK-mediated damage to the corneal nerves. At the same time, Boston ophthalmologist Perry Rosenthal was compiling multiple case reports suggesting that a similar post-LASIK phenomenon was appearing regularly in patients with severe eye pain who had been referred to his clinic. Other researchers have documented phantom pain among patients who have had eye amputations or corneal transplants.

Waxler retired in 2000 and is now an independent regulatory consultant. He gave little additional thought to LASIK until a patient whose eyes had been damaged by the surgery called him about six years ago and angrily asked why it had been approved. Waxler listened, and began talking to other patients with similar stories. “I said, ‘Well, how could this happen?’” he recalled.

Based on his review of medical studies and documents on the FDA’s website, he alleges that many of the problems had been reported all along, but labelled as ‘symptoms’, a category deemed less serious than ‘adverse events’. Waxler made headlines in 2010 and 2011 when he went public to contend that the original studies actually documented an adverse event rate of about 20 per cent. The FDA later responded that symptoms like glare and dry eye are too mild to be considered adverse events.

Meanwhile, more patient advocates were going public with their own stories and documenting them on Facebook groups and multiple websites. One, LASIK Complications, created a page to track LASIK-linked suicides and attempted suicides, based on news accounts and patient reports filed with the FDA.

At a public meeting of the FDA Ophthalmic Devices Panel in April 2008, nearly 20 individuals spoke out against the LASIK procedure: optometrists who had treated patients after the surgery, patients recounting their own ordeals, and two speakers testifying about patients who had killed themselves.

New Jersey financial administrator Matthew Kotsovolos, now 46, was among those who testified. He describes his own misery after a 2006 LASIK eye surgery as “a pain that I am confident that most people do not recognise as existing in this world”. His surgeon considered the procedure a success because Kotsovolos’s uncorrected vision improved to 20/20. Even so, he suffered from constant, debilitating eye pain. “So I pretty much lived in Hell.”

Exploring outcomes

In October 2009, the FDA, the National Eye Institute and the Department of Defense responded to the lingering controversy by launching the LASIK Quality of Life Collaboration Project “to help better understand the potential risk of severe problems that can result from LASIK”.

The collaborative effort tested a web-based questionnaire on 242 naval personnel – most of them male – who received free LASIK at the US Naval Medical Center in San Diego. A subsequent phase then surveyed 292 civilian patients, split roughly between male and female, who had LASIK surgery at five other clinical centres. In October 2014, Malvina Eydelman, director of the FDA’s Division of Ophthalmic and Ear, Nose and Throat Devices, presented the preliminary results from both phases of the study.

The study agreed with most previous surveys in suggesting a patient satisfaction rate of more than 90 per cent. As Waxler and other critics have repeatedly emphasised, however, satisfaction rates cannot take the place of safety profiles.

In that regard, the FDA’s study results were more mixed. Although the prevalence of patients with ghosting (seeing a faint double image) dropped significantly after surgery, for example, more than one-third still had halos and starbursts. In addition, up to 4 per cent had “very or extremely bothersome” visual symptoms, and up to 1 per cent “experienced a lot of difficulty with or were unable to do usual activities due to visual symptoms” three months after LASIK.

Among respondents who lacked symptoms before LASIK, roughly 30 per cent reported new dry eye symptoms and 45 per cent reported new visual symptoms three months after the surgery.

Instead of a randomised epidemiological study of eye pain, visual symptoms and satisfaction among the existing pool of LASIK patients, Waxler alleges that the “best-case” study used highly specific inclusion criteria for patients and LASIK devices, sharply limiting its applicability to the general population. Even so, he asserts that the FDA and refractive surgery industry have spun the study “as support for the safety and effectiveness of LASIK when in fact it confirms LASIK patients’ problems”.

In response to a request for comment, a spokesperson for the American Society of Cataract and Refractive Surgery offered a November 2014 press release as the society’s official statement. That release characterised the preliminary FDA-led study results as “overwhelmingly positive”, while ASCRS President Richard Lewis called the high rate of success for LASIK “unprecedented as a surgical procedure” and said the collaborative research effort confirms “the remarkable efficacy of LASIK”.

The press release notes that “no surgery is 100 per cent risk free” and quotes Lewis as saying: “Our understanding of those at risk for dry eyes and visual disturbances from LASIK procedures is critical and evolving…Identifying individuals at high risk for complications of LASIK is valuable. However, this must be determined in a well-controlled and timely trial.”

Separate reports suggest that many post-surgical problems will eventually resolve. Few studies, however, have followed patients beyond six months or a year to find out for sure. Rosenthal’s observations of 21 patients with post-LASIK chronic eye pain, for example, suggest that the pain didn’t even begin until a year or more after the surgery for eight of them. A separate survey by The Cornea Research Foundation found that post-LASIK dry eye symptoms actually worsened at the one-year mark before recovering somewhat at two years.

A survey of nearly 800 adults conducted by the Consumer Reports National Research Center and reviews in the American Journal of Ophthalmology, Cornea and Ocular Surface have similarly suggested that chronic dry eye and other symptoms are relatively common six months after LASIK. A new review in the journal Molecular Painasserts that the percentage of patients reporting “persistent eye symptoms” has ranged from 20 per cent to 55 per cent, and the authors invoke corneal nerve damage as one potential contributor.

A recent investigative report from Consumers Digest details a range of other potential flaws in the clinical trials and reporting system used to assess LASIK’s safety. The FDA has not yet released its six-month results from the second group of patients surveyed. Under the heading ‘Public Health Impact’, however, Eydelman’s slide presentation concluded: “Given the large number of patients undergoing LASIK annually, dissatisfaction and disabling symptoms may occur in a significant number of patients.”

Based on industry estimates that more than 40 million patients have undergone LASIK worldwide, the tally of those with chronic eye symptoms could run well into the millions. Although demand for the surgery has fallen over the past five years, Waxler said the market for eye drops that treat dry-eye-associated discomfort has “exploded”, and some manufacturers are specifically aiming their ads at LASIK patients. “It’s no happenstance,” he said.

Waxler filed a petition in 2011 asking his former employer to rescind its approval of LASIK. Three years later, the FDA shot him down, responding that his allegations were unfounded and that data submitted to the agency suggested the surgery’s benefits outweighed the risks. Waxler filed another petition in July 2014 asking the FDA to reconsider. But he’s tired, he said, and has done all he can do: “I have no magical wand to fix this.”

Activists haven’t given up, however. In December 2014, three consumer advocates launched a new petition drive to force the FDA to add a ‘black box’ warning label to LASIK lasers, citing the agency’s own study results to argue that the high incidence of visual and dry eye symptoms represents an epidemic caused by an unnecessary surgery. And in May 2015, more than 1,000 LASIK patients and their supporterssigned a letter urging the federal agency to reopen Waxler’s petition for consideration.

Where does the FDA go from here? In response to questions about Eydelman’s scientific presentation and the agency’s next steps, an FDA spokesperson told me the researchers were preparing the manuscript for publication in a peer-reviewed journal and couldn’t comment publicly about any findings until its publication.

And when might that be? She couldn’t say.

 

© Peta Bell and Grzegorz Krzeszowiec

In the blink of an eye

Some people suffer eye pain so excruciating they feel suicidal, yet ophthalmologists see nothing wrong. Meet the 82-year-old doctor whose radical idea about the real source of this pain is turning heads.

8 September 2015

Razor blades. Jabbing needles. Barbed wire.

Screaming, howling, red-hot-poker-in-the-eye pain. The impulse to gouge your own eyes out or overdose on sleeping pills – anything to make the pain go away.

Blinking can be so excruciating that some people have had their eyelids partially sewn shut. One patient said the pain felt like shards of glass were jutting from her eyes. “Imagine a knife in your eye. Forever,” wrote another.

Most causes of eye pain – a stray eyelash, a chemical burn, a dirty contact lens – are obvious and short-lived. But what happens if the source isn’t immediately apparent and the agony doesn’t stop? Ophthalmologists have made surprisingly little headway understanding the origins of severe and lasting eye pain. Many doctors, in fact, are outright dismissive of intense eye discomfort, deeming it of secondary importance to vision. Patients are often written off as being hyperbolic, narcissistic or even psychiatric.

At 82, Boston ophthalmologist Perry Rosenthal hears regularly from people who are desperate for answers. Although he no longer sees patients himself, he has become the nerve centre of a small but growing network of researchers and clinicians who are defying conventional wisdom and seeking out new explanations for the often jarring disconnect between brutal symptoms and a lack of clear signs.

Rosenthal’s nearly singular focus on resolving the mystery has frayed professional relationships, forced him to leave his own charity and nearly shut him out of a field in which he was once hailed as a hero. A recent burst of research, however, is prompting a new question about his unorthodox ideas: what if he’s right?

In blink of eye 2

Neil Brooks’ problems began at birth. Colorado-based Brooks, 51, was born long-sighted with crossed eyes and pronounced astigmatism, or irregularly shaped corneas. But it took decades for an ophthalmologist to diagnose a painful eye spasm in the ciliary muscle that helps the eye shift its focus. When his condition forced him to quit his job in commercial real estate, Brooks began searching online for a potential cause and came across a condition called accommodative spasm.

An ophthalmologist finally agreed to test Brooks’ hypothesis by treating him with drops used to dilate a patient’s eyes before an examination. “About four months later, I woke up with tremendously less eye pain and significantly better vision,” Brooks says. The dilating drops had finally broken his muscle cramp.

He went back to work, this time at an online flower shop, but the long hours of computer work required him to keep increasing the frequency and strength of the eye drops. Then a new kind of eye pain appeared – a burning sensation that steadily intensified, until it felt like his corneas had been seared by the sun. Bright light became nearly intolerable. Despite trying a range of standard therapies, the new symptoms eventually eclipsed his old ones and he was again declared disabled.

Brooks talked to doctors around the world. Finally, one realised that his eye drops contained a toxic preservative known as benzalkonium chloride. The preservative, which is widely used in artificial tears and eye drops for glaucoma, has been linked to dry eye symptoms, inflammation and cell damage in multiple studies; only some manufacturers have replaced it with other chemicals or preservative-free solutions, however.

An ophthalmologist in Paris who specialised in preservative-induced toxicity confirmed the worst: six years of using the drops had ravaged Brooks’ corneas at the cellular level. Brooks searched online for what to do next and eventually came upon Perry Rosenthal and his charity, Boston Foundation for Sight.

In blink of eye 3

Our clear, disc-shaped corneas serve two roles: first, as vision-enabling windows that refract incoming light and, second, as the foundations for protective films that fend off disease.

The protective ‘tear film’ contains three parts. First, the same kinds of cells that secrete the mucus lining our intestinal and respiratory tracts similarly coat the cornea with a thin layer of sticky mucus. Next, the lacrimal gland above each eye supplies a thicker gloss of tears. Finally, several dozen meibomian glands in the upper and lower eyelids pump out a mirror-smooth oil slick that keeps the tears from evaporating. In response to perceived threats, our eyes water or we blink, which replenishes the tears and oil. Any disruption of the tear film can result in blurred vision; repeated breaches can permanently damage the cornea.

In 2013, the nonprofit Tear Film & Ocular Surface Society launched an international public awareness campaign, Think Blink, about the importance of blinking regularly to maintain healthy eyes. The official campaign song ‘Blink Around the World’, a high-energy dance anthem sung by Italian pop star Sabrina, wouldn’t have been out of place in the Eurovision Song Contest.

There’s considerably less harmony among researchers struggling to reach a consensus on the main contributors to the condition targeted by the blinking campaign: an unwieldy catch-all of dysfunction known as ‘dry eye disease’. Depending on how it’s defined, studies suggest that up to one-third of the population of Japan and Taiwan may be afflicted; risk factors range from old age, smoking and low humidity to LASIK surgery and use of contact lenses or video display terminals. Women make up roughly two-thirds of all patients, for unclear reasons.

Many ophthalmologists have blamed the symptom that all patients have in common, dry-feeling eyes, on insufficient tear production or excessive tear evaporation. Other researchers suspect inflammation, and some are convinced that things still aren’t that simple. The Tear Film & Ocular Surface Society has played the part of independent arbiter and recently launched its second round of workshops aiming to forge a better consensus on how dry eye disease should be defined and diagnosed. The intensive workshops are also delving deeply into subcategories such as surgery or drug-induced dry eye and abnormal pain and sensation.

Why all the bother? Studies suggest that moderate to severe dry eye can disrupt someone’s quality of life just as much as hospital dialysis or moderate to severe angina, while mild dry eye can be as disruptive as severe migraines. And some researchers believe that the true spectrum of associated pain can range from occasionally scratchy eyes that could be alleviated with a simple change in lifestyle or environment to severe and unrelenting stabbing sensations that will resist nearly every intervention.

Perry Rosenthal has known two patients who committed suicide after finding no relief from the pain, and he has heard from many more who contemplated it. One woman told him that when she goes to sleep every night, she prays that she’ll never wake up. “And nothing helped. Nothing helped,” he says. “The worst was being abandoned by the medical profession, who say it’s in your mind.”

In blink of eye 4

Rosenthal grew up in northern Ontario, Canada, and considered a career as a classical pianist – his mother’s preference – before choosing medicine instead. In 1960, as a 26-year-old medical resident, he founded the contact lens service at the Massachusetts Eye and Ear Infirmary in Boston. The “father of the gas-permeable contact lens”, as he is sometimes known, pioneered the introduction of lenses that didn’t smother the eyes – unlike other body parts, the surface of the eye depends on air instead of blood for its oxygen supply. From research begun in a garage with two chemists, he created the Boston Lens system that was eventually bought by eye care giant Bausch + Lomb.

In the mid-1980s, as an assistant clinical professor at Harvard Medical School, Rosenthal resurrected a peculiar type of oversized contact lens first developed in Germany and Switzerland a century earlier and initially made of glass. He modernised the lenses by fashioning them from permeable acrylic and made headlines when legally blind patients suffering from corneal diseases could suddenly see after trying on what amounted to custom-built prosthetic corneas inserted with the aid of miniature plungers.

Rosenthal founded the nonprofit Boston Foundation for Sight in 1992 to help get the expensive scleral lenses to patients who had run out of other options, regardless of their ability to pay. He was featured on The Oprah Winfrey Show in 2003 and lectured at medical centres around the USA. The dome-shaped Boston Scleral Lens, as he initially called it, acts like a reservoir for artificial tears and rests on the relatively insensitive sclera – the white of the eye – instead of the hypersensitive cornea. At the charity, some of Rosenthal’s patients had such severe eye damage that the lenses couldn’t restore their sight. But with the lenses on, they were no longer in agony.

For Rosenthal, the turning point came in 2007, when he examined a patient from Oregon who suffered from intense eye pain and light sensitivity after she was accidentally exposed to ultraviolet radiation at work. Insufficient or quickly evaporating tears seemed like a woefully inadequate explanation for her severe symptoms. When she removed her wide-brimmed hat and dark sunglasses in the dim light of his examining room, Rosenthal watched as abundant tears spilled down her cheeks.

He fitted her with his oversized scleral lenses, which submerged the surface of each cornea in a pool of oxygen-rich artificial tears. Other specialists had accused her of lying – of malingering – to receive workers’ compensation, but she responded immediately to the scleral lenses. “It was like magic. All of a sudden, she could open her eyes wide without any light sensitivity,” Rosenthal says. Over time, however, the pain returned. “Her response was dramatic. Why? And why did the lenses soon become much less effective? I became obsessed with the need to find an answer.”

Ophthalmologists are still unable to fit cases like this into the traditional definition of dry eye disease, Rosenthal contends, because the existing framework largely ignores the significant contribution of corneal nerves or wiring in the brain that may be sending faulty information. Eyes that feel dry, in other words, may not necessarily be dry.

In blink of eye 5

Our corneas have a far higher concentration of nerve endings than anywhere else in the body – one reason why corneal pain can be so intense. A recent description of corneal nerve anatomy, based in part on corneas from donated cadavers, suggested that 44 thickly branched nerve bundles are crammed into a space only slightly wider than the home button on an iPhone.

“It’s not leaving a single point in the cornea in which there is no possibility of stimulating a pain fibre,” says Carlos Belmonte, founder of the Institute of Neurosciences in Alicante, Spain, and among the first to study the physiological basis of eye pain. The dozens of meibomian glands lining our eyelids are likewise among the most sensitive glands in the body.

One point of all those pain-producing nerves, according to evolutionary biologists, is self-preservation. The stronger the pain, the more unmistakable the message: reduce the threat now! The density of nerves in and around the cornea may help the brain send a clear warning if it senses a threat to the protective tear film that keeps our eyes healthy.

One type of pain, known as nociceptive pain, follows a relatively straightforward cause-and-effect chain of action. “You poke me in my eye and it hurts,” says Anat Galor, an ophthalmologist at the Bascom Palmer Eye Institute at the University of Miami in Florida. Ditto for staring too long at a computer screen or exposing your eyes to a strong wind.

Belmonte’s research has suggested that sensors at the ends of specialised corneal nerves can indirectly measure the thickness of the eye’s tear film by sensing a drop in temperature at the corneal surface. As the tear film evaporates and exposes more of the cornea to air, Belmonte says, these sensors detect a colder surface temperature and trigger an alarm that’s perceived as a dry, painful sensation. For most people, crying or blinking restores the tear film to its normal thickness, and the pain fades away. In mice missing a crucial part of the cold temperature sensor warning of dryness, Belmonte found that the normal rate of tear production fell by up to half.

A second type of pain, called neuropathic pain, transmits sensations linked to damaged, diseased or otherwise altered nerve fibres that fire spontaneously or react to light or other signals that wouldn’t usually bother us. A poke in the eye hurts much more than it should; even a light touch can be excruciating. “The nerves have kind of taken on a life of their own,” Galor says.

Rosenthal likens this system to a faulty fire alarm that’s been set to go off at a certain temperature. Based on Belmonte’s research, he believes damaged nerve sensors can become so hypersensitive that they send pain signals to the brain even with a normal surface temperature and an intact tear film. In other words, they continually raise a ‘false dry-eye alarm’ that results in chronic pain.

In what he calls his “last hurrah”, Rosenthal teamed up with Harvard University pain specialist David Borsook to lay out his ideas in a May 2015 review in the British Journal of Ophthalmology. The publication makes the case for ocular neuropathic pain – eye sensation rooted in dysfunctional corneal nerves – and for a related type of pain, dubbed oculofacial pain, that is instead initiated by faulty pathways in the brain. The latter condition, which Rosenthal refers to as an “invisible, suicide-provoking eye pain”, may explain some of the most extreme cases lumped under the dry-eye disease umbrella, including the woman from Oregon.

His explanation goes something like this: the patient’s scleral lenses covered her tear film and temporarily quieted the pain-provoking dry eye alarm by preventing even a slight drop in the surface temperature due to tear evaporation. If the damage had been limited to her corneal nerves, maybe it would have been enough. But Rosenthal believes years of heightened pain and light sensitivity can rewire the brain, unplugging some connections and reinforcing others. Although his treatment may have initially disrupted her pain signals, he suspects her brain gradually reset its faulty connections and overrode the dampened alarm.

With this type of centralised pain, in fact, many patients cannot tolerate scleral lenses at all: “The eyeball itself is tender,” he says. The unusually sharp, burning sensation, he believes, may originate from abnormal signals in the brain’s pain-control centres that radiate out through the three branches of the trigeminal nerve supplying sensation to the head and face. “Even though they feel it in their eyes, it’s not coming from their eyes; it’s projected to their eyes,” Rosenthal says. Or put another way: just as nearly one in four Danish patients in a 2010 study felt phantom pain after having their eyes amputated, some patients with oculofacial pain might still feel the intense cutting sensations even if they were to have their own eyes removed.

In blink of eye 6

None of his ideas are proven, Rosenthal concedes; they’re still only hypotheses. And in any one patient, multiple problems on or under the eye’s surface could be contributing to the discomfort. Nonetheless, he and his supporters are taking direct aim at lingering scepticism over whether nerve-mediated eye pain is even a real phenomenon. As Borsook points out, few doctors now doubt the existence of similar sensations in an amputated arm or leg.

“Yes, if you have your limb blown off, I see something missing and it’s more tangible that you have pain and I’ve heard about phantom pain,” he says. “But if you’ve just had a small incision in your body and you have incredible pain – it could be a tooth removal or the eye, and you still look normal – you know, what’s wrong with you?”

Most ophthalmologists, Galor says, have been trained to identify evidence of cataracts or defects in the retina, not the less visible signs of abnormal nerve function. The idea that many patients with dry eye symptoms have chronic pain, then, is “completely new and radical”, she says. “They look at it like, ‘If I don’t see it, it doesn’t exist’.”

Patient advocates hail Rosenthal’s 2009 study, ‘Corneal pain without stain: is it real?’ as a breakthrough in advancing the argument that debilitating pain could occur without the clinical signs detected by using fluorescent stains on the cornea and other standard tests. Citing his pioneering work, Galor calls Rosenthal “the father of this field”.

After his initial study on chronic eye pain, however, Rosenthal says the ophthalmology community largely censored his views. Even his own charity, the Boston Foundation for Sight, was roiled by internal conflicts. When the foundation fired his son, Bill, in 2011, Rosenthal was briefly arrested for trespassing in Bill’s office to gather up some belongings, according to a police report of the incident. Bill sued over his dismissal and recently reached an undisclosed settlement with the foundation. Then in 2012, after a 20-year tenure, Rosenthal was forced out of the foundation too – an abrupt firing that he alleges was linked to his focus on eye pain and what some at the charity referred to as his “off the wall” treatments.

“Boston Foundation for Sight has had numerous disputes with Dr Rosenthal over the past many years, some of which involved his son,” responds foundation spokesperson Karen Schwartzman. “All disputes were settled to the satisfaction of all parties in May 2015.

“With respect to Dr Rosenthal’s ideas about the neuropathic origins of severe and lasting eye pain, we hope his work will encourage research on this paradigm to the benefit of patients suffering from severe eye pain.”

Based on his clinical observations at the foundation, Rosenthal wrote a paper describing 21 patients who underwent LASIK or similar laser-based surgeries and subsequently had severe eye pain lasting more than two years. After two ophthalmology journals rejected the article, he published it himself on the website of the Boston EyePain Foundation, another nonprofit that he launched in 2013 to continue his work. Since then, he has regularly posted patients’ stories and railed against what he alleges is the medical community’s willful suppression of mounting evidence that much of what is considered dry eye disease is instead a broken alarm mediated by faulty nerves and circuits in the brain.

David Sullivan, a Harvard ophthalmologist and founder of the Tear Film & Ocular Surface Society, is cautious about the details of Rosenthal’s hypotheses, which he says are based mainly on clinical observations and may or may not be supported by further studies. “But I think the bottom line is this whole area of pain and sensation is very, very important,” he says. And so far, he concedes, doctors don’t have answers for many patients.

In his crusade for a solution, Rosenthal is finding himself increasingly accompanied by other researchers who say the general outlines of his ideas fit many of their own observations. Twenty years ago, for example, a group led by Japanese ophthalmologist Kazuo Tsubota described an unusual form of dry eye disease in which patients had no injury to the corneal surface and no drop in tear production but an unstable tear film and intense pain. “This is a very interesting group because the symptoms, very bad. But signs? Almost nothing,” says Tsubota, who practices at Tokyo’s Keio University School of Medicine. “I love Perry Rosenthal’s idea because his hypothesis can explain our findings.”

Donald Korb, an expert on meibomian gland dysfunction, says Rosenthal likewise opened his eyes to the concept of neuropathic pain. “When I think back about how ignorant I was seven years ago, I’m appalled,” says Korb, a clinical professor of optometry at the University of California at Berkeley and a long-time friend of Rosenthal’s.

“What I like about the argument that Perry has put forward is that it’s shaking the field to ask the question, ‘Is this a true neuropathic syndrome with pain?’” Borsook says. “And if it is, then the current treatment of [eye] drops is not that useful.”

Eye drops are by far the most common over-the-counter remedy for dry eye, representing a multi-billion dollar global industry. The only prescription drug to win widespread regulatory approval so far, however, is ciclosporin – sold as Restasis by Dublin, Ireland-based Allergan and billed as an anti-inflammatory medication that can increase tear production. Within the past decade, more than a dozen other companies have failed in their bids to win FDA approval for a dry eye drug, although a handful of candidates are showing promise in clinical trials.

The links between corneal nerves and the brain may be more difficult to study, but Galor says most treatment strategies based on the prevailing understanding of dry eye disease haven’t shown a sufficient connection between treating the signs and resolving the symptoms. Other efforts have recruited patients who may be suffering from vastly different conditions. “We need to rethink the biology of dry eye when we design our studies,” she says.

Several groups already are. Galor says she is finding “fantastic” success with patient-derived autologous tears, or drops made from a patient’s own blood serum and filled with growth factors that might aid nerve regeneration. Others are refining the use of anticonvulsant drugs to reduce the spontaneous activity of neurons.

Sullivan is investigating a lubricating, anti-friction protein called lubricin that may reduce symptoms by preventing the tear film from becoming abnormally concentrated and unstable. Tsubota and Korb have reported promising results with goggle-like moisture chambers for some of their patients, and Korb has developed a device called LipiFlow that uses heat and pressure to relieve painfully clogged meibomian glands.

If he can secure funding, Borsook hopes to conduct an MRI imaging study of LASIK patients that might show differences in the brains of those with chronic eye pain. “There’s certainly a neuroscience interest in it,” he says, “but the biggest thing is, can you help patients get to a point where doctors believe them?”

In blink of eye 7

That point cannot come soon enough for patients who tell remarkably similar stories about being accused of lying, of having psychiatric issues, of wasting their doctors’ time.

For these patients, “there is nothing that is more damaging to their psyche than being dismissed and invalidated by eye doctors, and they’ve all been through it,”, Neil Brooks says. Doctor after doctor told him that because he had tears and an intact tear film, his severe pain couldn’t be as bad as he described. “And I had to come up with comebacks,” he says. “I found myself never making progress on why my eyes might hurt because I was spending all my time trying to convince a doctor that [they did].”

In the absence of help from the medical community, Facebook has become a vital hub for many patients to share tips, encouragement and information. So have websites like the Dry Eye Zone, a collection of community forums, patient stories, blogs and an online shop run by Rebecca Petris, a former financier for the airline industry turned off-the-grid homesteader in rural Washington State.

Since her own LASIK surgery in 2001, Petris has faced more than a decade of experimental therapies and corrective surgeries to resolve chronic vision and dry eye symptoms, although she counts herself lucky that she doesn’t have severe stabbing sensations.

With no common language for chronic pain, she says, patients who aren’t taken seriously may use increasingly dramatic descriptions, only to have the strategy backfire when doctors view them with mounting suspicion. Petris now advises patients to go to their appointments armed with standardised questionnaires like the Ocular Surface Disease Index, a 12-question survey on the severity of symptoms that’s now available as a smartphone app. “The difficulty of putting pain in terms that doctors can understand is huge,” she says. “I don’t know how you get over that.”

For relief, Petris sometimes recommends one of the Dry Eye Shop remedies she’s curated over the years. Sometimes she becomes an impromptu therapist instead, urging callers to hang on and seek help before they take their own lives. “People find me on the internet because no one’s listening to them,” she says. “They’re at the end of their rope.”

Both patients and researchers say the message may finally be getting through. Every big advancement in medicine seems to follow the same cycle, Neil Brooks says: people don’t believe it and then an avant-garde researcher questions the prevailing truth and pushes the envelope to find out what’s really happening. “Perry Rosenthal, to my knowledge, was at the vanguard of saying, ‘What if these people aren’t crazy?’” he says.

After reaching out to Rosenthal, Brooks agreed to see whether a pair of custom-built scleral lenses might relieve his symptoms. He endured long and painful fitting sessions but immediately noticed a difference when he left with a new pair. “There are no miracles when you’ve gotten to the point where my eyes are, but it was the single best, most effective treatment,” Brooks says. The lenses not only reduced his pain but also made them less sensitive to the dry, bright and windy conditions back home in Colorado.

The relief wouldn’t last. Because Brooks had undergone multiple surgeries to correct his crossed eyes, three specialists told him that the suction of the scleral lenses was putting his eyes at risk for even more damage. A “life-changing” transformation was once again cut short. “So I went from [being] that guy who could do things back to being the guy who can’t,” he says. At the same time, the “invisible disease” was wreaking havoc with his personal life: a simple disagreement over barking dogs that continually interrupted his desperately needed sleep – he didn’t seem sick to his neighbours – spiralled out of control and eventually forced him out of his house.

Brooks made one last big push to reclaim his life: he sold his house, put everything in storage and immersed himself in the ultra-humid tropics of Central America. For the first ten weeks, life was great; the high humidity helped to keep his tear film intact. Then the effect began to wear off, and the pain returned. The body is a self-regulating mechanism, Rosenthal told him. Eventually, his brain may have instructed his lacrimal glands to acclimate to the new environment by reducing their tear production.

He has since retreated to Colorado, where he lives with relatives. Nearly two years later, his remaining strategy is avoidance. “I don’t do anything,” Brooks says. “If I am lucky, I get the dog out for a walk four or five times a week.”

Perry Rosenthal is still in battle mode and pessimistic about whether ophthalmologists are truly motivated to get at the root cause of chronic eye pain. Even his supporters aren’t in full agreement on the chain of events triggering the sensitivity. But more researchers are at least coalescing around the idea that neuropathic eye pain may be caused by an accident, disease, drug use or surgery.

What Brooks has left, he says himself, is hope. “A once full and big and wonderful life has been reduced to next to nothing,” he says. “And I know that’s true of a lot of other people, and I have to tell myself the same thing I would tell them, which is don’t give up – the same doctor you saw today might read a paper tomorrow that lets him help you next week.”