When Charles Miller Fisher, MD celebrated his 90th birthday in 2003, he could look back at a career as one of the most respected neurologists and neuropathologists of the 20th century.
Born in Waterloo, Ontario, he graduated from the University of Toronto Medical School in 1938, served as a physician in the Canadian and British navies during World War II, and finished neurology at the Montreal Neurologic Institute in 1948. After a formative year in neuropathology at the Mallory Institute of Boston City Hospital and Harvard Medical School, he returned briefly to Montreal. Harvard invited him back to Massachusetts General Hospital (MGH) in 1954 to start the first stroke service at a major teaching hospital. Over the next 29 years, he exhaustively examined neurologic patients and pathologic specimens, and meticulously recorded his observations. No one else had ever performed clinicopathologic correlation so skillfully and intensively in neurology. He defined nearly all the principles that underlie our current understanding of cerebrovascular disease. The embolic basis of cerebral infarcts, the clinical manifestations and pathogenesis of lacunes, the pathology of spontaneous carotid and vertebral artery dissection, the use of anticoagulants in threatened stroke, the relationship between cervical carotid atherostenosis and hemispheric stroke, and the link between aneurysmal subarachnoid hemorrhage and vasospasm—all are his. He originated the terms “TIA,” “one-and-a-half syndrome,” “string sign,” “lipohyalinosis,” “ocular bobbing,” and “wrong way eyes.”
He retired from the Harvard faculty in 1983, but has continued for the past 20 years to come to his office at MGH, perform research, and round on the neurology service. In 1998, he was elected to the Canadian Medical Hall of Fame.
This interview took place in his office on August 9, 2003.
JDT: You have written that “it was assumed I would become a doctor.” Who assumed that?
CMF: It would have been my parents.
JDT: Were there other doctors in the family?
CMF: No, I was the first. There was another doctor named Fisher in Waterloo (Ontario), but he was no kin.
JDT: Did you have a role model as you were growing up?
CMF: No, but I always thought I’d like being a doctor.
JDT: After you finished medical school at the University of Toronto, you accepted a medical internship at Henry Ford Hospital in Detroit. Why leave Canada?
CMF: They paid. We got $125 a month—the same as a worker in the Ford plant. In Canada, the chief resident might get $75 a month, but the rest received nothing except room and board. Besides, I’d heard that it was the best place for internship in the country.
JDT: Any recollections of that year in Detroit?
CMF: Oh yes, vivid ones. All the chiefs of departments were top notch. I would have stayed in the States, but war broke out in Europe in 1939, and I was in the Canadian militia reserves, so I returned to Canada and signed up for active duty.
CMF: Canada was very British—and Britain had declared war on Germany after Poland was overrun. Right after Dunkirk there came a call from the Royal Navy for 12 Naval Medical Officers. I was asked, and I said yes.
JDT: And you were shipped to England?
CMF: Yes, we arrived in the middle of the Blitz so I spent several nights under constant air raids in London and Portsmouth. I was assigned to an armed merchant cruiser. Six months after I came on board, we ran into a German raider in the mid Atlantic. We came out second best.
JDT: What was this German raider?
CMF: It was smaller than a destroyer, 5,000 tons or so. But very fast, up to 25 knots. Very good guns–accurate at 16 miles.
JDT: What happened?
CMF: When the alarm sounded at 0600, I went out on deck, and I saw the raider flashing signals. The next thing I knew, they had fired a blast that hit our bridge. We started going in circles. Then we began to sink. It all happened so fast we couldn’t get any lifeboats in the water.
JDT: You had to jump?
CMF: Right, but not very far. We were going down quickly. I had on a Mae West—an inflatable life vest.
JDT: Were you frightened?
CMF: It’s a long story. My wife Doris was expecting our first child on that very day. I thought perhaps she was in more trouble than I was.
JDT: Was the water cold?
CMF: No, it was the equator, you see.
JDT: Was it lonely out there?
CMF: Well, you couldn’t see far. When you’re in a trough, you can only see the rising walls and the sky. When you’re carried up by a wave, you can see into the next trough, and then I’d spot a couple of others, so I knew I wasn’t alone. Our ship had gone down and the raider was nowhere in sight. I had to decide whether to swim to Freetown, Africa or to Brazil, but I knew it would be about 1500 miles in either direction.
JDT: What were you thinking?
CMF: There was nothing I could do. I hoped that there might be British vessels around.
JDT: What actually happened?
CMF: After six hours, the raider came back. They picked up as many of us as they could find. There were about 160 survivors out of 350 on board.
JDT: Where were you taken?
CMF: To a prisoner-of-war camp in Germany.
JDT: What was that like?
CMF: Unpleasant. To think that you had no future…the German guards told us “you’ll never get out of here.” There were always escape tunnels being dug, but doctors were forbidden to participate by the Geneva Convention. Even in those circumstances, the British were completely honorable.
JDT: How long were you there?
CMF: Three and a half years—I was fortunate enough to be repatriated in 1944. I went back to the Royal Victoria Hospital in Montreal in internal medicine. As part of that, I was to spend a month in neurology at the Montreal Neurologic Institute.
JDT: Something important happened to you there…
CMF: Yes, there was an American colonel who had seizures that started with the sound of tom-toms. I had no knowledge of seizures, but I stayed up all night preparing a grand rounds presentation to Dr. Wilder Penfield on that patient. During my presentation, they asked me where I thought the seizures were coming from, and I replied “Heschl’s gyrus.” After rounds, Dr. Penfield offered me a three-year position as a registrar in neurology.
JDT: And you accepted?
CMF: Yes, it was an appointment—something definite, and part of the organization.
JDT: After finishing, you went to Boston, why?
CMF: It was common to go to London to “polish up” neurology. But I would have had to take my family overseas. Dr. Roy Swank, who had taken over our multiple sclerosis service, had just returned from Harvard, and he said there was no other place to go. He was very impressed with Dr. Raymond Adams, the neuropathologist at Boston City Hospital, and Dr. Derek Denny-Brown, chief of neurology there. He made a call and in a minute it was settled, I was going to Boston.
JDT: Soon after you arrived in Boston in 1949, an interesting story developed …
CMF: Yes, the chief resident in neuropathology had formalin dermatitis, so right from the beginning I was cutting all the brains—maybe three a day. The brains were sliced vertically like a loaf of bread. Cutting them that way always severs the basal arteries so you could not examine them in continuity. One day, three months after I’d arrived, I had the opportunity to examine the cerebral arteries before slicing three brains that had large hemorrhagic infarcts. The basal vessels were empty of thrombus.
JDT: And so?
CMF: People were signing these cases out clinically as cerebral artery thrombosis—but pathologically there was no thrombus. Afterwards, I looked up the records on these three cases and they had all been in atrial fibrillation and the general autopsy had shown infarcts in the spleen and kidneys. I speculated that that they might be cases of embolism from the heart. The emboli had evidently dissolved and moved on. The hemorrhagic change was from reperfusion of blocked vessels. In later dissections, I occasionally found pieces of emboli in the outlying vessels.
JDT: So was it your contribution to say that even if emboli cannot be found, embolism may cause brain infarcts when there is no thrombus?
CMF: Yes. The emboli lyse.
JDT: Before your work, what did people think caused the brain infarcts when the vessels were patent at autopsy?
CMF: Vasospasm. An authoritative American text in 1952 asserted that 70% of brain infarcts were caused by vasospasm. Even what we now call TIAs were attributed to vasospasm. I only found out about this later–I was ignorant of it at the time. Perhaps I would not have pursued the idea of embolism had I been aware of the dogma.
JDT: What did people think that vasospasm came from?
CMF: I don’t know. I read several tomes on vasospasm and none made much sense.
JDT: But your work on hemorrhagic infarction and heart embolism was never published?
CMF: No, Raymond Adams and I reworked the paper several times, but the editor must have had a different theory. Anyway, at that time I got side tracked to the internal carotid artery in the neck…
JDT: Is that the story of the man in the tavern? As I recall, he told his drinking buddies that he was worried about repeatedly losing vision in his right eye for a few minutes? His friends reassured him, but weeks later he developed a left hemiplegia…
CMF: That was the second patient. The first man had a left hemiplegia and happened to comment that it was strange to him that he kept losing the vision in his right eye before the stroke. I had ignored that comment until I came upon the second patient three weeks later. It occurred to me that internal carotid blockage on the side of the eye symptoms might explain everything. There were papers on arteriography in the German and Swiss literature describing carotid artery blockage, but the artery had only been looked at in biopsy and described as having “thromboangiitis obliterans” (Buerger’s disease). Hultquist had written an extensive monograph on carotid disease but it was short on clinical detail.
JDT: And did you eventually get the pathology?
CMF: Yes, the first patient died while I was out of town. His wife asked if there was going to be an autopsy and was told is wasn’t necessary. When I returned, I got permission from his wife to do an autopsy at midnight before the funeral the next morning.
JDT: And what did you find?
CMF: Atherosclerotic occlusion. No inflammation. No Buerger’s disease.
JDT: So now you had another explanation for stroke?
CMF: Yes, carotid occlusion.
JDT: And do you believe that stroke in carotid stenosis is caused by emboli or low flow?
CMF: Low flow. TIAs and stroke do not occur unless the residual lumen is narrowed to a millimeter or less. I’ve written somewhere that there are forty objections to the embolic theory of TIAs. For example, there is the fact that the neurologic manifestations are often identical and that TIAs may occur upon sitting up from a lying position, and so on.
JDT: Do you think that a TIA occurs when something happens to further compromise marginal flow?
CMF: Yes, that would be correct.
JDT: As a matter of fact, didn’t you introduce the term TIA (transient ischemic attack)?
CMF: Yes. TIAs were not recognized as warning signs of stroke.
JDT: And weren’t you responsible for introducing the idea of anticoagulation in TIAs and large extracranial artery stenosis?
CMF: Yes. The first patient I anticoagulated with heparin had basilar TIAs. We’d turn on the heparin and the TIAs would stop, turn it off and they’d start up again. I set up the first anticoagulation trial. Seven centers cooperated. We had so many fatal bleeding accidents that it appeared unlikely that a benefit could be shown.
JDT: Where does carotid endarterectomy fit into your professional life?
CMF: The first procedure was performed in Argentina shortly after our paper was published about carotid stenosis and stroke in 1952. The surgeon told me he operated after he read it.
JDT: How do you feel about the efficacy of carotid endarterectomy in preventing stroke?
CMF: I think it works in the right circumstances. It should not be done too early—50% stenosis is too early. And preferably patients should have symptoms.
JDT: When you appeared on the scene, what was the concept of lacunes?
CMF: Lacunes were studied in detail by Foix at the turn of the 20th century. These “holes” were thought to be infarcts, but there was uncertainty. No vascular occlusions had ever been found because serial sections had not been done. To find the occlusions, you needed to do a lot of pathologic sections. When I started in neuropathology, we were using celloidin blocks. It took nine months to prepare the celloidin sections. By that time, I could not recall the case at all. And with celloidin, you couldn’t make as many or stain as many sections as you needed. I soon realized that to study lacunes properly, I’d have to abandon celloidin and go to paraffin. Once I did that, I could make many more stained sections. It took me 15 years to find the microatheromas in the penetrating vessels. They would narrow the lumen to 60 micra or so and then on top of that, there’d be a tiny thrombus.
JDT: And these changes occur only in patients with hypertension?
CMF: Lacunes do not occur with atheroma unless there is hypertension.
JDT: How do you know that?
CMF: I did the sleuthing myself. I tracked down records, talked to family doctors, and found that the patients all had high blood pressure or a thick left ventricle or some other sign.
JDT: So lacunes result from a local vascular wall change plus microthrombosis, changes caused by hypertension?
CMF: Hypertension causes 80% of lacunes. In 20% of my cases, lacunes have had no thrombi. I do not know the cause of those. I prefer not to speculate. We have to get the facts.
JDT: Speaking of the facts, did you not “get the facts” on stroke after aneurysmal subarachnoid hemorrhage?
CMF: Yes, patients would become wrecks a few days after rupturing an aneurysm. Everyone knew from arteriography that this was stroke caused by delayed vasospasm. But the cause of the vasospasm was not really known. By careful study of CT scans, we were able to deduce that the vasospasm occurred at the place where the subarachnoid blood was thickest. So the blood was “irritating” the vessel wall and causing constriction. Nowadays, patients with heavy subarachnoid hemorrhage often have their aneurysms repaired before vasospasm develops.
JDT: Were you among the first to recognize that spontaneous carotid dissection was not a rare event?
CMF: When our paper appeared in 1972, there were only seven reported cases. When Dr. Robert Ojemann opened the cervical carotid artery for endarterectomy, he knew this was not an ordinary case of atherosclerotic carotid blockage, so he removed a section. Under the microscope, I could see the entrance of the blood into the media. The arteriogram had shown a long narrowing of the blood column that I called the “string sign.” Three hours later, Dr. Shirley Wray asked me to look at the arteriogram of what was considered an unusual case of carotid “arteritis.” The arteriogram showed the string sign. Surgery disclosed another dissection.
JDT: What about your famous observation of the white plug moving through the retinal vessels in a patient with transient monocular blindness? Do you have a recollection of that?
CMF: Oh my, do I ever. The patient was to be presented at rounds. I happened to pass by his stretcher just before rounds and he said “I’m having one of those.” So I got three colleagues, took him into a side room, and we all took turns looking into his eye with an ophthalmoscope. We drew what we saw, but we never got pictures. There was embolic material, perhaps the only time it has ever been seen—passing through the retinal arterioles. The patient had a carotid occlusion on the same side.
JDT: What role did that paper play in our understanding of stroke?
CMF: A misleading role. People say “you said in that paper that transient monocular blindness (TMB) episodes are embolic.” But this was a very long episode—lasted over an hour. Not the usual TMB episode.
JDT: So most people who have TMB episodes are not having emboli?
CMF: No, low flow to the eye. I had a patient who’d mow the lawn and get TMB. Flow to the muscles lowers perfusion to the head.
JDT: In 1980 you published a paper that described a group of older adults who had transient neurologic deficits and no evidence of vascular disease. You called these deficits “migraine accompaniments.” What was the significance of that work?
CMF: To avoid arteriography in people in whom it might be dangerous. What started that was an older businessman driving past the hospital on his way to the airport when he suddenly saw double. “That’s odd,” he thought. So he stopped at the Massachusetts Eye and Ear Infirmary. He was referred to the MGH, had an arteriogram, and was dead a few hours later—a complication of the procedure. This might have been avoided.
JDT: How? By recognizing that the double vision was a migraine equivalent?
CMF: Yes. Late in life, people may newly get scintillations, aphasia, hemiparesis, or numb tongue. And the attacks recur every three or four years. Unless you get the history, you’re apt to go off on the wrong track.
JDT: What other criteria do you use to decide that it isn’t a TIA?
CMF: Gradual spreading of the symptom like numbness marching up the leg and then up the arm and to the tongue. Not typical of TIA. No need for a history of migraine headaches. We all have a migraine taint. Some of us simply get these “accompaniments” after age 50 or 60 or so.
JDT: Let’s talk about the “Fisher variant” of Guillain-Barré syndrome. You know, triple A—absent eye movements, ataxia, and areflexia.
CMF: That came about because of a patient admitted here who was quite lively with full strength and in full charge of his faculties. He could not move his eyes. He had a tremendous ataxia so he could not feed himself and had no deep tendon reflexes. Others wanted to do a vertebral angiogram. I told them, “I’ve seen this before and the patients get better.” So they didn’t do the angiogram and the patient eventually recovered completely. I had seen two other similar cases, you see.
JDT: It was the lead article in the New England Journal of Medicine in 1956. Why?
CMF: Because it had not been previously described with complete sparing of limb strength.
JDT: There is great controversy as to whether the lesions are central or peripheral or both. What do you think?
CMF: They are all peripheral. There have been some detailed pathologic studies that have never been published. They’ve never demonstrated any abnormality in the central nervous system. French neurologists for years had known that in peripheral neuropathy you can get severe ataxia.
JDT: How did you come up with the name for the “one-and-a-half syndrome?”
CMF: Almost on the spot. Perfectly obvious. One for the whole gaze palsy to one side and a half for the adduction deficit to the other side.
JDT: What about ocular bobbing?
CMF: That came from my interest in coma. When we started a stroke service here in 1954, we saw more patients than the rest of neurology and neurosurgery combined. Unresponsive patients were simply not examined except to say that they were unresponsive. The history would state, “the patient is so unconscious there is nothing more to say.” We began looking carefully, and regularly saw new things in comatose patients—especially with the eyes. I had one or two stroke fellows every year who’d come running down the hall with new findings in stroke patients. I guess those days are gone forever. In the patient with ocular bobbing, the eyes would not move sideways with ice water caloric tests, but the eyes would come down spontaneously and then bob up. That observation led to important considerations about the organization of eye movements. There are many different spontaneous eye movements in comatose patients…
JDT: Such as ping pong gaze?
CMF: Well, one of my fellows called it that, but I called it “ocular agitation” because the eyes don’t really move regularly from side to side. They move a bit, then stop, then start again. It means double trouble up above—acute bilateral hemispheral disease.
JDT: As you look back over your 60-plus years in the stroke business, how do you think the approach to stroke differs now as compared with when you started out?
CMF: A half century ago, there was nothing to be done for stroke, so it was not worth knowing what was going on. Patients with stroke were not admitted to hospital in Montreal unless you thought they had a subdural hematoma. Later, here in Boston, stroke patients got a lumbar puncture if they didn’t have papilledema. If there was blood in the spinal fluid, they’d get an arteriogram to look for aneurysm. Treatment of anterior circulation aneurysm was tying off the ipsilateral carotid in the neck. Later we began to get arteriograms to look for carotid blockage and patients might have endarterectomy.
JDT: Our approach has certainly changed, in large part because of your contributions. What was the basis of your success?
CMF: I attribute it to careful clinical observation and a grounding in neuropathology.
JDT: What do you recommend for physicians who are following you?
CMF: Examine thoroughly and if something doesn’t fit, re-examine and read what others have written. Of course, the era of descriptive neurology is passing. From now on, it will be chemistry.
JDT: And what about you, now that you are nearing 90?
CMF: When I retired 20 years ago, I proposed that I become a full-time neuro-ophthalmologist. That wasn’t accepted, but I have continued coming into my office every day and making neurology rounds with the residents on Monday mornings. I see puzzling cases—much more puzzling than the young people recognize. I am always smarter at the end of each day.
JDT: 37 years ago you were my instructor in the second year Harvard Medical School course in neuropathology. One balmy spring afternoon, when you were leaning over our shoulders to help us interpret neuropathology slides, a bell rang outside the classroom. You hurried over to the window, turned around, and scampered out of the lab and down the stairs. We had no idea what you were doing. A few minutes later, there you were with 25 ice cream bars in your arms!
CMF: I have no recall of that—but I trust your memory.