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Joseph F. Panarelli MD, Steven J. Gedde, MD, and Vikram Paranjpe MD, MPH discuss the Primary Tube Versus Trabeculectomy (PTVT) study.



BLOG: The PTVT Trial and Clinical Applications

Sadun discusses research targeting LHON

, Alfredo A. Sadun, MD, PhD, chief at Doheny Eye Center – UCLA, discusses a paper titled Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

The paper has been nominated for a Cozzarelli Prize, which is awarded annually to 6 research teams whose PNAS articles have made outstanding contributions to their field. Each team represents one of the 6 classes of the National Academy of Sciences (NAS): Physical and Mathematical Sciences; Biological Sciences; Engineering and Applied Sciences; Biomedical Sciences; Behavioral and Social Sciences; and Applied Biological, Agricultural, and Environmental Sciences.

“Yes, we were very proud of that paper,” Sadun said. “It came out in the Journal of the National Academy of Sciences a couple of months ago.”

Sadun is the senior author on the article.

“I’ve spent my life studying Leber's hereditary optic neuropathy, or LHON,” he explained in the conversation.“And it got into some really deep biology and then physics and then quantum mechanics as part of the answer. It's really neat to do something so fundamental and basic with implications that probably go beyond this disease, and go to how the chemistry of life works.”

Scientists at Doheny Eye Institute, in a collaboration with colleagues at UCLA and the University of Texas, have shown how a single gene mutation in the enzyme complex that produces the energy used by cells causes LHON.

According to a Doheny Eye Institute news release, the researchers found the mutation affects the cells’ tiny mitochondria, miniature power stations that generate the energy molecules called ATP, that all cells of the body require to do their jobs and stay alive. The mystery of how LHON causes blindness is now illuminated: the mutation causes alterations in quantum electron tunneling.

Quantum tunneling is an amazing process, totally unlike classical chemistry, that enables elementary particles, like electrons, to penetrate through energy barriers. What is now shown is that quantum tunneling is likely central to many biological reactions and may be key in explaining other human diseases.

Sadun worked with biophysicist Steven Barnes, PhD, both of Doheny Eye Institute and UCLA’s Department of Ophthalmology, tapped the expertise of UCLA Department of Chemistry’s Anastassia Alexandrova, PhD, and Jack Fuller, PhD, to address the disease using state-of-the-art computational chemistry tools.

Sadun pointed out that one mystery of the disease is why it strikes primarily young men in their 20s.

“The patient usually diagnosed with the disease is usually a health young person in his early 20s and thought everything was fine. It is a mysterious disease in many ways,” he told

. “There is no effective treatment in the United States. There is no FDA-approved treatment.”

Sadun noted that Idebenone has been approved by the European Medicines Agency for use in LHON.

According to scientists, the maternally-inherited genetic disorder typically waits for two decades before it strikes its victims, causing severe loss of vision or blindness, usually in young adult men, and to a lesser extent women, in their twenties.

According to the news release, the scientists previously showed that this disease kills the eye’s retinal ganglion cells (RGCs) not by causing poor energy production, but rather by producing ‘reactive oxygen species,’ or ROS, normal cellular molecules that when over-produced seriously impair cell protein function. In LHON, these damaging ROS are an unnoticed problem that waits decades before damage suddenly exceeds a threshold, triggering the death of RGCs, neurons that transmit electrical signals coding patterns of light from the eye to the brain.

In order to determine the origin of the ROS, the team of scientists looked at how the single genetic mutation affects a key subsection of the cell’s mitochondria with a single amino acid swap. It is in this subsection, called Complex I, that the mobility of the energy-trafficking molecule CoQ10 is seriously impaired. CoQ10, getting into and out of a tight-fitting channel in Complex I, defines the rate of the quantum tunneling of electrons that play a central role for generating ATP.

Powerful Molecular Dynamics simulations were performed using the National Supercomputer network to analyze the impact of the single amino acid swap from alanine to threonine in Complex I on the mobility of CoQ10 at different speeds via calculation of the positions and free energy of the molecules. They found that CoQ10 exits the mutated channel a billion times slower than it would in a normal channel.

The continuous supply of electrons to Complex I, now having nowhere to go, produces excessive rates of electron backup and spillage that generate ROS. This conclusion supports earlier observations that neurons with models of LHON produce near-normal amounts of ATP but high levels of ROS, which facilitate RGC death.

“We used molecular dynamics and FEP simulations to elucidate the mechanistic impact of the m.3460G>A mutation on the function of the ND1 protein, leading to Leber’s hereditary optic neuropathy,” the researchers concluded. “These simulations show how, in the case of the m.3460G>A mutation, the alanine to threonine substitution at position 52 leads to the extended CH3 and an additional OH in the path of the CoQ10. “

According to the study, this creates a kinetic hindrance for CoQ10 to pass through the binding channel. The scientists noted the thermal energy required to move the CoQ10 out of the channel is estimated about 50 kT, far too much to allow diffusion to occur at appreciable rates.

“Failed electron transfer will lead to electron spillage and ROS production at the proximal end of the FeS cluster series,” the scientists concluded. “ROS are a known cause of the blindness from Leber’s hereditary optic neuropathy, and this work thus links the molecular origin of ROS overproduction to the disease process.”

Fuller JT 3rd, Barnes S, Sadun LA, Ajmera P, Alexandrova AN, Sadun AA. Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2304884120. doi: 10.1073/pnas.2304884120. Epub 2023 Sep 21. PMID: 37733737; PMCID: PMC10523484.

Scientists at the Doheny Eye Institute, in collaboration with UCLA chemists, demonstrate how a single gene mutation in an enzyme complex known to produce the energy required by cells causes a sudden, blinding disease.

Videos

Alfredo A. Sadun, MD, PhD, discusses research targeting LHON

A recurring feature at the 2024 American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting in Boston, Massachusetts, was the call for environmentally friendly practices worldwide, with the goal of decreasing the impact of ophthalmic surgeries on the planet.

A driving force in this movement is EyeSustain

 an organization dedicated to the development of such friendly environmental practices, that exists as a global coalition of eye societies providing education and resources to support sustainable practices in ophthalmology.

Here is a sampling of the ASCRS discussions on the topic.

Greening eye care: reducing ophthalmology’s environmental footprint

The presenters, led by first author Sarishka Desai, BA, described the EyeSustain platform and its 5-pronged mission: educate the global ophthalmic community about more sustainable practices, collaborate with industry to reduce our carbon footprint and surgical waste, support research and innovative solutions that reduce ophthalmology’s environmental impact, support advocacy and education about the public health impact of climate change, and collaborate with industry to reduce our carbon footprint and surgical waste.

Desai, of the University of Connecticut School of Medicine in Farmington, and colleagues presented EyeSustain’s approach to reducing the ophthalmic carbon footprint. She was joined in the study by Nitya Devireddy, BS, MPH, of Penn State College of Medicine in Hershey, Pennsylvania; Sofia Miguez, BA, of Yale School of Medicine in New Haven, Connecticut; and Barbara Erny, MD, of the Department of Ophthalmology at Stanford University in California.

The greenhouse gas data associated with health care are startling. Health care is responsible for 4.4% of all global greenhouse gas emissions, 71% of which arise from the manufacturing, use, and disposal of medical supplies. Ophthalmology has the highest procedural volume of any surgical specialty, with 50 million cataract surgeries expected to be performed globally each year by 2050, Desai reported.

In light of the procedural data, the authors highlighted 6 areas that are currently undergoing research and quality improvement initiatives through the EyeSustain system.

 of cataract surgeons and nurses by David Chang and Cassandra Thiel found that 93% of respondents believe that the trash associated with OR procedures is excessive, and that methods to reduce waste should be identified and implemented.

 encouraged regulatory agencies to allow electronic instructions for use be disseminated in lieu of the traditional paper instructions included with each cataract pack.

Ongoing projects spearheaded by EyeSustain members, including medical students and ophthalmology residents, are taking a look at educating surgeons and surgical staff about sustainability and the impact of OR waste, OR water consumption, and evaluation of flash sterilization associated with cataract surgery.

In recognition of the fact that medications in the OR represent an estimated $560 million in waste annually, a multisociety position paper

 recently formulated 3 key recommendations: topical drugs in multidose containers can be used for multiple patients in surgical facilities if proper guidelines are followed; topical drugs in multidose containers can be used until the manufacturer’s labeled date of expiration if proper guidelines are followed; and, when applicable, patients should be able to take their partially used medication home for postoperative use.

The Aravind Eye Care system’s low-carbon model from Madurai, India, uses alternate energy sources, transport, infrastructure, and equipment maintenance.

 Studying global systems of eye care and waste produced can provide a deeper understanding of the impact of hospitals and providers on climate change, as well as ideas on how western eye care systems can proactively reduce carbon emissions.

The EyeSustain platform includes ophthalmology-specific action steps for greening offices and clinics in collaboration with the 

Partnerships can be established with large manufacturers to reduce packaging, make instruments reusable, and streamline the manufacturing and distribution processes.

In addition to the impact of practice waste on the environment, EyeSustain also recommends studying the effects of climate change on the incidence rates of ophthalmologic conditions, including cataracts, allergic disease, and glaucoma, among others.

Desai and her colleagues recommended that institutions take the following steps:

Conduct a waste audit to quantify the carbon footprint of an institution’s OR emissions. This includes using the EyeSustain-Zasti Carbon Footprint Calculator, using the Sustainability Index for Disposables in Cataract Surgery calculator for cataract packs to evaluate the item-by-item potential for carbon dioxide savings, and surveying clinical staff to identify areas of perceived excess waste.

Identify key stakeholders at an institution and an enthusiastic, multidisciplinary team and completing the OR Sustainability Pledge (

), which has been completed by ambulatory surgery centers/hospital outpatient departments from 9 countries thus far.

Implement best practices; multisociety recommendations for sustainability are easily accessible at eyesustain.org and My Green Doctor for outpatient/clinic resources and local legislation using the American Academy of Ophthalmology Topical Medical Waste Reduction Act legislative template.

Using phacoemulsification waste to guide changes in surgical sustainability

Adjustments to improve the sustainability of ophthalmic surgical practice can have a large impact when scaled to case volume, according to author Margaret Tharp, BSc, who described this study at the ASCRS meeting. She and her coauthors Stella Protopapas, BA, MPH, and Minka Gill, BSc, are from the Indiana University School of Medicine in Bloomington, whereas David J. Palmer, MD, ABO, is from the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

In their study, they sought to draw connections between results from a 24-hour waste audit at an outpatient surgical center and current resources available from EyeSustain to improve the sustainability of ophthalmic surgical practice.

The authors documented the extensive waste generated from 1 day of surgeries in an institution that included 13 phacoemulsification procedures, 5 plastic surgeries, 3 urologic surgeries, and 5 otolaryngologic cases. The waste products were sorted as medications (eg, propofol, eye drop containers), textiles (eg, surgical gowns, drapes), metals (eg, metal wiring, disposable instruments), and plastics (eg, hard, soft, wrappings).

When the amounts of the waste products were tallied, the authors found that “ophthalmology produced the greatest amount of waste in a single day relative to other operating specialties, despite producing the least amount of waste per case. Most ophthalmic waste was from textiles, hard plastics, and medications,” the authors reported.

The specific 13 phacoemulsification procedures resulted in 95.4 lb of waste broken down as follows: 18.5 lb of hard plastic, 5.5 lb of soft plastic, 8.3 lb of wrapping, 13.5 lb of medications, 41.2 lb of textiles, 6.7 lb of miscellaneous waste, and no metals. Compared with other operating specialties, ophthalmology produced the least amount of waste per case but the greatest amount of waste in total due to the relatively high case volume.

It has been reported that “discarded/unused pharmaceuticals from US cataract surgeries demonstrated waste of [approximately] $150 per case while generating carbon dioxide–equivalent emissions that approximated 25,000 to 100,000 flights from San Francisco, California, to Boston annually.

Small changes can have dramatic results. Tharp and colleagues suggested that the following would have positive consequences.

Revising the use of tetracaine bottles intraoperatively; for example, reusing the bottles between cases or sending the bottles home with patients

Optimizing packaging of surgical supplies and electronic instructions

Utilizing intravenous sedation to limit anesthesia gas carbon dioxide–equivalent emissions

Focusing on cutting waste also creates an opportunity to explore the practices of global leaders in sustainable eye care, such as the efforts of the Aravind Eye Hospitals, which provide similar surgical success rates at a fraction of the waste produced by US practices.

 A downside may be that such practices require significant reuse of materials, central sterilization, and stakeholder diligence, which can require complex interventions, according to Tharp. 

EyeSustain’s Surgical Facility Sustainability Pledge can serve as a guide for ophthalmologists to improve the sustainability of their practice in an approachable and lasting manner.

Factors contributing to the carbon footprint of cataract surgery

Omar Taboun, MSc, a medical student at Western University’s Schulich School of Medicine & Dentistry in London, Ontario, Canada, working under the direction of Netan Choudhry, MD, FRCSC, also described the negative impact of cataract surgery on the environment at the ASCRS meeting.

He commented, “We know that climate change can affect human health through various means, such as adverse weather events causing injury and exposure to pollutants [exacerbating] underlying health conditions. As health care providers, it is our responsibility to treat patients for their conditions that may ultimately be influenced by environmental factors. Counterintuitively, the health care sector is itself a greenhouse gas emitter,” Taboun said.

Surgery contributes significant emissions to the environment through the necessary materials and tools used during procedures. In addition, the need to maintain sterility increases waste.

The term footprint indicates the sum of all emissions direct and indirect resulting from this procedure, Taboun explained, the resultant value of which is typically reported in carbon dioxide equivalents

And although cataract surgery requires only a few minutes to complete, the procedural volume has increased exponentially over the past 2 decades,

Taboun and colleagues developed a 2-fold goal: they wanted to increase their understanding of the carbon footprint and waste accumulation to identify the primary contributors and pinpoint areas for improvement to enhance the sustainability of cataract surgery.

They conducted a literature search of PubMed, Google Scholar, and Medline to identify studies related to the carbon footprint and the elements of cataract surgery. The results yielded 6 studies, with 2 being the basis for this discussion,

He highlighted 3 main points extracted from the published data: the lowest footprint published was just under 6 kg of carbon dioxide equivalents; the highest published footprint was just over 180 kg of carbon dioxide; and the major factors contributing to the footprint include procurement of pharmaceuticals and materials, building and energy use, such as heating/cooling, lighting, electricity-powered tools, and travel by patients and staff to the location where the procedure is performed.

Taboun directed attention to centers that already have sustainable practices in place, such as the Aravind Eye Hospital, which reports the lowest footprint. These sustainable practices include the use of multiple operating tables in a single room; reusing gloves, gowns, and various medical equipment;

and using highly efficient autoclave settings.

Importantly, when these changes were implemented in the Aravind Eye Hospital,

 the rates of endophthalmitis remained comparable to other centers: 0.02% vs from 0.04% to 0.07% reported.

Taboun offered 3 ways that surgeons can offset the negative effects of cataract surgery on the environment—by focusing on procurement, energy use, and travel emissions.

Reduce emissions associated with procurement by collaborating with manufacturers to reduce packaging as much as possible and encouraging recycling in every OR.

Reduce building and energy use by incorporating renewable energy, such as solar panels, and more strategic lighting protocols and optimizing energy use within surgical centers.

Establish outreach clinics closer to more populous regions, whereby mostly staff members must travel, and patients less so, which will reduce travel emissions, along with performing bilateral procedures.

“Implementing sustainable practices, although challenging, will allow us to continuously provide this procedure and restore vision for millions of people at less of a cost to the environment,” Taboun said.

1. Chang DF, Thiel CL; Ophthalmic Instrument Cleaning and Sterilization Task Force. Survey of cataract surgeons’ and nurses’ attitudes toward operating room waste

. 2020;46(7):933-940.doi:10.1097/j.jcrs.0000000000000267

2. Schehlein EM, Hovasesian J, Shukla AG, Talley Rostov A, Findl O, Change DF. Reducing ophthalmic surgical waste through electronic instructions for use: a multi-society position paper. 

. 2024;50(3):197-200. doi:10.1097/j.jcrs.0000000000001381

3. Cleaning and Sterilization Task Force. Reducing topical drug waste in ophthalmic surgery: multisociety position paper

. 2022;48(9):1073-1077; doi:10.1097/j.jcrs.0000000000000975

4. Goel H, Wemyss TA, Harris T, et al. Improving productivity, costs and environmental impact in International Eye Health Services: using the ‘Eyeficiency’ cataract surgical services auditing tool to assess the value of cataract surgical services. 

. 2021 ;6(1):e000642. doi:10.1136/bmjophth-2020-000642. 2021

5. US EPA O. Greenhouse gas equivalencies calculator. United States Environmental Protection Agency. Updated January 2024. https://www.epa.gov/energy/greenhouse-gas-equivalencies-calculator

6. Gadani H, Vyas A. Anesthetic gases and global warming: [otentials, prevention and future of anesthesia. 

. 2011;5(1):5-10. doi:10.4103/0259-1162.84171

7. Thiel CL, Schehlein E, Ravilla T, et al. Cataract surgery and environmental sustainability: waste and lifecycle assessment of phacoemulsification at a private healthcare facility. 

. 2017;43(11):1391-1398. doi:10.1016/j.jcrs.2017.08.017

8. Pandey D, Agrawal M, Pandey JS. Carbon footprint: current methods of estimation. 

. 2011 ;178(1-4):135-160. doi:10.1007/s10661-010-1678-y

9. Pandey D, Agrawal M, Pandey JS. (2011). Carbon footprint: current methods of estimation. 

. 2011;178(1-4):135-160. doi:10.1007/s10661-010-1678-y

10 Rachmiel R, Trope GE, Chipman ML, Buys YM. Cataract surgery rates in Ontario, Canada, from 1992 to 2004: more surgeries with fewer ophthalmologists. 

11. Morris DS, Wright T, Somner JEA, Connor A. The carbon footprint of cataract surgery. 

. 2013;27(4):495-501. doi:10.1038/eye.2013.

12. Latta M, Shaw C, Gale J. The carbon footprint of cataract surgery in Wellington. 

13. Ravindran RD, Venkatesh R, Chang DF, Sengupta S, Gyatsho J, Talwar B. Incidence of post-cataract endophthalmitis at Aravind Eye Hospital: outcomes of more than 42,000 consecutive cases using standardized sterilization and prophylaxis protocols. 

. 2009;35(4):629-636. doi:10.1016/j.jcrs.2009.01.002

14, Pershing S, Lum F, Hsu S, et al. Endophthalmitis after cataract surgery in the United States: a report from the Intelligent Research in Sight registry, 2013-2017. 

. 2020;127(2):151-158. doi:10.1016/j.ophtha.2019.08.026

Organization eyes green practices, shifting ophthalmology landscape.

Minimizing the carbon footprint of ophthalmic surgeries

A large international study conducted by the LHON Study Group reported that a unilaterally administered 

 to treat Leber hereditary optic neuropathy (LHON) caused by the 

gene variant resulted in bilateral improvement in visual acuity with improved quality of life and good overall tolerability up to 5 years after treatment.

The first study author, Patrick Yu-Wai-Man, MD, PhD, and colleagues commented, “These results demonstrated the persistent benefit over time from 1 dose of lenadogene nolparvovec (rAAV2/2-ND4, Lumevoq, GenSight Biologics SA), which is promising for the use of gene therapy in LHON due to the 

gene variant,” the most common cause of LHON.

Yu-Wai-Man is from the Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, and the Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, both in Cambridge, United Kingdom; and Moorfields Eye Hospital, and the Institute of Ophthalmology, University College London, both London.

LHON, a genetic disease that affects the retinal ganglion cells,

results in severe bilateral sequential vision loss.

A large international study demonstrated that a single unilateral administration of lenadogene nolparvovec gene therapy for Leber hereditary optic neuropathy (LHON) due to the MT-ND4 gene variant resulted in sustained bilateral visual acuity improvement and enhanced quality of life over five years. The RESTORE study, a follow-up to the RESCUE and REVERSE studies, confirmed the therapy's efficacy and safety, showing persistent benefits and good tolerability. These findings underscore the potential of gene therapy for treating LHON, offering hope for long-term visual improvement in affected patients.

The multinational, multicenter, prospective RESTORE Study is the 5-year follow-up study of the phase 3 clinical RESCUE and REVERSE Studies of lenadogene nolparvovec to treat vision loss from LHON due to the MT-ND4 mutation.

Steven J. Gedde, MD

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