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C. Miller Fisher, MD, FRCP, Emeritus Professor of Neurology at Harvard Medical School, who died on April 14, at the age of 98, was a founder of modern stroke neurology. In 1949-50, Dr. Fisher (CMF, Fig. 1) identified extracranial carotid artery disease as a frequent source of cerebral stroke, at times preceded by momentary warning signs, which he called ‘Transient Ischemic Attacks (TIA's)’. These findings came on the heels of his recognizing that atrial fibrillation also was an important cause of embolic stroke. These two discoveries – of potentially preventable ischemic processes – swept away long-standing theories of vasospasm and of middle cerebral artery (MCA) thrombosis as the primary substrates of cerebral ischemia, opening the modern era of stroke diagnosis and management.

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Figure 1. C. Miller Fisher, December, 2006, on the occasion of his 93rd birthday.

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Dr. Fisher was born in 1913 in Waterloo, Ontario, Canada. He was graduated from the Faculty of Medicine, University of Toronto, in 1938, did an internship at the Henry Ford Hospital, in Michigan, and an assistant medical residency at the Royal Victoria Hospital in Montreal. He originally intended to focus on diabetes and metabolic diseases, but his career plans were interrupted by World War II. In 1940 he enlisted in the Canadian Navy, but was transferred ‘on loan’ to the British Royal Navy in response to the United Kingdom's urgent call to its dominions for more naval medical officers. In 1941 he was ship's doctor on an Armed Merchant Cruiser, the Voltaire (Fig. 2), when it was attacked and crippled by a German vessel in the South Atlantic. As the Voltaire listed to 45 degrees, all surviving hands had to jump or slide into the warm waters, from which they were rescued by the enemy six hours later. Of the original 272 men on board, 197 survived. CMF spent 3½ years in a German prisoner-of-war camp. In September, 1944, he was repatriated as one of the supervising doctors involved in an exchange of wounded prisoners.

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Figure 2. HMS Voltaire (F 47) Armed Merchant Cruiser.

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On his return to Canada he took a refresher course in medicine, which included a two-month rotation at the Montreal Neurological Institute (MNI). On bedside rounds, Dr. Wilder Penfield, a distinguished neurosurgeon and the Director of the MNI, quizzed CMF on what might be the cause of a patient's focal seizures, which were ushered in with the sounds of beating tom-toms. CMF had spent long hours in the library the night before, studying just that question. His reply, ‘A tumor in the region of Heschl's gyrus’, became Miller's ‘open sesame’ to neurology. He had formulated correctly the diagnosis of the lesion that later was found at surgery. Dr. Penfield then arranged an acting-registrar position for him at the MNI (1946-48), and subsequently encouraged him to do post-graduate training in the U.S. or U.K. At the insistence of a leading MNI neurologist, Dr. Roy Swank, CMF arranged a one-year neuropathology fellowship with Dr. Raymond D. Adams (RDA) at Boston City Hospital (BCH).

Within weeks after arrival at BCH, CMF made his first ground-breaking observations. In one afternoon he had done post-mortem examinations on three consecutive patients who had MCA territory ischemic strokes and had presented in atrial fibrillation (AF). In each case the autopsy showed widely patent vessels from the aortic arch to the brain, but revealed punctate hemorrhages in the infarcted cortical ribbon. CMF hypothesized that a clot from the fibrillating left atrium had lodged in the MCA long enough to cause an infarct, and then underwent ‘dissolution’, initiating reperfusion of the dead tissue and secondary petechial hemorrhages. The concept of lysis of an embolic clot had never before been proposed. Neither had this mechanism of hemorrhagic infarction, nor the possibility of a strong association between AF and stroke. Dr. Fisher and Dr. Adams spent the next year verifying these new patho-physiological hypotheses.

CMF returned to Montreal, in 1950, as neuropathologist at the Montreal General Hospital. He was permitted to establish a lab devoted to the study of stroke, a field which had been receiving scant attention. In fact, strokes commonly had not been admitted to hospital, and at autopsy the carotid arteries typically had not been examined. Miller changed all that. He was beginning to find an association between stroke and carotid artery disease, the significance of which he demonstrated by removing eventually 1100 pairs of carotid arteries, documenting the frequency with which carotid stenosis/occlusion was the only identifiable lesion that might explain ipsilateral stroke. Propitiously, the report of his findings, in 1951, came at a time when surgeons were beginning to operate on the peripheral vascular system. By extending their reach to the carotid bifurcation they introduced carotid endarterectomy as a therapeutic tool.

When RDA became chief of neurology at the Massachusetts General Hospital (MGH), in 1954, he invited CMF to join him. This resumed an intensive collaboration that ultimately impacted the construct and culture of neurology, including the recognition of stroke disease as primarily a neurological discipline.

Although CMF's seminal contributions were in the field of stroke neurology, over the next 50 years he became a giant figure in both stroke and non-stroke neurology. Amongst these achievements: He founded the first formal Stroke Service, training many world leaders in the stroke field; resurrected lacunar (penetrating vessel) infarction, by describing the four major clinical and pathological syndromes of lacunar disease (pure motor hemiparesis, pure sensory stroke, ataxic hemiparesis, dysarthria-clumsy hand); discovered, with Dr. Robert Ojemann, carotid dissection as a cause of stroke; verified that migrainous accompaniments are important causes of stroke-like events in the elderly; described the clinical and pathological syndromes of thalamic and cerebellar hemorrhage; and reported, with Dr. Raymond Adams, the syndrome of transient global amnesia. Other syndromes he described included normal pressure hydrocephalus (NPH), rostral-caudal brain deterioration in the comatose patient, one-and-a-half (ocular-pontine) syndrome, and what is now known as the Miller-Fisher syndrome – descending Guillain-Barre.

Dr. Fisher had many collaborators in many disciplines within and without the Harvard system. At the MGH, in the neurosciences, these particularly included, Drs. Adams and E. Peirson Richardson in Neurology, Drs. Ojemann and William Sweet in Neurosurgery, Drs. Glenn Roberson and Kenneth Davis in Neuroradiology, and, of course, all the contemporary fellows of the MGH Stroke Service. The latter included Drs. Jay P. Mohr and J. Philip Kistler, who respectively succeeded CMF as head of the Stroke Service after Miller's (semi-)retirement in 1972, and Drs. Louis Caplan, Carlos Kase and Michael Pessin. Dr. Salomon Hakim, a visiting neurosurgeon from Colombia, collaborated with Dr. Fisher in the description of NPH.

Of his professional colleagues, Dr. Ojemann was perhaps most integral to CMF's clinical cerebrovascular endeavors. He provided the neurosurgical insight and expertise necessary for elucidation and validation of many emerging concepts. Dr. Fisher's devoted wife, Doris, made the most critical contributions to his work, giving Miller the time, space and uncompromising support to successfully pursue his career. She died in 2008.

Dr. Fisher received many awards and honors at home and abroad, the most singular of which was his induction, in 1998, into the Canadian Medical Hall of Fame.

Amongst CMF's many strengths as a doctor, the most evident were those as a clinical scientist, humanist and professional colleague. His humanism was evident in the attentive care he provided his patients, whose devotion to him still reverberates in the Greater Boston community, and in the concern he had for the well-being of all those who worked with and for him. CMF's professional collegiality was evident by its open access to anyone of any station who approached him with an earnest effort to learn from him or to participate in his activities; he had an infinite talent for becoming a life-long mentor to those who shared his devotion to clinical neurological science. But even above this, he participated in a special level of collegiality that made the MGH the pinnacle of neurological training and care. This was the collegial academic environment mutually stimulated by the members of the Great Triumvirate – Raymond Adams, Peirson Richardson and Miller Fisher (all three of whom were both neurologists and neuropathologists). This collegiality was the fire in the hearth that warmed the most miserable days of residency training, and the breeze that freshened the sunniest.

As a clinical scientist, CMF was inquiring, innovative, and precise, as required of all scientists. But he sustained, as well, two particularly distinctive features – his great patience and his remarkable aptitude for observation, especially of minute details. Both characteristics perhaps were residual reflections of his years as a prisoner-of-war (POW). CMF seemed almost to have had an indifference to time. Dr. Edward Wolpow, a neurologist with whom I shared residency training at MGH, recalls Dr. Fisher saying, ‘Good morning’, to a semi-comatose patient with bilateral medial-frontal cerebral damage due to a ruptured anterior cerebral artery aneurysm. The patient did not answer. CMF, suspecting an abulic syndrome (delayed cognitive/motor responsiveness), said he would wait for a reply. Twenty-six minutes later the patient returned the greeting. Miller was there to receive it.

I first met CMF when I was looking for a neurology slot in 1967. Jay Mohr, who was then CMF's fellow, invited me to make rounds with him and Dr. Fisher. Jay had been a medical resident at Bassett Hospital, in Cooperstown, NY, when Phil Kistler and I interned there. I blanched when Jay told me that Dr. Fisher's routine rounds with the fellows were from 6 to 11 at night, but that the three of us would meet to see a few patients at 10 pm. After several bedside visits we three adjourned for a discussion that went on until 2 am. For the majority of the time, Dr. Fisher philosophized about neurology. It was then I first heard two often-repeated themes to which CMF remained committed over the years. The first was his conviction that, ‘The care of the patient is the most important thing.’ The second was the key role of clinico-pathological correlation in the advancement of diagnosis. He anticipated that the cumulative knowledge harvested by ongoing clinico-pathologic correlations eventually would teach us how to localize at the bedside all central nervous system lesions; in concert with pertinent history these data would provide near-faultless diagnosis and, hence, better management. Six and sixteen years later, CT and MR imaging, respectively, began to intercede, vastly accelerating the localization process. CMF was impressed greatly by the efficacy of these new tools. He worried, however, that many clinicians didn't appreciate that even MRI was not necessarily a reliable surrogate for pathology. Indeed, just in the month before he died, as we discussed, by phone, a complex patient who had had controversial MRI findings, he repeatedly asked, ‘What did the pathology show?’ and closed the discussion with, ‘You have to have pathology.’

CMF had become concerned, as well, about the increasingly negative effect of CT and, especially, MRI, on the precision and comprehensiveness of the routine neurological exam, which too often might be performed after the imaging study and then be focused mainly on the neurological systems that might relate to the imaging findings. For Dr. Fisher, the word ‘clinico’ – as in clinico-pathological – encompassed not just the findings that resulted from stimulating the nervous system, but also those details representing the system's spontaneous cognitive, affective and behavioral outflow. Whereas experience and an in-depth knowledge of the literature was CMF's well-tempered anvil, keen observation was his tool for forging new concepts he could test in the office, at the bedside or at the microscope.

Miller was a proud man who felt vulnerable if he appeared weak. This, too, might have been a residual of his POW exposure. Until about five years ago, he had attended almost every meeting of the Boston Stroke Society since its inception, in 1983. When he became dependent on a cane to ambulate, he refused to come to any of the sessions, even if a car were to be sent for him and a wheel chair made available at the door. He said he did ‘not want to be seen weakened.’

For several years his only useful vision was in a very small temporal field in the left eye. Despite what must have been a painfully slow reading pace, he somehow managed to keep up with one or two major journals and to write articles, more lately with the help of his children: Elizabeth, Hugh and his wife, Susan, and Peter Fisher. So, if one asked him about some recondite neurological condition, he might quickly reply, ‘Oh, didn't you see the review of that in Lancet Neurology two weeks ago?’ Indeed, for CMF, knowledge was more important than the time and effort taken to acquire or to dispense it.

Miller, with other great neurologists, neurosurgeons and neuroradiologists of his time, provided a fertile groundwork for the roots of modern stroke neurology and clinical neuroscience. He served as a role model for many students and fellows. But interval demographic, cultural and economic changes will make it difficult in the future for even an aspiring-CMF to match the focus and productivity of his run.

And what a run it was!