Drs. Richard John Leigh and David Zee

Janet Rucker (JR): Today, I am interviewing Dr. Richard John Leigh, Blair-Daroff Professor Emeritus of Neurology from Case Western Reserve University, and Dr. David Zee, Professor of Neurology at Johns Hopkins University,who holds an Endowed Professorship (Figs. 1-10). As a team and individually, these internationally recognized clinician-scientists have published innumerable seminal articles and spent their careers learning and teaching about the ocular motor system. Together, they published 5 editions of the textbook "The Neurology of Eye Movements. "It's a true pleasure and honor to be here with you for this interview today. Why don't you both begin by speaking about the earliest days of your career paths, medical school, residency, including where your training was completed, and how those experiences influenced your next steps?

Great Conversations Section Editors: Meagan D. Seay, DO Rachel Calix, MD Drs. Richard John Leigh and David Zee FIG. 1. Dr. John Leigh (left) and Dr. David Zee (right) wearing Frenzel lenses with their mentor, Dr. David A. Robinson (middle), in about 1980. Janet Rucker (JR): Today, I am interviewing Dr. Richard John Leigh, Blair-Daroff Professor Emeritus of Neurology from Case Western Reserve University, and Dr. David Zee, Professor of Neurology at Johns Hopkins University, who holds an Endowed Professorship (Figs. 1-10). As a team and individually, these internationally recognized clinician-scientists have published innumerable seminal articles and spent their careers learning and teaching about the ocular motor system. Together, they published 5 editions of the textbook "The Neurology of Eye Movements." It's a true pleasure and honor to be here with you for this interview today. Why don't you both begin by speaking about the earliest days of your career paths, medical school, residency, including where your training was completed, and how those experiences influenced your next steps? David Zee (DZ): Okay, I'll start out. I came to Johns Hopkins in 1965 as a medical student, and I became excited about neuro-anatomy, enthralled with the fact that we could look at these connections and relate them to how people were behaving. I spent my first summer on an elective with the chair of the anatomy department, David Bodian. For those of you Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 who've done histology, there's the Bodian silver stain. But he was most famous for discovering the pathogenesis of polio virus as it traversed the gastrointestinal tract and then reached the brain. So, I had my summer elective with him. And my project was to look at the connections of cervical propriospinal fibers, but the amazing thing was Dave would sit with me 4 of 5 days of the week for about a half an hour at the microscope at the FIG. 2. Dr. John Leigh in a chair in a magnetic field search coil system, with Dr. Grace Peng preparing to place coils in Dr. Leigh's eyes, as Dr. David Zee looks on. e17 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations FIG. 3. Dr. John Leigh (left) and Dr. David Zee (right) with Dr. Fred Plum at an American Academy of Neurology meeting, about 1980. FIG. 4. Dr. David Zee (left) and Dr. John Leigh (right) hard at work writing the third edition of their book "The Neurology of Eye Movements" in Siena, Italy, 1997. end of each day. I wonder how often a chair now will (or can) sit with a first-year medical student every day at the microscope? DZ: I took a year off between my second and third years of medical school and worked with a hematologist. We actually worked on a problem to which neuroophthalmologists can relate, the parasite, Toxocara canis, which can settle in the back of the eye, and the diagnosis can be confusing because it looks like retinoblastoma. This was in the 1960s, and our project was to try and find in the blood of young children evidence for infestation by this parasite by looking for specific enzymes that were unique to the worm. This was the equivalent of an old, old-style PCR. As I started reading about the biology of these worms, I learned they were Ascaris species, and actually went through a metabolic change from aerobic to anaerobic during their life cycle, and thought, "Oh, this would be a good way to see how enzymes change as an animal goes through a major change in how it metabolizes and develops energy." DZ: And, we studied this problem for a year and wrote a few papers, and it was exciting. And, what it really taught me was that you can start out in a research project, but once you start researching the field you discover that there may be a very different way you might want to attack a problem. Anyway, then I came back to the medical school and eventually to neurology, and neuro-ophthalmology, and much of this was driven by a summer elective in neurology that I spent in Rochester Minnesota at the Mayo Clinic. Of course, Mayo was very well known then for neuro-ophthalmology. And as students there, we were "forced" to take a week of neuro-ophthalmology and I was exposed to Tom Kearns and Robert Hollenhorst. And, Mayo had quite a tradition of neuro-ophthalmology. Wilbur Rucker described venous sheathing, and of course, there are Hollenhorst plaques and the Kearns-Sayre syndrome. And so, I was bitten by neuro-ophthalmology at that time. DZ: The other key event at Mayo was the influence of my attending neurologist, Dr. Frank Howard, who was one of the first people to write about using Tensilon and Lancaster red-green testing in myasthenia. And, I also saw a patient with a cerebellar degeneration, and Dr. Howard told me to read a classic article on the subject by Victor, Adams, and Mancall in the Archives of Neurology. The paper was 110 pages long. It reviewed the entire literature up to that time. There were 10 tables, 29 figures, and 235 citations, and the summary was 3 and a half pages. But the beauty of that paper was its pathological, anatomical, and functional correlations, and I was smitten. DZ: So that was medical school. And then to briefly tell you about residency, there were some tipping e18 FIG. 5. Dr. David Zee (left) and Dr. John Leigh (right) being inducted into the Johns Hopkins Society of Scholars, 2004. Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations FIG. 7. Dr. Bernard Cohen (left) and Dr. John Leigh (right) in 2011 at Mount Sinai Medical Center. FIG. 6. Dr. David Zee speaking at the Festschrift in honor of Dr. John Leigh in Buenos Aires, Argentina, in 2011. points. I guess some people make decisions by pondering and fretting and dithering. I just make decisions more or less based on something that suddenly happened to make me change my mind and so I would decide what I wanted to do. And, one of these experiences was with Neil Miller. Neil Miller was working with me a student when I was a first-year neurology resident, and we were sent out to Bayview Hospital, it was Baltimore City Hospital back then, to do consults. We had no attendings then, and we were truly on our own. DZ: And, I must tell you one anecdote about Neil.well, two. Number one is Neil was running around with red caps on Mydriacyl bottles testing everybody's visual fields. He had just spent some time, I think, with Lawton Smith, and I thought the neuro-ophthalmology bedside examination was so cool. Then one day, Neil and I decided to do a pneumoencephalogram ourselves on a patient who had dementia and a diabetic retinopathy, and we could not check her fields very well. In those days, the pneumoencephalogram was the procedure of choice to look for a midline lesion causing dementia. There were no neuro-radiologists at Baltimore City Hospital, so Neil and I took a book from the library on how to do a pneumoencephalogram, and we found a dental chair and a technician who would take pictures. And, after a lumbar puncture to put air in, step by step, page by page in the book, we positioned the patient here, there, and so forth. Finally, Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 we had the patient lie supine in the head hanging position and we were extremely disappointed because we could not fill the third ventricle with air. So, we figured the test was a failure. About 5 days later, I took the films over to the one neuroradiologist we had at the main hospital. And he said, "You guys are terrific. What a beautiful demonstration of a tumor in the anterior third ventricle." So, the patient had an adult craniopharyngioma and was operated on, and did well. DZ: To finish on my time as a resident, that was when I got to know Frank Walsh. He was so good to young people, kind, and he took care of me. He had a conference every Saturday morning, his famous conference, in which Frank Ford would attend and John Chambers and Frank Otenasek, neurosurgeons. And he wanted me to come, but my wife wanted me to be at home on Saturdays with our young children. Frank wrote a letter, to my wife-note I was just a resident-asking if I could just come every other week. And, that's how things were in those days between FIG. 8. Dr. David Zee, Dr. John Leigh, Dr. Scott Eggers, Dr. Mathew Thurtell, and Dr. Janet Rucker (left to right) at the American Academy of Neurology in 2013. e19 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations FIG. 9. Dr. David Zee (left) and Dr. John Leigh (right) in 2014 upon completion of the fifth and final edition of their book "The Neurology of Eye Movements." FIG. 10. Dr. David Zee (left) and Dr. John Leigh (right) at Oxford University in 2016. famous professors and young students. Just a couple more things about Dr. Walsh. There was a pupil meeting in Detroit, and no one from Hopkins was going. And, Dr. Walsh called me to his office and said, "Dave, you should go to that meeting. We need someone from Hopkins at this pupil meeting." And I was just a resident! I met Irene Lowenfeld there, and Larry Stark, who was talking about control system models of the pupil and other luminaries in the pupil world. Dr. Walsh was terrific, although he could be quite direct. When I told him I was interested in eye movements, he said, "Well, someone has to be interested in the minutia of neuro-ophthalmology!" DZ: Another great neuro-ophthalmologist who influenced me greatly when I was a resident was Bob Daroff. I recall going to St. Louis where he was giving a neuroophthalmology course at the AAN, and he just infected me with enthusiasm for eye movements. I did not always follow his advice either, choosing to focus on OKN early in my career which he thought was a dead-end field. The turning point in my scientific career was when I went to one of our resident lectures, and David Robinson, who became my scientific mentor, was telling us about internuclear ophthalmoplegia and the medial longitudinal fasciculus and how you could apply simple mathematics and control systems to understand this condition and make predictions about what kind of eye movements you should find. I had my epiphany with that lecture. I went up to see him immediately after and asked, "Can I come and work with you?" He said, "Sure." I then used my third-year resident elective period to begin working with him. So, this was how my medical school and residency experiences put me on a track to neurology, neuro-ophthalmology, and then eye movements. JR: Fantastic. And Dr. Leigh? John Leigh (JL): Well, I trained at Newcastle upon Tyne Medical School, in the northeast of England, and after graduation, I did a medical residency. And one of those rotations was through neurology, and they were terrific clinicians at the time, John Walton, Niall Cartlidge, David Shaw, and David Bates. And about this time, they were setting up a multicenter study of the outcome of medical coma with Fred Plum from New York Hospital. And so I read Plum and Posner's book Stupor and Coma, and I was sort of hooked. And, I volunteered to be the research fellow to enter and code the patients coming into the study. And at the same time, I did my own research project, which was on disturbance of respiration in unconscious patients, something that Fred Plum had also studied. The really important point is when Fred Plum came to Newcastle, it was like, "Behold, the clinician-scientist!" The neurologists in Newcastle were terrific, they were classic neurologists, but I'd never come across a neurologist before who had such a grasp of basic science and brought that to bear in what he was doing clinically, and that just. that was an epiphany. JL: And so, I made this slightly crazy decision to do a residency in neurology. I'd bring my wife, who was pregnant, we had another kid, over to the States, to New York. And, I started that in 1975. And, I still was unsure what to do afterward at that time. I wrote a chapter on controlled respiration with Fred Plum, but it seemed like a very narrow field. And so, I was looking around and I talked to Kathy Foley who was the pain maven of Memorial Sloan Kettering Hospital in New York, and she suggested Dave Zee. Now, she knew Dave Zee because they'd been interns together at New York Hospital, and she told me about the work, and that rang a bell because just before I left Newcastle, I read a paper in the Archives of Neurology about the mechanism of downbeat nystagmus. And I remember reading a sentence, I'll just quote it here. "Eye movement abnormalities such as nystagmus can be better understood by considering them as disorders of control systems." Well, I sort of was aware of that a little bit about respiration, but that sounded interesting. I wanted to know how the brain worked. And so, I went and read something by, a paper by David Robinson. And, I remember it was a discussion between David Robinson and Morris Bender. e20 Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations JL: And Morris Bender said, "Can anybody explain to me what's going on with this patient? I have a patient who's got a blind, normally moving right eye, and a seeing but immobile left eye. And if I stimulate the seeing immobile eye, the blind eye moves much faster than the optokinetic stripes." And, Dave Robinson explained in very lucid terms that this was a classic open loop situation. For the first time, I started to understand feedback control systems and that led me to. plus of course, Kathy Foley's recommendation, to contact Dave and Dave in Baltimore. I visited and they took me on as a research fellow postdoc. JR: So, you both have talked about how you became interested in eye movements initially, and lead up to the point at which both of you met. Why don't you carry on from there in terms of that initial meeting and where things lead at the beginning, and then into your first faculty positions, the early days of your collaboration, and your faculty positions? DZ: Well, after my residency, I went to the NIH to give my 2 years to the country in the Yellow Berets, who were the public health service officers during the Vietnam War. And, I met Dr. David Cogan there. And again, pure chance. He had just left the Mass. Eye and Ear, at Harvard, and had been invited to come and spend his retirement years, so to speak, at the NIH. So, his office was next to my office and I got to know him. And like Dr. Walsh, he was so supportive of a young person. In fact, he sent me to my first overseas eye movement conference in Sweden. I didn't have anything to present, he just said, "It's a good idea, you should go to that." DZ: Now, Dr. Cogan was one of the sweetest, most supportive people whom I knew, but inside there was a fire burning, and he never saw a patient on whom he did not make any notes on one of his index cards. And, he always wanted to keep you involved in seeing the patient and writing about the patient. And as an example, I was in the elevator with him one day and we had seen a patient who had made slow saccades and he thought it might be due to a muscle problem. And he said, "Dave, I'd like to do an EMG on you and put an EMG needle in your lateral rectus." And I'm in the elevator, and I thought for sure he was kidding. And I said, "Dr. Cogan, any time you want to put a needle in my eyeball, that's fine." And literally, 7 or 8 minutes later, I was lying on a bed facing a huge needle, the EMG needles in those days were large, and this big needle was coming toward my eye. It actually didn't hurt much; it was more psychological fear. But Dr. Cogan was terrific, both Walsh and he were interested in young people. Something I've tried to carry on in my career is get young people to go to meetings, meet other people, and see the rest of the neuro-ophthalmology world. DZ: And, Dr. Cogan is also important because, and I'm going to ask John explain this, it was Cogan's eye movement book that we had both read and were very excited about. Anyway, I came back to Hopkins and started workSeay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 ing with Dave Robinson in his laboratory. Dave was another person who paid tremendous individual attention to me, sitting with me every day for an hour or 2 over a summer trying to teach me a little control systems. And, this little course that he gave me became a course that he gave all our neuro-ophthalmology fellows who came here over many years. And then John came along, and will take it from here. JL: Yeah well, when I came to Hopkins, I mean it was a little challenging financially and so forth, but I really felt I was in heaven. Because Dave Robinson, as Dave Zee just described, gave one-on-one lectures on control systems several times a week. Dave Zee would spend all the time I wanted just answering my questions as I learned more and more things. And then, there were things like Vernon Mountcastle gave this talk with a visiting anatomist, Thomas Powell, on distributed neurological systems. And so generally, the. I guess you'd call it the intellectual environment, was just fantastic. And, we had good camaraderie. And, the other thing is I learned for the first time how to do science, how to set up an experiment, do it, write up a paper, and so forth. And, Dave and Dave showed me that. And in those early days, we had some great studies [chuckle]. JL: One of the first studies that Dave Zee and I did was to look at eye movements in the blind. And we went out to a factory on, I think the west side of Baltimore, and just clinically examined the eye movements of perhaps 20 blind individuals. And that was quite revealing. And then, we studied our first patients with periodic alternating nystagmus, we made a model out of that, which led to eventually insights on how our treatment worked. And actually, found a patient just like Morris Bender's, with the open-loop condition and wrote that up. So that was just a terrific period. And after that, I managed to get an investigative award from the Aging Institute actually and start to develop my own research. JL: So that was like my second period at Hopkins. And once again, great support, they put up with me. I was, you know floundering around a bit, but I managed to develop my own career, once again, because of the environment here. So, Marshal and Susan Folstein got funds to study Huntington disease, and they brought me in to study the eye movements, so that was one thing I did. And, the other is I followed up on my interest in coma and looked at eye movement abnormalities in coma along with Dan Hanley, whom I had known since New York Hospital, and who was interested in neuro-intensive care. So, I really fell on my feet when I came to Hopkins, it was a terrific period. And then, I got the idea for the book, and that, as Dave says, really came out of reading David Cogan's second edition of Neurology of the Extraocular Muscles, which is a great book. But so much has happened since, and I was aware of this burgeoning field of the neurosciences, and I thought, "Well, why don't we write another book?" Which e21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations was probably a somewhat crazy idea. And, in fact, both Dave Zee and Guy McKhann said it's a crazy idea because it's going to divert you from writing grants and writing papers, and they were right [chuckle]. I didn't get an RO1, and that's why I left and went to Cleveland. But eventually it worked out with our book, and of course, we've done 5 editions of that. JR: So, why don't you talk a little bit about the book itself? You talked about the idea behind it. And talk a little bit about how it's changed over the years. You've done 5 editions, primary authors on all 5 editions, not edited volumes. So how has the process, the content, how have things changed over the years with the book? JL: Well, the field has grown enormously. I mean I think. I can give one example. For the fourth edition, the penultimate edition, I said to Dave, "Well, we should really have something on eye movement abnormalities in autism because it's important." So, I remember we wrote I think a couple of paragraphs because that summarized most of the literature at the time. When we went back 5 or 6 years later, I counted over 1,000 peer-reviewed papers on eye movement abnormalities in autism [laughter]. What do you do, you know? You gotta. You read them through, the abstracts, and the abstracts that look really interesting, you read the papers and then you try and boil it down into some sort of synthesis. So, the field had really got much, much bigger, as has the size of the text. And, I actually think in the future it's going to have to be a multiauthor thing because it's such a big field. So that's a very positive thing, and it was very time-consuming to write each edition, but at the end, it was rewarding I think. DZ: Yes, it was rewarding, but only after it was out [laughter]. I mean the last edition took a good year of almost all our time. I have to say one thing, the first edition, when John and I working with Dave Robinson, had most of the fundamental ideas that are still most important. I mean there has been great growth in our field and so many citations and new ideas, but Dave Robinson, our mentor, revolutionized how we think about eye movements and how we bring them to the bedside. One of the best things we had with Dave were "eye rounds," and Dave would bring his postdocs and graduate students, and John and I would dig up some patients with a resident or 2, and once a week, we would go see a patient at the bedside and usually it would end up us challenging Dave to make a model, like superior oblique palsy, the Bielschowsky head tilt test, internuclear ophthalmoplegia, etc. DZ: And, it was a truly invigorating, exciting way to collaborate. And it brings up an important point, if you're a clinician and you want to collaborate with a basic scientist, you can't just send the patient over to their laboratory and expect a paper to come out. It's a lot of work, often by the clinician to go over to the laboratory, to educate the basic scientists, and it's hard nowadays because we have many other obligations, not that much time nor the freedom e22 and luxury to go over and talk to basic scientists. But I think for both of us collaborating with a basic scientist really made our careers so much more exciting and fulfilling. JR: So, you've talked a lot about David Robinson as an important mentor to you both. Do you want to mention any other mentors, either in or outside of the medical field? JL: Well, I would say that many colleagues were mentors. And so, for example, when I was at Hopkins, Dave introduced me to the greats, Walsh and Cogan, but also to the outstanding scientific group at the NIH, Bob Wurtz, Mickey Goldberg, and Fred Miles. And, these have been lifelong mentors in a sense, actually. When I moved to Cleveland, Bob Daroff was certainly a mentor and was always very supportive of me. But I think that collaborations in a sense can lead to a form of mentorship, and that's been one of the great things about this. Just to followup on what Dave said about collaborating with basic scientists, I think you've got to spend time to read their papers and then go to the meetings and talk to them about their papers and make friends with them, and that's the way forward. That's what a real clinician-scientist does I think. He or she really knows what's going on in the basic aspects of his field, and talks to peers, and they respect him or her for doing that. Because as basic scientists they want to see applicability of their work because, you know, when they're writing a grant it's nice for them to say that, "What I've done has actually made some difference in the clinical sphere." Outside of the medical field, I can't confess to many mentors. Though, I would say. in terms of written mentors, David Hume, the Scottish philosopher, the skeptic. Yeah. he has influenced me. DZ: I'd like to follow-up a little bit about what John said about the NIH. We were there together the last time, when we worked on the fourth edition, I guess. John brought to the NIH patients with oculopalatal tremor syndrome and pushed our basic science colleagues to make a model of how this fascinating disorder might come about. I also brought a family with a microsaccadic flutter, seemingly a small thing, but our work did lead to a lot of grant money. And with Lance Optican especially, with whom I spent 2 previous sabbaticals at the NIH, John and I brought the patients and their eye movement recordings. We all talked about them and how their clinical disorders might fit into current models of how the brain works. For my career, people complain that I travel too much, but by going and seeing how other people do things, and collaborating with people in many countries (and especially Italy and Switzerland), it's been a lot of fun and I believe it has brought a lot of scientific progress. JR: Let's move into some areas that you've touched on already. In terms of eye movements themselves, it seems that many clinicians find eye movement disorders particularly daunting or challenging to understand and certainly to master. What advice would you give to clinicians Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations on how to become more comfortable and skilled in this area? DZ: Well, I think a couple of things. Number 1 is you need to go visit and learn from someone who is good at this kind of thing. You really must do it hands-on. You cannot read a book and learn about the clinical examination of eye movements, you cannot even see a video, you need to do it and have someone who is experienced watch and critique you. I mean, a good eye movement examination can be done in 2 minutes, it's just a matter of mindset, learning how to do things in a very rational, repetitive way with a plan in mind, and then it becomes a little easier. The brain is complicated, cognition is complicated, all areas of neurology are complicated, so it requires a little bit of work. But I think if you find some good people to work with, the dividends are big. Because as we used to say in our department. My good friend and colleague was Jack Griffin, who used to be the chair at Hopkins and he was a peripheral neuropathy expert. And, the residents used to say that if Jack and I came to the bedside, I would examine things from the nose up and the eye brows down, and Jack would just look at the feet, and 90% of the time we nailed the diagnosis. So, neuro-ophthalmology is tremendously rewarding. Eye movements are complicated, nystagmus is complicated, but if you follow our book, look at our little algorithms and boxes and figures, you can make sense out of it. JL: Yeah, I think if you're really interested in something, and let's face it, eye movements can apply to many different disorders, from memory to muscles, then you have to spend some time reading about the basic stuff. Now, what you need to examine eye movements and so forth, it's just a matter of knowing some anatomy and physiology, that's not so difficult. But I think if you want to pursue a look at eye movements seriously, then you have to take out some time and work with a basic scientist. And that was the great gift that we got from David Robinson. Pick a mentor who will spend time with you, a basic science mentor. And they're not common, but you can find them. And it's a bit of a risk because, of course, you take time out from your other training, it is not part of the normal, "I'm going to do a neuro-ophthalmology fellowship or a neuromuscular fellowship," or something. You've got to actually step to one side and do basic science. It is a bit of a financial risk, you've got to have a spouse who will support you and so forth. JL: But if you do that, I think when the time comes to write a grant it makes an enormous difference because you've trained with a basic scientist. So, for people who are really serious about doing eye movements or any basic science, I think that's what's required. And, it's not what most people coming out of neurology or ophthalmology programs do, I think partly because of debt, medical school debt, and other factors. But that is still. the 2 or 3 years I spent training as a fellow were invaluable. Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 DZ: I think when I came to see Dave Robinson after his talk and said I wanted to work with him, he said, "Great, I've been waiting for a neurologist for 8 years." So, some of these people are receptive. But, I'm going to second what John said, the rigor, learning to try and prove your hypotheses wrong, trying to set up and do a careful experiment, being very critical of your own work, it doesn't come naturally to most clinicians who work more on impressions and make subjective decisions. Spending that time with a rigorous basic scientist will put you on the right track for a long period of time. JR: You both have been very strong advocates for young people throughout your careers. What advice do you have for young clinicians and young clinical investigators? JL: Well, I just mentioned a few, I really think if you can spend time with a basic scientist. Let's face it, the way that medicine is going in the present time, the advances, the clinical advances, are due to basic science research. Sure, clinical trials are very important, but the basic research is what's driving those trials. And so, if you get able to take time off and do some basic science with a good mentor, that I think is important. But I think also going to meetings and meeting people and talking about your research is very important, and forging collaborations, that's also very important. If you can, work at a center which has got a very rich intellectual environment. But if not, talk to people, go to meetings, go to all the meetings and talk to people and be interested and read about what they've done, and then that's very important. DZ: I think the other thing to do is try and make your clinics great scientific laboratories. We can learn so much from every patient, and when single patients come along with an unusual pattern of a problem, they provide, as Dave Robinson used to say, "One of nature's experiments that we can't always make in the laboratory." And bringing the anatomy, the physiology to the bedside is so much fun. And, patients are interested in learning about their problems if it's explained correctly why we are doing what we are doing, and that we are interested in them. Patients cooperate almost all the time. They will wear contact lenses if you just explain to them what you're doing; they want to support research. So, you must keep your eyes open in the clinic. You must spend time trying to dissect the clinical history. And, in the busy environment in which the tentacles of regulators and administrators are out, trying to make you focus on the pluses and minuses of your balance sheets, you have to stand up for getting the time to learn from your patients and do experiments. And, the rewards of learning how the brain works and being able to help patients with new treatments make up for any fiscal pressures from the department. One of the best examples of how much can be learned from a single patient began with a referral to us from Preston Calvert of a patient who had a small hemorrhage from a cavernous angioma near the middle cerebellar e23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations peduncle in the cerebellum. Preston astutely noted that when she attempted to track a target moving smoothly up and down, not only did she develop vertical smooth pursuit but also a peculiar torsional nystagmus that changed direction when she went up vs. down. This nystagmus was not present when she made vestibular up and down slow phases, nor with vertical saccades nor with up and down fixation. After pondering about this for a while, we realized that this combination of a vertical and torsional smooth movement with corrective torsional quick phases was like the type of nystagmus one sees with irritation of a vertical semicircular canal, as in benign paroxysmal positional vertigo. To make a long story very short, we hypothesized that as the smooth pursuit system evolved it commandeered some of the phylogenetically old vestibular scaffolding and that this tracking pattern reflected interruption of pathways coursing through the middle cerebellar peduncle. Indeed, subsequent similar cases have had a similar localization, and the lesion is almost always a cavernous angioma. So much about how the brain works can be inferred from a single patient. JL: I think having a hypothesis in your head when you go to the clinic helps. When I was really into PSP I loved hypotheses, I would test right there, I wanted to know. So that's really important. The other thing is keeping your eye open for things that are unexpected, serendipity in particular. So, just before I left Cleveland, we started giving 4-aminopyridine, Ampyra, for gait disturbance in multiple sclerosis. Now, I remember giving it to the first patient and he came back and I said, "Well, has it helped?" He said, "Doc, it has not done anything for my walking, but my vision is better." I said, "What?" So I took a look at him and he had internuclear ophthalmoplegia, and it seemed to have improved that. And we did that systematically then, we measured his internuclear ophthalmoplegia, gave him a dose of Ampyra, and it certainly changed. And that's led to Alex Serra now doing a controlled study to see if it's effective, not just for fatigue and for walking. JL: There are plenty of opportunities. Occasionally though, you have to be prepared for the fact that things don't work out. And I remember in the late '70s, Dave and I, 2 earnest investigators, were informed that there was a patient with cortical blindness on the floor, and were we interested? So, we went and saw her, she was an old lady, and she didn't talk much. She seemed to be aphasic, and by bedside testing, she sure looked like she was blind. And, she had appropriate lesions on the CT scan. And, we were keen to know whether she could still have preserved optokinetic responses. And the idea is that we have this brainstem, a visual pathway, which goes to the nucleus of the optic tract, and it's been well demonstrated in nonhuman primates and also in humans. JL: So, we managed to get everything correct and we took her down to Wilmer basement, which is where the e24 laboratory was at the time. And we sat her in the chair, she was happy to sit there, we put on the EOG electrodes. We surrounded her with an optokinetic drum, so it really was a full field stimulus. But we couldn't illicit any nystagmus. We got ready to take her back to the floor, a bit disappointed. And we were negotiating the area around there, which was basically the Strabismus Clinic. And, because there are a lot of children there, they had an aquarium with tropical fish and so forth. And as we just negotiated one corner, her IV pole started to fall over and Dave dived to catch it, and just at that moment, she came alive and said, pointing, "Oh, look at the fishes." And that's all she ever said. And when we tested her again, she appeared to have no vision at all. So, after that, we regrouped and had a beer. [laughter] DZ: She had an island of vision, obviously, and could only see something at a distance. I'd like to add one more thing I think, and neuro-ophthalmologists are so good at this, and that's make sure your teaching skills are good. Because when you teach, you find out what you don't know, and when people ask you questions when you're teaching, they lead to questions about hypothesis, new experiments. So, I think if you get the opportunity to do some teaching when you're starting out in your career, take it. JR: You both have vast experience in examining the eye movements of patients at the bedside, as well as in quantified eye movement recordings. With that experience, I'd like to ask you if you perceive in the future that eye movement recordings, quantified recordings, might become a part of daily clinical neurological practice, and if it's necessary? What do they really add for you on top of the clinical examination? And perhaps you can touch, as well, on what the barriers have been to bringing quantified eye movement recordings into the clinic. DZ: Well, you need both. There's never going to be a day in my mind when the taking of a good history and looking at the patient in the eye is not going to be an important part of taking care of patients, diagnosing them, and treating them. You know we're in a bit of a revolution now in the emergency department with video oculography and measuring vestibular responses in patients, trying to decide if a patient with an acute vestibular syndrome has a stroke or has a more benign peripheral problem like vestibular neuritis. And we're in the early phases of testing algorithms and getting quality recordings from sick people in the emergency department. But that's probably going to be part of-much like EMG and nerve conductions-the armamentarium of the clinician, quantifying vestibular function especially, but also making something out of saccades, for example, where the speed and accuracy of saccades can be so helpful for localization. DZ: There are a lot of artifacts still, and a lot of places you must be very careful. If the patient is falling asleep a little bit or not looking at the target. But of course quantification is good, Science is based on quantification Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations and numbers, and I think that quantification is going to become important for biomarkers, for diagnosis, for the natural history of disease, and for the results of treatment. So it's going to be both-technology and the astute clinical examination. And, I would emphasize the clinician has to know the artifacts of all these measuring techniques. It's not as easy as doing an electrocardiogram. JL: I agree. I think that there are certain situations clinically when it's tough to determine what's going on, especially oscillations. Nystagmus, saccadic oscillations, having a record really helps you there, apart from the vestibular thing that Dave's described. The other time that I think eye movement records are really useful is when you are actually doing an experiment and asking a question. And, for example, using saccades as tests of memory or volition, that sort of thing. And then you're talking about not just measuring eye movements, but very cleverly arranged stimuli, sequences of stimuli, and so forth. So that's really a research situation. Whether that will extend to clinical practice, I'm not sure, perhaps. But otherwise, yeah, I would agree. Most things you can see at the bedside with careful examination. DZ: Yes, eye movements now are for so many neuroscientists of all ilks, a read out for so much of what the brain is doing. Attention, salience, prediction, memory, reward, learning, etc. But a whole field of using eye movements to assay, measure the temperature of what's going on in the brain, is just beginning. So, it behooves us as neuroophthalmologists to take advantage of this. For example, the tools of the neuro-ophthalmologist are becoming key for the evaluation of concussion and trauma. JR: Absolutely. Very important. So, as we move into the last phase of the interview, I'd like to ask you what might you go back and tell yourself during the early portion of your career, based on where you've been and what you've seen and what you know now? JL: Well, I think over the passage of time I've come to realize the maxim that we know less and less in a sense. So, first of all, to realize that our knowledge is incomplete. Our cognitive abilities are actually quite limited, and so then it behooves us to be curious, skeptical, very aware of our own fallibility. It pays to treat everybody's opinion with respect because they just might be right. But also optimistic, I think that science is moving forward. And then finally, if I may: "This above all, to thine own self be true." DZ: Well, I must admit I've been lucky. I was just at the right place at the right time, and I fortunately was able to take advantage of that. At the beginning, I would spend a little more time trying to know what has been done in the past. I do that now, but as we used to say, it can usually be found in the old German literature, I see people nowadays not paying much attention to what's been done in the past, but there often is gold there. As I say, read and know but don't necessarily accept, all that has been written by the old masters. Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 DZ: Perhaps I can give one more anecdote about knowing the past. I had to give a talk in Canada, and I wanted to say something about Frank Walsh, who was a Canadian, and my talk was related to PSP. I'd looked up one of Walsh's old papers in which he had described what was later thought in retrospect a patient with PSP. But reading the paper, this was in the 1930s, the patient had some funny movements around his jaw and couldn't look up and down. And I thought, "Well, maybe this is Whipple disease, not PSP." And, we were able to dig out the old slides in the pathology department at Hopkins, which were still there from the autopsy in the 1930s, and we did a PAS stain, there was no PAS stain in the 1930s, and sure enough this patient had Whipple disease of the brain, even before the era of antibiotics. So, I would pay a little more attention to the past. And, I would try and learn as much mathematics as you can. So much of modern neurotology and modern neuro-ophthalmology depends on understanding some physics. It's not impenetrable. If you find a good mentor, you can appreciate enough so that you and your patients can make an important contribution. JR: Are there other aspects that we have not touched on with regard to your career paths or your approach to your research careers that you'd like to share? JL: Well, I was very lucky [chuckle]. Looking back, I took this big risk of coming across the Atlantic and all the rest of it, and I just landed on my feet. It's because I happened on good mentors, really, and great opportunities, and generous people. But I think. They say that fortune rewards the brave, or something like that, and I think that you have to be prepared to take some risks, believe in your future and take some risks, and with luck it will work out. DZ: I would just like to say how a little bit of my career transferred to my wife, who was a foreign language teacher and didn't do very well in geometry. I was at the movies with her, a Paul Newman movie, "Nobody's Fool," I think. And as usual I was falling asleep, and all of a sudden, I get an elbow in my side and she says, "Look, he has nystagmus." [laughter] And the actors are playing cards, and sure enough, one of them had congenital nystagmus. So, I felt that I was now accepted, my career was now accepted at home. JR: That's fantastic. So how are you both currently spending your time? DZ: Well, I'm still working. More teaching, and working with a couple of terrific fellows on research. I think as I've moved along, I can see my role more as a teacher. Some people become chairs and some people do other things, but at least right now, the fact that I can go out and talk to 75 or 100 neurologists in India and convey some new way that they can deal with their patients is particularly rewarding for me. So, I have so many good clinicians here at Hopkins, seeing all the dizzy patients and the nystagmus patients, so I'm fading away from direct patient care, but hopefully with a relatively long time e25 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Great Conversations constant, and doing more teaching and trying to keep up with my research. I spend a little more time with my grandchildren close by. JL: So I had this very. Another fortunate thing happened to me after we'd finished the fifth edition. We decided to retire, and because our son, Richard, is down here in Baltimore, we moved to Baltimore. And so, it's like coming home. I finished up my scientific career where I started, and David Newman-Toker and Dave Zee were. everybody's welcomed me back in here. So that's wonderful, that's wonderful. And, the only caveat I say about being an elder statesman is you have to be careful because the field's changing so rapidly. Unless you're really on the ball and following it, you have to be careful what you're doing. Besides that, besides family, well, theater's big for me, and travel, though not quite as big as it is for Dave, and writing. I like to. a lot of talks. One of the great things about being retired I think is that you can let your curiosity run wild. While you're actually in the field doing research, you have to focus on your field, be up to speed on exactly what's coming out [laughter]. Afterward when you retire, you can let your curiosity run wild, and I do. History of science is something I'm very interested in, and anything that catches my attention. DZ: John, tell us about your recent publication. JL: Oh. Well, I was always interested in Shakespeare, and I've run into the whole business of the Shakespeare authorship issue, whether the fellow from Stratford is e26 really the author. And what I found, to my amazement, was that English literature departments the world over totally poo-poo this. So for example, you can't do a PhD research project on the Shakespeare authorship issue because there is no such authorship issue in their view. Well, that sounds a bit like received truth, but of course, the information we have on the man from Stratford, about 100 documents, is very patchy. And so it's a hypothesis. And so, I wrote this paper [chuckle] to try and make the point that who wrote Shakespeare is a hypothesis which needs to be subjected to the scientific method. And, I'm sure it will receive very few citations. [chuckle]. JR: You never know! It's been wonderful to talk with you both today. Any final comments before we conclude? JL: I just hope you're as lucky as I was. JR: Thank you and thank you both so much for your time. Meagan D. Seay, DO Kathleen B. Digre, MD Departments of Ophthalmology and Neurology, University of Utah Moran Eye Center, Salt Lake City, Utah Janet C. Rucker, MD Departments of Neurology and Ophthalmology, New York University School of Medicine, New York, New York Seay et al: J Neuro-Ophthalmol 2020; 40: e17-e26 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.