The AGS Lecture is a signature event of the American Glaucoma Society’s annual meeting, given by a clinician-scientist whose career has had a sustained and influential impact on the understanding and management of glaucoma. This year, Louis R. Pasquale, MD, FARVO, was invited to deliver the AGS Lecture during the meeting in Rancho Mirage, California.

Dr. Pasquale is widely recognized for his contributions to glaucoma epidemiology, genetics, and risk assessment, as well as for his work linking vascular, structural, and systemic factors to glaucomatous optic neuropathy. He is the Shelley and Steven Einhorn Professor of Ophthalmology at the Icahn School of Medicine at Mount Sinai; site chair of the Department of Ophthalmology at Mt. Sinai Hospital; and vice chair of Translational Ophthalmology Research for the Mount Sinai Healthcare System. During his career, he has helped shape how clinicians think about glaucoma as a heterogeneous disease influenced by both ocular and extraocular factors, with implications for diagnosis, risk stratification, and long-term management.

During our conversation, which has been edited for length and clarity, Dr. Pasquale reflects on what it means to be invited to give the AGS Lecture and discusses the clinical and investigative themes that have guided his work, emphasizing the importance of careful observation, rigorous study design, and asking clinically meaningful questions in advancing glaucoma care.

Glaucoma Physician: Your AGS Lecture is titled “The Glaucoma Specialist of the Future: What Will it Take to Protect the Optic Nerve?” What motivated you to frame the lecture this way? 

Dr. Pasquale: The optic nerve is the Achilles Heel of the visual system. It is where visual information converges before being relayed to the brain. The optic nerve has several unique features that glaucoma specialists often overlook; however, these features have important clinical consequences for managing glaucoma patients.

1. No other cranial nerve (aside from the olfactory nerve) has a supporting strut (the lamina cribrosa) to protect the axons that relay information. The lamina cribrosa is needed because retinal ganglion cell axons make acute turns from the retinal surface into the optic nerve head. Optic nerves that are inherently dysmorphic are under increased mechanical stress compared to nerves without these dysmorphic features; yet this is not considered when determining target IOPs. Pathologic myopic changes have surprising impacts on the lamina cribrosa, that place retinal ganglion cell axons are mechanical disadvantage.
2. The optic nerve head contains the longest Node of Ranvier in the body. These nodes represent unmyelinated segments of nerves that enhance the saltatory conduction of action potentials, which carry visual information to the brain. Normally, these nodes are numerous but short to mitigate neuronal metabolic stress. In the optic nerve, this node is long because myelinating the retinal ganglion cell axons on the retinal surface that enter the optic nerve would increase the blind spot size, compromising visual function. Thus, the optic nerve head contains a high density of mitochondria that generate ATP to fuel the propagation of action potentials to the lateral geniculate nucleus. This puts the optic nerve head under undue metabolic stress throughout life. It turns out that mitochondrial dysfunction is a root cause of glaucoma, and we are only beginning to understand the nature of the special metabolic stressors in glaucoma.
3. Although the optic nerve's blood supply originates in the ophthalmic artery, the retinal ganglion cells that comprise the optic nerve are exposed to a complex vascular system under variable degrees of paracrine and autonomic control. Again, the biochemical systems that govern these autoregulatory mechanisms are another root cause of glaucoma, and we need to target these systems to preserve optic nerve function in glaucoma.
4. We think that there is something inherently wrong with the retinal ganglion cells themselves in glaucoma, especially in people with “normal tension glaucoma.” Nonetheless, the retinal ganglion cells have a complicated neuroglial support system that responds to genetic and nongenetic factors. The neuroglia can be friend or foe for retinal ganglion cells and their axonal projections. Interestingly, functional genomic studies do not implicate retinal ganglion cells in disease pathogenesis; rather, they do implicate this neuroglial system, a system about which we know little. 

The glaucoma specialist spends most of their time working in the anterior segment, attempting to modulate IOP favorably. IOP-centric approaches are clearly paramount in glaucoma; however, we need to expand that focus to better care for the glaucoma patient because our ultimate goal is to protect the optic nerve. This talk is designed to stimulate thinking about how to expand that focus and improve glaucoma care. Every day that we go to our offices, we encounter glaucoma patients who are “retinal ganglion cell challenged,” and we must ask ourselves, “Can we do better by these patients?”

GP: How has your own career shaped your perspective on what will be required to better preserve optic nerve health?

Dr. Pasquale: In 1987, when I was a first-year ophthalmology resident at Temple University Hospital, we used glaucoma treatments that caused significant side effects. Strong cholinergic agents caused miosis, compromising vision. Our filtration surgeries were cataractogenic and often failed due to our limited ability to modulate postoperative wound healing. As a glaucoma fellow at the Wilmer Eye Institute, I focused on developing a better surgical method to lower intraocular pressure (IOP). Drs. Harry Quigley, Henry Jampel, and Alan Robin supported my efforts, but I learned that improving glaucoma filtration surgery was challenging, even for patients with seemingly controlled IOP progressed. I shifted my focus to upstream factors in primary open-angle glaucoma pathogenesis. Susan Hankinson and Jae Hee Kang at Brigham and Women’s Hospital, in collaboration with Janey Wiggs at Harvard Medical School, were enlisted to help me understand how environmental and genetic factors trigger glaucomatous degeneration. Despite successes, we seemed to transition from patients with miotic pupils and dense cataracts of the 1980s to patients subjected to polypharmacy and considerable visual morbidity of the 2020s. 

Throughout my career, the question has been the same: Can we do better for our patients? However, the approach keeps changing. We are now framing research around answering questions like:

• How do we beat our genetic predisposition to disease?
• How can we leverage multiomic datasets to improve our understanding of disease pathogenesis?
• Can we use large language models to make designer peptides that improve mitochondrial function?
• Can we enlist neuroglia to support retinal ganglion cells by altering the microbiome?

GP: How do you envision the glaucoma specialist’s approach to optic nerve protection evolving beyond pressure-centric paradigms?

Dr. Pasquale: First, we need a systemic biomarker to monitor disease activity and assess treatment effectiveness. Serum proteomic analysis of people with and without glaucomatous neuropathy may reveal such biomarkers. Perhaps novel dynamic optic nerve imaging modalities will provide such a biomarker.

Second, remote tools with granular IOP profiling can help identify patients with non-ambulatory IOP spikes that are responsible for disease progression despite registering low  IOPs during office hours.

Third, we’ll embrace technologies that fix, not just stent, the trabecular outflow pathway, as what is emerging in myocilin-induced glaucoma.

Fourth, treatments that enhance mitochondrial function may lower IOP and protect the optic nerve directly.

Fifth, glaucoma polygenic risk scores are clinically useful for managing glaucoma, allowing for earlier diagnosis, patient stratification, and aggressive treatment. Future multiomic risk scores incorporating data from other platforms (metabolomics, proteomics, epigenetics and the microbiome) may enable precision medicine approaches to glaucoma care, with plans to modify each omic profile that the patient presents with.

Will there be a need for direct optic nerve surgery? Maybe, especially if novel neuroprotective strategies are developed for such an approach.

GP: Advances in imaging are changing how clinicians detect and track progression. Which technologies do you believe will most meaningfully alter the ways that specialists assess optic nerve risk and intervene earlier?

Dr. Pasquale: While circumpapillary retinal nerve fiber analysis is extremely helpful, it is subject to annotation errors, displacement of the retinal nerve fiber bundle position in high refractive error patients, and alterations due to disc torsion and tilting. Imaging modalities like spectral-domain OCT (Spectralis; Heidelberg) and swept-source OCT (Topcon) that use Bruch’s membrane landmarks to quantify the neuroretinal rim tissue may be more resistant to those issues and will allow us to more confidently call glaucomatous optic neuropathy at an early phase.

GP: Training the next generation of glaucoma specialists presents its own challenges. What skills or competencies—clinical, analytical, or even interdisciplinary—do you think fellowship programs should emphasize to prepare physicians for the future you describe?

Dr. Pasquale: Minimally invasive glaucoma surgery skills will come in handy because they can be used to deliver genetic engineering tools to fix glaucomas caused by rare genetic variants.

Should methods to deliver neuroprotective interventions directly to the optic nerve emerge,  glaucoma specialists may need to be facile in performing vitrectomy and feel comfortable with using instruments to access the optic nerve directly.

Clinically, training may be required to learn how to integrate genetic data in glaucoma decision-making.

GP: The AGS Lecture is a significant professional honor. What does being selected to deliver this lecture mean to you?

Dr. Pasquale: I am humbled to have the opportunity to deliver the AGS Lecture. It provides me with a platform to motivate my colleagues to propel our field forward. I portray myself as someone eager to explore new vistas that will help patients with glaucoma. The fact that my colleagues recognize my efforts means they are reading my work, attending my talks, and that my efforts resonate with them. That is extremely satisfying. GP