Baptist Health Miami Neuroscience Institute invites Dr. Michael J. Aminoff to discuss groundbreaking research and clinical insights in the field of neurology.
That Melissa's here, Christine's here. Awesome. Um, we have our functional neurosurgeon, of course, you know, um, nobody else except for me. Um, but, um, So, um, today we have Doctor Michael Amanoff, who's come from UCSF, um, And the reason Doctor Amanoff is here is a visiting neurology lectures because I made that decision um in 2020 when I was planning. Um, to try and convert Baptist neuroscience into something more academic. Um, I think this is our 5th lecture invited lectureship. Everybody that we've had has been, you know, uh, extremely well known in their respective fields, and the same for Doctor Amanoff. And because Doctor Torres arrived, Diego Torres arrived on Monday. To start as the division of neurology um director, I thought it would be most appropriate if he did the formal introduction for Doctor Amanoff. Thank you so much, uh, Michael. Um, this is, uh, This is a, a true honor and an, and an immense uh pleasure, uh, really. Uh most uh people in academic neurology and academic neuroscience would be thrilled to do what I'm about to do. Uh, it is an, an immense honor to introduce to you Doctor Michael Aminoff. Um, Many know him as MJ Amenoff because of the very uh famous last name in neurology and all of the things that he has done. He graduated from the University College London and University College Hospital uh as MBBS and uh then completed his neurology training and neurophysiology. At the world famous Queen Square Hospital. And uh you know, it it is one of those dream places where neurologists would love to uh go visit and see so much history and so much of what we do in neurology has happened and has come from there. Uh, Doctor Aminov, then, uh, came to the United States and uh has been working at the University of California San Francisco uh for many, many years and he has been instrumental in the building of the neurology department there and beyond that on the building of neurology as a whole. He has part I, I truly believe that neurology would be different in the United States and in the world if Doctor Amenov would not have done all the things that he has done. He, uh, was, he headed the neurology board. He headed uh so many um uh efforts in neurology education that he holds the most prestiged neurology educator award in the United States. Uh, from the American Academy of Neurology. Um, in all honesty, there are very few words that would describe Doctor Aminov better than a giant in neurology, and therefore, we are so honored to have him here. Thank you so much for coming. Well, after that remarkable introduction for which I, I really thank you very much. The best I can do is now keep quiet. um, thank you. And let me also thank, um, Doctor McDermott for your invitation and for this named lectureship. Um, there are, when one looks back over one's professional career, there are obviously high points and low points, but certainly being here today and with this name lectureship is a moment of undiluted pleasure, so thank you. Having accepted your invitation to come and give a talk, I was then stuck with what to talk about. And what I didn't want to do was come and talk about neurophysiology to people who are immunologists, or try to talk about immunology, which I couldn't do, to neurophysiologists and so on. Um, and then knowing that this was going to be a mixed audience, I decided in the end to talk, to, to take a more general approach. And I'm going to talk about something that all of us think we know about, but actually, we really don't. And that's the Brown-Sacca syndrome and sensory physiology in the spinal cord. But I'm gonna do it, uh, by going over, first of all, the history of the syndrome. I'm gonna tell you who Brown Sicard was, uh, and then what he did, and then how he changed his mind, and nobody now believes what he said, although, in fact, modern science holds that he was correct in his later views. I should disclose first of all that I have in the past written a biography of Brown Sicard, which was published in 1993. Um, I get no royalties at all from this book. You can still buy it on eBay for vast sums of money. I don't get a cent out of it. Um, in 2011 or 2012, I published an enlarged. Biography of the same man, Brown Sicard, published by Oxford University Press, and I do receive occasional dollars and cents from the press. So as I said, I'm gonna tell you about the man and his career, then about his clinical and scientific achievements, then how he refined his theory on spinal sensory function, and then compare that with what we now know or don't know. So, starting with the man and his career, this is uh a picture, it's one of the one of the few pictures of Charles Edward Brown Sicard. He died in 1894. When he died, obituaries were published all over the world about him. They were published in newspapers, in magazines. The International Congress of Physiology was in session in Rome at the time that he died. It immediately sent a telegram of condolence to the French Academy of Sciences, of which he was a member. The French Academy of Sciences had a 5 minute meeting in which this death notice was read out, and the meeting was immediately adjourned by the president out of respect for the late uh Doctor Brown Sicard. Pasteur, shown here is said to have cried when he heard that Brown Sicard had died. This letter shows you with what regard Pasteur held ros the gar, dear Grand Master and friend, the letter begins. Well, who was Brown Sicard? He was born on the island of Mauritius, which is between uh Africa and India. And he was born of an American father, a sea captain who was lost at sea before the boy was even born. So he was born fatherless. His mother was French, and he was a British subject. And the reason he was a British subject was that in 1815, the island of Mauritius was seeded. From France to Britain by the Treaty of Paris, which ended the Napoleonic War. So he was born a British subject, and this had a profound influence on his career, as we'll see a little bit later on. As a teenager, he was unhappy and felt stifled in Mauritius, and persuaded his mother to come with him to Paris, uh, where he eventually enrolled in the faculty of Medicine, um, and graduated in 1846 after publishing a very, very exciting thesis that quite clearly the examiners did not understand. Because if they had understood it, they would have failed him. In that thesis, he challenged the current concepts of sensory physiology. And we're going to talk more about that in just a little while. Over the following years, he became a very eminent and widely respected scientist. He was elected a fellow of the Royal Society of London, the oldest scientific society in the world, in 1860. Shortly after, he emigrated to the United States and was elected a member of the of the fledgling National Academy of Sciences of the United States of America, and some years later, when he moved to France, he became a member of the French Academy of Sciences. Yeah I I thought you might like just to see his signature here on the book. Uh, of that fellows have to sign, signing their uh signing their understanding of the obligations of fellows of the Royal Society. So here is Brown Sicard's signature. Note that it's in the same column as Joseph Lister, the founder of antiseptic surgery. And also of Francis Bolton, who was a remarkable polymath, as you know, he was a meteorologist, he was a um a psychometrician, a mathematician, a statistician. He was the person who introduced um the use of twins to distinguish nature from nurture. He introduced the the use of fingerprints as a means of identification. He is not popular or well regarded these days because Galton believed in eugenics. And after what happened during the Second World War, eugenics, uh, is something that is really frowned upon by many people today. Anyway, there is Brown Zica's signature to the Book of Obligations of Fellows of the Royal Society. Just so you can see, this was the notice that he received when he'd been elected a member of the Institute of Paris. How do I get rid of that top thing, I wonder. Um. And um These are some of the positions he held. He was a founder physician of the National Hospital at Queen Square. In 1863, he resigned. His wife was an American. She was ill, there was illness in the family. Family came from Massachusetts, so he emigrated to Harvard, to Boston and got a position at Harvard as professor of physiology and pathology of the nervous system. The first professor of neurology in the world. In 1867, his wife had died, uh, he was depressed, he was fed up with academic life in Boston. He felt he wasn't given his due merit, his due desserts, and he left, and he moved to Paris. Where he was appointed in charge of the course of experimental and comparative pathology at the University of Paris. He could not be named professor because he was not a French citizen. Under Napoleonic law, you had to be a French citizen to hold a university chair. He resigned from Paris in 1872 after the Franco-Prussian War, and then there followed a period of several years where he wandered between the United States, Mauritius, his place of birth, and Europe, holding or being offered chairs in Glasgow, in Geneva, in Ireland, turning them down. And becoming destitute. And finally, in 1878, Claude Bernard, the professor of medicine in the College de France in Paris, died. Claude Bernard and and Bern Brown Sicard were rivals. The minute Claude Bernard died, Brown Sicard rushed from the United States to Paris. Became a French citizen, that this is his citizenship document signed by the President of the Republic. And then applied for the job of professor at the College de France, the most eminent medical position in France, and was appointed to the chair advocated by Claude Bernard, who had died. A little bit more about the man, before we move on, who's married 3 times. Had 3 children, founded 3 journals, one of which is still going strong, the Journal of Physiology in Paris, French Journal. And he crossed the Atlantic more than 60 times. It is said that he spent 6 years of his life at sea. So, apart from traveling around the world many times, what did he do? Well, let me just tell you about some of his scientific achievements. He clarified the sensory pathways in the spinal cord, and that's what we're gonna talk about uh more in in just a few minutes. Let me leave that for the moment. What else did he do? He emphasized functional processes in the integrative action of the nervous system. He pointed out that one part of the nervous system could excite or inhibit distant parts, and how those distant parts performed then depended upon the sum total of excitatory and inhibitory influences. Now his experimental evidence to support this was really not, not, not good. You can read his papers and they're really rather poorly formulated. And it was left to Charles Sherrington. To really demonstrate that this was indeed correct, and Charles Sherrington got the Nobel Prize for this work in the early 1930s. He uh he discovered the function of the vasomotor nerves. And just let me tell you briefly about the vasomotor nerves. In 1851, Claude Bernard found that if you section the cervical sympathetic nerve in rabbits, the ear becomes hot on that side. And Claude Bernard thought, wrongly, that the sympathetic nerves therefore regulate the local production of heat. That is incorrect. Brown Sirca did exactly the same experiment in the same year as as Claude Bernard, but he was traveling from uh France to Philadelphia at the time and so he didn't publish the work until 1852. Valdegaard's findings were identical to those of Claude Bernard, but in addition. Brownicard stimulated the cut end of this of this uh sympathetic nerve. And when he did that, the heart ear of the rabbit showed a peripheral vasoconstriction. And so Brownickard argued that the sympathetic nerves therefore control the caliber of the blood vessels. In other words, they control the physics of circulation, and that of course is the correct interpretation. Just out of your interest, on the right hand side of this slide is shown a stimulator like we use in the EMG lab today. You can see how small and compact it is. On the left-hand side of the slide is showing the apple rate is required to stimulate a nerve in the 1850s. This bit here fits on here. And you can see how just how complex the equipment was uh to do the sort of experiment I've just told you about very briefly. And finally, Brown Sicard was the father of experimental endocrinology and hormone replacement therapy. And anyone talking about Brown Sicard has to say a few words about this work. So, the father of experimental endocrinology, that claim is based on the following. In 1855, Thomas Addison, at Guy's Hospital in London described 11 patients. Who During life, had malaise, were anemic, they had rather bronze, a curious bronzing of the skin, um, and so on, a variety of non-specific symptoms, but who at autopsy were found to have bilaterally diseased adrenal glands. It had tuberculous involvement of the adrenal glands. Well, Anderson published it, it's now called Addison's disease, published this in 1855, and the, and immediately Brown Sca went to the laboratory and excised both the adrenal glands in a variety of laboratory animals and showed that the animals could not survive. Until Brown Sca did this work, the adrenal glands were thought to be vestigial structures of use to the fetus but of no use after birth. So now row of card shows that indeed they have some sort of vital function in life. Other investigators, nobody would believe rats. The other investigators showed, for example, that white rats survived the loss of both adrenal glands. Brown sugar would then go into the white rats and show that they actually had exceptionary glands, but if you remove the accessory glands, they die. So he showed that the adrenal glands are essential to life. What did the adrenal glands do? Well, at first he believed that they removed the toxic chemicals from the blood. After all, that they are next to the kidneys, and that seemed a perfectly reasonable thought initially. But then in 1869 when he was holding that uh. When he was running the course of experimental pathology in Paris, but not actually named as a professor, he said that these glands, the adrenal glands. Have internal secretions and burnished to the blood useful if not essential. In other words, he is describing a hormone. And it's based upon this work, remarkable work, very good work, very carefully planned, that he's regarded by many as the father of experimental endocrinology. But on June 1st, 1889. Something else occur. Browns the card He's now aging. He's now in his early 70s, and as he walked the beach in Massachusetts, he became increasingly aware of his age. He was tired. He couldn't concentrate as well. His urinary stream was leak. He tended to constipation. He needed to have a nap in the afternoon. He decided that he was getting old. And he decided to inject himself with the mashed up testicles of of rabbits, guinea pigs, and whatever. And that's what he did. And on June 1, 1889, he stood up in this in the Society of Biology in Paris. And announce this. And he announced what happened. He felt stronger. He didn't need a nap in the afternoon. his urine stream was more powerful. um, he was less constipated and so on and so forth, and he suggested that this was worthy of further investigation. He didn't make any other claims. He published the details of his. So that's what we've just talked about here. However, other people capitalized on his findings. This is an advertisement from the Strand Magazine, an English magazine published in 1912, and you can see all the various claims made for Sicard's elixir. Its secondly, um. None of these claims were made by Browns. When he stood up and he made the he he made his announcement at the Society of Biology, a lot of people laughed at him. Newspapers started to publish cartoons I think. Here is a cartoon from the feeder of French newspapers showing the newly built Eiffel Tower to the world. And here is Browns a car taller than the Ear and stronger because the Eiffel Tower age but browns a car to go on red and an exhalight as they call it. Here is a cartoon from the American magazine. I, um, but, um, you can see Civil War veterans. Being injected with browns and dogs and exhali, that's. And here's one guy who's just had it, um, so, uh, a lot of people made fun of Brown Sca, and others claimed that he was gonna make a lot of money exploiting this supposed elixir of life. Actually, he didn't make a penny. He made these extracts available to everybody, to every scientist or doctor, free of charge. This is a label from one of his extracts, and when I say one of his extracts, I should go on to add that after he'd made his testicular extract and claimed that, he made a thyroid extract, a liver extract. He made a variety of organ extracts, and as you can see, it says at the bottom here, um, sent free by Mr. Grayar and Mr. Dassel Baca's sister. Under no pretext in this he so, it was given away free by his laboratory in Paris. Within 18 months of this, That was the first treatment for hypothyroidism with thyroid extract. And this is, this is the beginning then of hormone replacement therapy. So again, a remarkable achievement, um, at least in principle. Here are some other things that Brown cigar did. I'm not gonna go through them. Let me just well I just mention this neurogenic pulmonary edema. Brown Sicca noticed in his labor animals that an acute cerebral lesion seemed to give the animals pneumonia. Nobody took any notice. And then the First World War came along, 2030 years later, and French soldiers began to die following acute head injuries with pulmonary edema. And so this was first discovered by Graca uh 30 years before the First World War. And now of course we all know the autonomic consequences that can occur following acute or with acute head lesions. So let me go back to the sensory pathways in the spinal cord. And let me just say that uh Galen said if you cut the spinal cord. There was paralysis below the level of the lesion and loss of sensation. If you didn't call any section, there was it's an actual analysis, but G did not investigate the effects of any of any any section of the sensory function in the laboratory animals. I think we'll miss that slide and the next slide. I just go to this slide. So when Van Sca was a medical student in Paris in the late 1830s and the early 1840s, the prevailing view of sensory function is that the posterior columns were the continuation of the posterior roots and that they were the main sensory pathways in the court. Whereas the anterior columns were thought to contain the descending motor pathways, and that's what Bran Sca was taught. This is one of the few pictures that there are of Branca. I showed you one earlier, this is another one. This is in in his 40s, so he was younger than he is when he did the work I'm about to tell you of. And this is taken from his book published in 1860, showing various lesions made in the spinal cord. And I'm going to show you now the simpler versions that I've made, like here. Um, so remember I told you that the posterior columns of the cord was thought to be the main sensory pathway in the cord for brazocardio various laboratory animals cut the posterior columns and left the rest of the spinal cord intact. And as you can see, there was no sense with us, so that would not really jive with the post you remain sense. In fact, There hypoesthesia, animals seem overly sensitive to any thermal stimulus or pain stimulus. When in other animals he cut uh the entire corn except for the boats really he got. Now we essentially lost, but now we don't know. So, um these first experiments showed that the prevailing sensory theory. was incorrect. And then he made other lesions in different parts of the spinal cord, which showed that with the with the lesion involving the laxal funiculi, there was no sensory loss, but again there was hyperia. When he cut the anterior when he died. He said that there was no mark said sweetheart, I, there may have been some. Then he did a heavy section from the back to the center of the cord or from the center to the front of the cor and found in both cases that there was sensory loss. So he concluded that the sensory pathways must reverse the way a coding that. And then he made his famous hemit section, his lax or he sex. And what he found was that when he made a natural hair section, there was a loss of pain appreciation, particularly on the opposite side. On the Ipsilat inside, you see those paralysis of the leg and there was like aesthesia, that sensitivity that I told you about a moment ago. The ground to come concluded that the sensing fiber must cross from one side of the coin to the other. When he made hemi sections at at uh at one side and then on the other side, uh, he was able to show that this crossing of sensory fibers must occur very soon after they entered the spinal cord. And so we come to what Brown Sicard and others now believe, which is essentially the fibers come into the spinal cord, and then they synapse in the posterior horn, and they cross to the other side and they ascend in the anterolateral or the anterior funiculus of the spinal cord. Some go go up to the posterior column, but the pain and temperature uh here. Brown Sca followed up this work by a very careful study of humans, patients with spinal cord injuries. And he came up then with what you and I would now describe as the grounds. So here is the anatom partway up here. Now the the syndrome on its side opposite where the lesion was made, there is a loss of pain and temperature nereciation, and on the ipsilate of side there is paralysis. Plus, in position sets and vibration. But in addition, and something which most technicalology never mentioned. There's hyperesthesia on the syna side, spontaneous pain on the syna side, and itch on the insy side. And most of the books don't mention this because they can't explain it. Over the following, so now we're we're going up to 1892, so over the following 30 years. All doctors came to believe what I just told you. And many still. um, so believe what I just told you, and the Brown Sirca syndrome was born, was established, and came to be widely believed. Until 1892, when Frederick Malt published his experiments in Mons, Frederick Malt was the man who founded the Morse Hospital in London, a famous psychiatric hospital in London. He was also the man who showed that GPI, um, is treating neurosyphilis. In 1892, he reported on experiments in monkeys, and he found that heavy sections, natural heavy sections. Reduced uh paid localization contraactly but a not and that's the exact opposite of what I just told you. So, It raises the question. Is there a Brown Sicard syndrome? What are the consequences of a lateral cord hemsection, and if there are consequences, what do they do to? So let's now go on to how Brown Sickard refined his theory. Here is Brown Sicard in the late 1880s. This is a uh a drawing taken from Harper's Weekly showing Brown Sicard lecturing at the Academy of Sciences in Paris. A very distinguished man, his career was made on his sensory physiology experiments. And here is this young upstart in London, Mott, saying that he, he got it wrong. How did he respond? Well, 3 months before he died. In 1894, he published a five-page paper in response to Mark's paper. He began by losing Mok's work. He then pointed out that he had revised his own views 15 years earlier, and he published his revisions. He now doubted that cutting a hardwired system explained all the findings that that that you encountered clinically. He showed, for example, that a small lesion in the posterior column was called a pinprick. Could actually produce contralateral analgesia, loss of pain contralaterally. Again, if there was if there was a contralateral analgesia after a chord hemisection, stretching the sciatic nerve on that side, i.e., changing the affluent input to the cord, could abolish the analgesia. And then he did this remarkable experiment, absolutely astonishing. He made a cord lesion, a cord heavy section, and got the Brown-Sacca syndrome, right? He then made a second cord lesion on the same side, another hem section below the 1st 1. And guess what? The sensory findings reversed. The analgesic side became hyperesthetic, and the hyperesthetic side became analgesic. Now, you're cutting, if you believe you're you're cutting telephone wires, you're cutting the same wire on both first down up, first up, down up here and then down here. So, just cutting the telephone wire cannot be the explanation for the findings I've just told you about. Browerca thought that maybe the the analgesia or anesthesia from cord lesions related to inhibitory processes occurring in the spinal cord on the central sensory pathways and that the hyperesthesia related to excitatory effects on those central sensory pathways. Well, what's happened since then? In 1991, I was actually writing that that first biography I told you about Brian Sicard, and I was really puzzled by this paper I've just told you, by Page paper, which is astonishing experimental findings that nobody seemed to know about or care about. And so I wrote to Pat Wall, um, who was professor of anatomy at University College London, when I had been a student years before, um, and a famous pain researcher. Um, and I asked him what did he think of this, and this is what he wrote back to me. I hope the clerks will help you. I read the 1894 paper and one of the most important in neurology. Most neurologists have never heard of it would be incapable of understanding but um thank you very much. Um, but what he did do was he sent me a, a, a reprint of an article by Danny Brown. Danny Brown was a very well respected professor of neurology at Harvard at the time, the Massachusetts General Hospital. And this is what Danny Brown had published in 1979. He'd made lesions in the thoracic cord of monkeys. With an incomplete and resection, we've got a typical balance of card syndrome. With a more complete and resection, it reversed and he got it that's what mark syndrome. But it's allergies and yeah. More interestingly, he did a similar experiment in what what I told you about his car. He made a heavy section. Um, of the spinal cord and got a typical. Then above the first lesion, he made another lesion. He either made a more complete head section. Or what they they didn't stop they made it here and he's found that the the contralateral analgesia was replaced by hyesthesia and it's an actual analgesia, in other words, he was able to reverse. The ground cigar mine is due to, to cause a mock syndrome by simply extending the bleeding. Now if you look carefully at the drawing up here, you can see that the anterior column is not completely cut. Here it is. When he extended the hemi section even more. To involve both ends of the columns sensing responses in the monkeys returned by accident. So here is an animal with with cold lesions, which then first lose a cut sensation and then sensation returns to on both sides. This is by Danny Brown, a very, very respected uh neurologist. And so Danny Brown thought that the fibers in the angioa column have an inhibitory effect on spinal mechanisms which is managed to get an excitatory effect uh produced by fibers in the androla. That he again now thought that there was a balance in the spinal cord of excitatory and inhibitory effects. Now, what about more recent work on the spinal cord? Well, recent work has shown that both descending fibers and affluents coming into the cord fibers can influence sensory deficits after cord lesions. The neural, the neurons in the brain stem can turn the neural pain mechanisms in the spinal cord off or on. Knowledge about the precise circuitry is still unclear. So here is What we saw before the spinal cord with the fiber coming in synapsing and the first thing we touching the other side of the A7. And here are various regions in the brain stem. Where depending on exactly where you stimulate, you can either turn on or turn off uh. They also want yeah. You can turn the spinal pain mechanism on or off. Uh, by stimulating in these various brain stem. So Brown Sicard found that sciatic nerve stretch or posterior column lesions can also affect pain sensation. Uh, and we now know from clinical studies that if you do a chordotomy on patients, for example, to relieve pain, after a while, the pain commonly recurs. Why? Or how? Could local affluent or intraspinal circuits be responsible? Well, this is a cartoon that I followed to not invest. UCSF. He and I have had long discussions about what we were talking about uh here is uh. The grounds and can syndrome. See, yeah. Interrupting the pain part is going up and there's contralax or analgesia. Yeah, in this fine we get 2 houses. So double N resection and there's a loss of pain at this time. Let's go over here. Here, we've got various interneuronal circuits within the spinal cord. OK, here's the original one going up, giving us synapses here and here to a number A7 the system and then it's asking back and so you can come up with these in spinal circuits that can carry aid information from one side to the other side of the board so that you can still feel pain even if the original ascending pain pathway is cut. We don't know the precise details of this. But increasingly, this is what appears to be the case in the spinal cord. So Brown Sicard's final concept of sensory physiology, and specifically of pain physiology, is not far removed in principle from views that are now evolving among modern neuroscientists. It's more than simply cutting a telephone wire. Changes in dynamic cord mechanisms seem to bear also on the alter sensation that results from cord lesions. So you may say sort of so what? Or what are the implications of all this? Can sensory deficits be reversed by making new lesions in the spinal cord? How confident can we be about the precise localization of a cord lesion by clinical exam? Yeah. Do we need more anecto clinical correlation studies, and I believe we do, to try to clarify uh essentially changes with anatomical sites of lesions in the spinal cord. Well, Brownsard died in 1894. There are very few mementos of him. There are a few in in Mauritius. There's a psychiatric hospital in Mauritius also, there's a street in Paris named after him. In 1972, the the the Paris Mint issued a medal commemorating Brown Sicca. Uh, on the side of the medal here listed many of the things that he did, opiotherapy is hormone therapy. But I think my time is up, and I will stop there and thank you very much for that.
