Neuro-ophthalmology enters new period of therapy

Disclosures: Cockerham stories being a medical advisor for Horizon and Viridian. Lee stories consulting for AstraZeneca and Bristol Myers Squibb and being on the audio system bureau for Horizon. Liao stories no related monetary disclosures. Subramanian stories consulting for Horizon and Viridian.


Neuro-ophthalmology enters new period of therapy

Neuro-ophthalmologists have a lighthearted angle concerning the notion of their specialty as a result of, for a few years, neuro-ophthalmology was strictly a diagnosing specialty.

“The joke was that we have been ‘diagnose and adios,’” Healio | OSN Neurosciences Part Editor Andrew G. Lee, MD, mentioned. “We have been excellent at being detectives for issues that didn’t have good therapies.”

Developments in therapies for neu­romyelitis optica are among the many largest improvements in neuro-ophthalmology, in accordance with Prem Subramanian, MD, PhD. Supply: College of Colorado Division of Ophthalmology.

Lee mentioned neurologic issues comparable to ischemic occasions, stroke or optic atrophy trigger nerve injury that’s not reversible, so neuro-ophthalmologists might assist sufferers by figuring out the situation however not way more.

“As soon as the mind or any mind tissue, together with the optic nerve, has injury, it actually can’t regenerate,” he mentioned.

Lee was not the one neuro-ophthalmic knowledgeable to recall one of many inside jokes of the specialty’s previous. Y. Joyce Liao, MD, PhD, had an analogous anecdote.

Y. Joyce Liao

“There’s an outdated joke that neuro-ophthalmologists admire ailments,” she mentioned. “We’re the sort of people who find themselves fascinated by unexplained imaginative and prescient loss and good sufficient to determine it out. However now, we’re actually on the forefront of attempting to generate new, efficient remedy, and that is solely doable by medical trials and translational analysis.”

Over the course of the previous few years, the addition of latest therapies has prompted a shift. Neuro-ophthalmologists are now not simply admirers of illness. Now once they determine circumstances, they might help sufferers discover the correct therapies.

“Simply in optic nerve ailments, there are novel therapeutic approaches like gene remedy, neuroprotection and cell-based remedy,” Liao mentioned. “This will doubtlessly be administered by an ocular formulation, which can be related to decrease unintended effects than a systemic formulation like a tablet or an intravenous infusion.”

There are additionally some nonpharmacologic interventions, Liao mentioned. One of many areas she is most enthusiastic about is visible stimulation.

“This might be visible stimulation within the regular sense, that means that you’re principally utilizing your eyes to have a look at one thing to stimulate the visible a part of the mind to maybe improve one other drug’s efficacy,” she mentioned. “Neurons fired collectively survive collectively.”

One other doable method is to stimulate the mind straight. Doing that helps improve neurons and connection of networks.

“These are a few of the key issues which are being explored in a very explosive method in neuro-ophthalmology,” Liao mentioned.

Lee mentioned the paradigm started to shift with a number of key improvements, notably in stroke care.

“We’ve ‘clot busters’ now,” he mentioned. “So, earlier prognosis and recognition of strokes have moved to a brand new period the place stroke intervention and complete stroke facilities are routine now for the care of sufferers who’ve transient imaginative and prescient loss or have had an ischemic occasion associated to a stroke and current to the neuro-ophthalmologist.

“The altering paradigm in stroke has made us into diagnosing and treating docs, particularly if we’re within the window of alternative.”


Therapy of transient imaginative and prescient loss as a result of ischemic occasions is just not the one space present process speedy innovation in neuro-ophthalmology. Lee mentioned a brand new specialty, neuroimmunology, is rising to deal with continual issues which are typically autoimmune or inflammatory.

“There are new therapies which are each disease-modifying therapies and, in some circumstances, lifesaving or vision-saving,” he mentioned. “These monoclonal antibodies have made the therapy of lots of our beforehand untreatable or poorly handled issues reversible.”

Lee mentioned circumstances comparable to neuromyelitis optica (NMO) and different blinding and paralyzing issues required common therapy with standard immunosuppressants or steroids, typically with harsh unintended effects for sufferers. Now, FDA-approved monoclonal antibodies have made some beforehand blinding ailments into manageable issues.

“That’s what we imply after we say we’re transferring in direction of being therapy docs,” Lee mentioned.

Prem Subramanian, MD, PhD, added that revolutionary therapies for sufferers with diplopia and ptosis attributable to myasthenia gravis even have superior the sector.

“Earlier than, we needed to deal with these sufferers with steroids or presumably have them do eyelid crunches to assist with ptosis,” he mentioned. “However these therapies had a number of unintended effects, they usually weren’t very particular. Now, our therapies are aimed extra particularly at treating the underlying illness and placing it into remission withfewer unintended effects.”

Since 2019, three medicine have obtained FDA approval for NMO: Soliris (eculizumab, Alexion) in 2019, adopted by Uplizna (inebilizumab-cdon, Horizon Therapeutics) and Enspryng (satralizumab-mwge, Genentech) in 2020.

In accordance with a launch from the FDA, a research confirmed that eculizumab helped scale back relapses of neuromyelitis optica spectrum dysfunction by 95% over 48 weeks. Sufferers additionally skilled fewer hospitalizations and had much less want for therapy with corticosteroids and plasma change for acute assaults.

In a medical trial comprising 230 sufferers, Uplizna demonstrated a 77% diminished threat for relapse. A current research that used MRI knowledge confirmed that it helped scale back formation of asymptomatic optic nerve lesions in sufferers with neuromyelitis optica spectrum dysfunction.

In a submit hoc evaluation of the SAKURA section 3 research, researchers discovered that sufferers handled with Enspryng had a 79% discount in threat for extreme relapse in contrast with placebo. In a double-masked interval and open-label extension, the drug additionally diminished relapse threat by 51% in contrast with sufferers initially within the placebo group.

“That’s lots of progress that has been made within the spectrum of therapies that we will provide,” Subramanian mentioned. “Every considered one of these three FDA-approved therapies for NMO could be very particularly focused to one thing within the illness course of. It’s been proven to be way more efficient in decreasing the probability that the affected person may need a relapse and have a blinding occasion.”

Advances in NMO remedy have been among the many largest and most spectacular improvements in neuro-ophthalmology, Subramanian mentioned.

“You had a illness that was blinding, crippling and sometimes deadly,” he mentioned. “When these sufferers introduced to the neuro-ophthalmologist, you have been sort of telling them, ‘Get a cane, and get an excellent life insurance coverage coverage.’ Now, we will inform them we’ve got medicines that may allow them to dwell a reasonably regular life and never have the identical horrible threat of going blind, being paralyzed or having a deadly end result.”

One other space for focused remedy is thyroid eye illness (TED), with a number of pipeline medicine seeking to be part of Tepezza (teprotumumab-trbw, Horizon Therapeutics) on the checklist of FDA-approved therapies. Kimberly P. Cockerham, MD, Healio | OSN Neurosciences Board Member, mentioned having a pharmacologic remedy for TED has been a recreation changer.

Kimberly P. Cockerham

“Extra has occurred within the final decade when it comes to altering the way in which I take care of advanced neuro and orbit sufferers than the previous 50 years,” she mentioned. “Teprotumumab makes the extraocular muscle tissue and intraconal fats behind the globe shrink again to a extra regular quantity in a method that nothing else does. My surgical procedures definitely don’t, however neither does IV steroids or different therapeutics.”

Cockerham mentioned she first began prescribing teprotumumab in the course of the COVID-19 pandemic when many main care and endocrinology places of work have been closed and surgical interventions have been curtailed.

“It got here alongside at simply the right time,” she mentioned. “I undoubtedly needed to tackle a bigger position within the administration of the sufferers and be the first prescriber but in addition the first monitor.”

The shift to having a TED therapy out there, with much more candidates within the pipeline, has been radical, Cockerham mentioned.

“I consider there are roughly 9 merchandise within the pipeline, which is unparalleled in orbital therapeutics,” she mentioned. “There had been no growth in anyway in thyroid eye illness and orbital illness generally. When teprotumumab was first in growth, I bear in mind it had a very arduous time getting the preliminary funding as a result of there was this impression that there weren’t sufficient sufferers that had the illness. It’s nonetheless comparatively uncommon, however the truth that we’ve got therapeutics for a uncommon illness like thyroid eye illness could be very thrilling.”

Cockerham is an investigator on medical trials of VRDN-001 (Viridian Therapeutics), a monoclonal antibody that inhibits the exercise of insulin-like development factor-1 receptor. In a section 2 proof-of-concept research, researchers randomly assigned 27 sufferers with lively TED to considered one of 4 therapy teams: two infusions of both 3 mg/kg of VRDN-001, 10 mg/kg of VRDN-001, 20 mg/kg of VRDN-001 or placebo.

At 6 weeks, 67% of sufferers within the three VRDN-001 teams had at the very least 2 mm in discount of proptosis and at the very least a two-point discount in medical exercise rating. Within the 10 mg/kg group, 83% of sufferers met the general response fee.

Moreover, imply proptosis discount and discount in medical exercise rating remained constant at 12 weeks. Based mostly on these outcomes, VRDN-001 will proceed on to section 3 evaluation in each lively and continual TED, Cockerham mentioned.

“The drug is working in two infusions with efficacy that’s extra dramatic than teprotumumab,” she mentioned. “The sturdiness is but to be seen when it comes to an extended follow-up, however the security seems to be superior.”

Monoclonal antibodies have spurred large adjustments in neuro-ophthalmology, however Lee mentioned there could be much more alternatives to make use of these newer therapies. He mentioned he expects that physicians will begin transferring to monoclonal remedy earlier within the illness course of.

“We have already got some expertise with TED and teprotumumab and large cell arteritis and tocilizumab,” he mentioned. “It can simply proceed to evolve towards the sooner use of monoclonal antibodies to change ailments at their core slightly than treating them after they have already got vital, irreversible imaginative and prescient loss by utilizing upkeep remedy to keep away from relapses. Along with being therapy docs, we’re going to be prevention docs.”

Gene remedy

One other space of innovation in neuro-ophthalmology is gene remedy and stem cell transplant. Lee mentioned these pathways open up much more alternatives to deal with beforehand untreatable ailments.

“We actually don’t have something to reverse optic neuropathy,” he mentioned. “Nonetheless, the event of gene remedy, like CRISPR-Cas9, has the potential to reverse beforehand irreversible genetic circumstances that have an effect on the optic nerve, the mitochondria or different genes.”

Lee mentioned CRISPR acts as a form of GPS to assist RNA discover particular bits of DNA, whereas Cas9 is sort of a genetic molecular scissor.

Andrew G. Lee

“As soon as we find the place the gene must be reduce, the genetic scissor can reduce it, and we may give the brand new gene or the brand new gene product utilizing a viral vector to hold the brand new gene into the cell.”

Liao mentioned gene remedy is just not a brand new idea in ophthalmology.

“Gene remedy as therapy for any sort of illness was first authorised by the FDA for imaginative and prescient,” she mentioned. “As these therapies progress, I feel they’ll first take root within the eye as a result of it’s such an accessible organ.”

Liao is a lead investigator in medical analysis in gene remedy for Leber hereditary optic neuropathy (LHON), the most typical maternally inherited optic nerve illness. It is not uncommon in boys of their teenage years or youthful, and Liao mentioned they normally current with quickly progressing bilateral blindness.

“They’ve extreme central imaginative and prescient loss and higher peripheral imaginative and prescient, and that’s as a result of sufficient unhealthy copies of the mitochondria accumulate, and it has a cliff impact,” she mentioned. “In a method, it’s like age-related macular degeneration the place it hits the central imaginative and prescient. Nonetheless, the distinction is it’s extreme and really speedy.”

Whereas AMD may progress over the course of years, LHON may cause blindness in each eyes in as little as 1 month, Liao mentioned. In a earlier trial, Liao labored with a 20-year-old affected person who had been experiencing a void in his central imaginative and prescient. Inside a month of initiating remedy on the research drug, Raxone (idebenone, Santhera Prescription drugs), he was already starting to see enchancment.

“He really went all the way in which again to twenty/20 imaginative and prescient, which is superb,” she mentioned. “He was in a position to go on to his promising job and future profession.”

Liao can be an investigator in trials for medicine that concentrate on different genetic issues, together with autosomal dominant optic atrophy (ADOA).

“The most recent waves of therapy are particularly focusing on genetic issues, that are essentially the most devastating, particularly to a household,” she mentioned. “ADOA is the most typical hereditary optic neuropathy, so I’m actually glad that we’re in a position to provide one thing, and I feel the longer term is vivid.”

As extra therapies enter the device equipment of neuro-ophthalmologists, Lee mentioned their position will proceed to alter. Lengthy gone are the times of “diagnose and adios.”

“We’re transferring away from our outdated paradigm, which was ‘diagnose and goodbye,’” he mentioned. “It will likely be ‘stop, diagnose, deal with and rehab.’”

New roles might find yourself resulting in a distinct tradition inside the specialty. Lee mentioned increasing parameters and obligations will in the end have a optimistic affect on neuro-ophthalmology by the brand new individuals recruited.

“I feel it’s an thrilling time for us sooner or later as a result of it’ll deliver in additional individuals to our specialty who up to now might have been much less inclined to affix a specialty the place you weren’t really treating individuals. Including this therapy and prevention arm to our armamentarium of neuro-ophthalmology in all probability will enhance curiosity within the discipline,” he mentioned.

Lee mentioned that each one of those adjustments could be quite a bit for some neuro-ophthalmic veterans, they usually should adapt to the altering world.

“In the event that they’re not able to enter into the fashionable period of monoclonal antibodies and gene remedy, they’ll in all probability should accomplice with somebody, possibly even a junior physician, who’s prepared to do these items,” he mentioned. “For the younger individuals, it’ll simply be regular, and that’s an excellent factor. We wish individuals to enter into our discipline realizing they’ll diagnose and deal with.”

Even will all of the advances within the discipline, Subramanian mentioned neuro-ophthalmology stays extremely diagnostic. He mentioned neuro-ophthalmologists might want to proceed to work collaboratively with colleagues to search out the correct therapies for his or her sufferers.

“We have to assist them say when the correct time is to prescribe a remedy for a affected person but in addition to know when the affected person’s remedy isn’t working,” he mentioned. “We’re those who consider the affected person and say, ‘It appears like you’re having additional discipline loss. We have to do one thing in a different way with a purpose to deal with your illness correctly.’”

Click on right here to learn the aspect bar, “Teprotumumab has been recreation changer in administration of thyroid eye illness”


FDA approves Genentech’s Enspryng for neuromyelitis optica spectrum dysfunction. Printed Aug. 14, 2020. Accessed June 16, 2023.

FDA approves new remedy for uncommon illness affecting optic nerve, spinal twine. Printed June 11, 2020. Accessed June 16, 2023.

New knowledge present Genentech’s Enspryng considerably reduces severity and threat of relapse in neuromyelitis optica spectrum dysfunction. Printed Sept. 9, 2020. Accessed June 16, 2023.

New evaluation of MRI findings present Uplizna (inebilizumab-cdon) diminished the formation of asymptomatic optic nerve lesions in individuals with neuromyelitis optica spectrum dysfunction (NMOSD). Printed March 14, 2023. Accessed June 16, 2023.