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(Stroke. 1996;27:559-566.)
© 1996 American Heart Association, Inc.
Articles |
Dr C. Miller Fisher and the History of Carotid Artery Disease
From the Instituto Cardiovascular de Buenos Aires (Argentina).
Correspondence to Conrad J. Estol, MD, PhD, Cerebrovascular Disease Section, Instituto Cardiovascular de Buenos Aires, Blanco Encalada 1543, 1428 Buenos Aires, Argentina.
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Abstract |
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Top
Abstract
IntroductionBackground and Purpose Our aim was to analyze the role that C. Miller Fisher (C.M.F.) had in promoting an understanding of carotid artery disease (CAD). Although Chiari in 1905 and later Hunt, Moniz, and Hultquist, among others, described the association of CAD and stroke, this received little attention until C.M.F. published his clinicoanatomic correlations in "Occlusion of the Carotid Arteries." Until then, some 55% of strokes were attributed to "vasospasm."
Methods We analyzed articles ("Occlusion of the Internal Carotid Artery," 1951; "Occlusion of the Carotid Arteries," 1954; "Transient Monocular Blindness Associated With Hemiplegia," 1952; "The Microembolic Theory of Transient Ischemic Attacks," 1976; "A Clinico-pathologic Study of Carotid Endarterectomy Plaques," 1986) and conducted personal interviews with C.M.F.
Results During the 1950s, C.M.F. described the clinical implications of transient ischemic attacks and their relationship to CAD and stroke. The last sentence in the 1951 article read: "Unexplained cerebral embolism may arise from thrombotic material lying in the carotid sinus." In the same article he also wrote that "it is even conceivable that some day vascular surgery will find a way to by-pass the occluded portion of the artery during the period of ominous fleeting symptoms," heralding the future surgical treatment of carotid artery disease. C.M.F. called attention to the commonness of carotid disease, described transient monocular blindness, and studied the relationship between plaque pathology and clinical findings.
Conclusions C.M.F.'s clinicopathologic observations were a major factor in promoting recognition of the clinical features, stroke risk, and treatment of CAD.
Key Words: carotid artery diseases • carotid endarterectomy • history
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Introduction |
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"This apoplexy is, as I take it, a kind of lethargy . . . a kind of sleeping in the blood."
William Shakespeare, King Henry IV, Part II
The history of cerebrovascular disease spans many centuries, although the observations that have influenced current practice were described within the last 45 years.
Chiari in 1905 and a few years later Hunt, Moniz, and Hultquist, among others, described the possible association of CAD and stroke. In Prague, Chiari1 found thrombus superimposed on carotid artery atherosclerotic plaques of 7 patients in a series of 400 consecutive autopsies. Four of these patients had suffered cerebral embolism, and he suggested that embolic material could arise from the carotid artery and affect the brain. This could be considered the first accurate description on the pathophysiology of cerebral embolism from the carotid artery. Hunt2 in 1914 reported the clinical characteristics of 20 patients with hemiplegia but did not have autopsy data. He proposed that "the cerebral lesions in most stroke victims could be the effect and not the cause."
On July 7, 1927, Moniz3 of Portugal reported the first case of cerebral angiography at the Societe de Neurologie in Paris. This valuable step in stroke diagnosis allowed for the first time identification of the affected vessel before direct visualization at surgery. Surprisingly, most angiograms were performed to visualize the intracranial portion of the carotids in cases of tumors to look for abnormal displacement of arterial branches, with little interest in the vascular disease per se.
In 1936, Sjøqvist4 reported the first case of internal carotid artery occlusion documented with cerebral angiography. In 1937, Moniz et al5 reported occlusion of the internal carotid artery in 4 patients diagnosed with angiography. Hultquist6 in 1942 published the clinicopathologic correlation of patients with stroke in a series of 1400 autopsies. He performed examinations of the entire carotid circulation in 400 patients and found a 3% incidence of thrombosis. These important descriptions did not flourish, however, because corroboration of the ideas proposed was hindered by the absence of routine postmortem study of the carotids at a time when angiography was either not available (Chiari and Hunt) or considered too dangerous (Moniz and Hultquist).
The data presented here have been gathered through a literature search and from interviews with C. Miller Fisher at the Massachusetts General Hospital.
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Background |
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An important milestone in the history of carotid stroke occurred in 1951, when C. Miller Fisher reported the occurrence of TIAs in relation to CAD.7 He completed most of his original work on CAD in Canada before moving to Boston in 1954. In his own words, "I consistently studied the carotids at autopsy, gathering over 1100 cases." Unfortunately, Dr Fisher discarded the carotid specimens when he moved to Boston, thinking that he would get many more there. However, obtaining the carotids at autopsy in Boston was much more difficult than in Montreal. In the United States, a law mandated embalming of bodies for burial, and to do this the undertakers used an embalming technique that required intact carotid arteries.8 Dr Fisher was also surprised to find that his data on CAD had not been amply recognized in his new environment. He noted that pneumoencephalograms were still done at Massachusetts General Hospital for evaluation of TIAs in search of a brain tumor. This probably reflected the slower spread of information particular to that time. In addition, clinical diagnosis was rarely confirmed with angiography based on the risks inherent to the procedure. Only one case had been diagnosed with the use of angiography in Montreal by 1937. The contrast agent used was Thorotrast, and the patient developed thrombosis of the vessels of the face and scalp. Because of this unfortunate result, no further angiography studies were obtained at the Montreal Neurological Institute for a few years because the examination was considered "too dangerous." Angiography was done infrequently at the Boston City Hospital and Massachusetts General Hospital until 1951.
According to Dr Fisher, the most important study preceding his work on CAD was published by Krayenbühl and Weber9 in 1944. The authors reported 16 cases of carotid thrombosis in the neck, with 11 total occlusions of the internal carotid. The patients were studied with angiography and autopsy, and the main diagnosis considered was Buerger's disease. Dr Fisher still shows surprise when mentioning that "I knew Gustav Weber since 1949 but he never told me about their work on the carotid. We even dined together many times." He was sorry, feeling that time had been lost because they (unintentionally) had not shared their findings.
Little attention was given to the mechanisms of cerebrovascular disease until Dr Fisher published his clinicoanatomic correlations on occlusion of the carotid arteries.7 10 Until then, some 55% of strokes were thought to be caused by vasospasm. This was the reason why sympathectomy was the procedure of choice in CAD and most authors kept looking for a mechanism of spasm. A postulated similarity to "migraine and vasospasm" was the argument most commonly used to explain transient visual symptoms. Dr Fisher stated, "During those years, everything was spasm. At the time of the first paper on carotid occlusion I was trying to figure out how this disease caused vasospasm." The second article took 2 years to be published by the Archives of Neurology and Psychiatry, probably reflecting the controversy generated by these novel ideas. A chronological analysis of the data published between 1951 and 1962 unravels what led to the present understanding of CAD.
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1951—The Etiology: `Occlusion of the Internal Carotid Artery' |
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Impressed by 45 reports of internal carotid artery occlusion since the introduction of angiography and his own findings, Dr Fisher established the consideration of the extracranial carotid artery in cerebrovascular disease, stating that "indeed it may well prove to be one of the major causes of apoplexy."7 A few observations guided his thoughts: (1) he recognized that the study of general pathologists and neuropathologists most often excluded the neck vessels, turning this into a "no-man's land"; (2) despite the frequent clinical diagnosis of MCA thrombosis, Dr Fisher failed to find a single case of MCA thrombosis among 200 cases studied within a year; and (3) in a study of cerebral embolism, in some cases he could not find a source in the usual locations, namely, left atrium, ventricle, and aorta.
A few crucial statements on the clinical aspects of CAD resulted from this initial article based on the study of eight cases of carotid artery occlusion. Transient hemispheric and retinal attacks were associated with CAD for the first time in this landmark article. Dr Fisher described that hemiplegia, being the basic clinical feature of carotid artery occlusion, was usually preceded by "premonitory fleeting symptoms" including paresthesias, monocular blindness, and aphasia. He noted that dizziness, loss of consciousness, fecal and urinary incontinence, formed hallucinations, and seizures were rarely associated with CAD, and when present they were probably the result of coexistent undiagnosed neurological or vascular disease.
Dr Fisher was also the first to associate the occurrence of loss of vision in one eye, which he termed TUB, with ipsilateral CAD. He noted that permanent blindness did not accompany the onset of hemiplegia, observing that in most instances TUB occurred before hemiplegia, only rarely presenting after the stroke was completed. Dr Fisher was surprised that patients did not spontaneously complain about this symptom but rather described "trouble with my eyes" or "blurred vision" on being questioned. He also emphasized the sudden onset ("like a blind pulled down") and short duration of TUB. The fundi of these patients were not studied during the episodes of TUB. Dr Fisher reported fundi findings during TUB a few years later.11 One year after the publication of the 1951 article, Dr Fisher published another study in which he changed the term TUB to TMB, probably to emphasize eye involvement and avoid confusion with unilateral loss of vision from hemianopsia.12 In a recent article, Dr Fisher discouraged the use of the term "amaurosis fugax" instead of TMB, mainly because of the greater clarity, seniority, and proper language use of the latter.13
Despite some controversy at the time, Dr Fisher found palpation of the carotid artery of great diagnostic importance, especially if absent pulsations were found in the acute stage of a presumed occlusion. He indicated the importance of pulse palpation "as high up in the neck as possible" and the clinical usefulness of palpation of the temporal vessels which, if absent, suggested occlusion of the common carotid artery. Auscultation was performed routinely in the first CAD study, but no carotid bruits were identified.
Other conclusions of interest were as follows: "a large group of cases" in which arteriography revealed an irregular narrowing instead of occlusion; bilateral carotid artery occlusions in some patients; a normal contralateral artery in others; no concomitant disease in intracranial arteries; patients with occlusion at the level of the common carotid, probably resulting from occlusion at the bifurcation with retrograde thrombosis; frequent coexistence of coronary atherosclerosis, myocardial infarction, and peripheral vascular disease, supporting the notion that CAD was part of "generalized atherosclerosis"; and finally, the fact that the pattern of infarction in the MCA and ACA territories was not fully explained by the anatomy (ie, collateral supply) of the circle of Willis.
In describing the clinicopathologic features of CAD, Dr Fisher recalls the confusion present at that time when the proper correlation of autopsy, angiographic, and clinical data was unknown. He described, with a certain sense of humor, the first patient studied in 1950 who was examined at the neurology clinic of Queen Mary Veterans Hospital. It was this patient who provided the initial clues that led to the understanding of CAD. The patient was a 68-year-old man who, during the 2 months preceding a left hemiplegia, had suffered five or six episodes of TMB of the right eye. While describing these events, he said, "Isn't it funny that I went blind in the wrong eye? My paralysis is on the left and it was my right eye that went blind." Dr Fisher first thought that the symptoms might have been related to hemianopsia, only later considering the possibility of CAD. Only 1 week after the first patient was seen by Dr Fisher, another man was admitted with an identical history of stroke preceded by multiple episodes of TMB. The episodes occurred while he was "imbibing at his local tavern." When he told his friends about his problem, they said, "Don't worry, everybody has those things. It will be all right in a minute." And it was. "After these first two cases, I probably got on the right track," Dr Fisher said. The appearance of these spells suggested that they were related to the thrombotic process in the carotid artery and that something could be done to prevent them.
The opportunity to prove that carotid occlusion was the cause of the symptoms arose when the first patient died while Dr Fisher was away during one weekend. On Monday, he found that an autopsy had not been done. When he asked the medical staff why they did not request an autopsy, to his amazement the answer was that "the resident on call did not consider it necessary." The family had actually asked if an autopsy was to be done, and on those grounds Dr Fisher requested permission for the examination to be performed at the funeral home. Dr Fisher called the undertaker and "midnight witnessed" him obtaining the carotid arteries (Dr Fisher interjected humbly, "I was a neuropathologist at that time"). Finding an occluded artery in this patient did not mean much in those years when the first diagnosis considered was "spasm." However, this finding caused great excitement in Dr Fisher, who had in front of him the first case in which an internal carotid artery occlusion, proved at autopsy, had been clinically suspected on the basis of characteristic premonitory phenomena of TMB and hemiplegia. All that was left was to define the mechanism by which occlusion caused the transient phenomena. At that time, Dr Fisher started collecting clinical data associating CAD and TIAs, calling attention to the variable frequency of episodes ranging from 1 to 500 in different cases. This was probably his most important contribution to the understanding of cerebrovascular disease. Also, establishing the sequential correlation of prodromal symptoms and stroke, Dr Fisher defined a therapeutic window for the administration of medications. He further speculated on the use of anticoagulation to arrest transient attacks. Although Dr Fisher referred to treatment as a "subject where there is little definite to state," he laid the foundations for what became the most important and controversial subject in CAD, ie, carotid endarterectomy. ". . . [S]ome day vascular surgery will find a way to by-pass the occluded portion of the internal carotid artery during the period of ominous fleeting symptoms." With this statement, Dr Fisher predicted in 1951 the surgical treatment of CAD.7 It required more than 40 years thereafter to scientifically establish the proven benefits of carotid endarterectomy.14 15
A brief historical review outlines the advancements in the surgical treatment of CAD that preceded these novel ideas. Pare in 1552 was probably the first to report the surgical treatment of a carotid artery after he performed a ligation of the common carotid artery in a patient who developed aphasia and hemiplegia after the procedure.16 From 1900 to 1950, embolectomy and arterectomies were performed with variable but, in general, poor results.
The idea that stimulated current surgical techniques originated when a surgeon from New Orleans told Dr Fisher, "They are doing wonderful things these days; they bypass the occluded segments of the iliac artery." This comment, a conversation "at the luncheon table" at the Montreal General Hospital with Dr R.R. Fitzgerald, and his own interest in carotid disease prompted Dr Fisher to think about a possible surgical solution to carotid disease.
The first successful carotid reconstruction was completed on the basis of the 1951 article by Dr Fisher in which he stated, "Anastomosis of the external carotid artery, or one of its branches, with the internal carotid artery above the area of narrowing should be feasible." He could not explain how the idea of carotid reconstruction was visualized by the Argentinean neurosurgeon Carrea, but further research clarified this issue. The operation was performed in Buenos Aires, Argentina, when Murphy, a neurologist in Mendoza, evaluated a 51-year-old businessman who suffered a right hemiplegia and left eye blindness and diagnosed a severe stenosis of the internal carotid artery by means of a left percutaneous carotid angiography. Murphy consulted Carrea, who had recently been at the Neurological Institute of New York working with F.A. Mettler. Carrea had just read Dr Fisher's article in the Archives of Neurology and Psychiatry and decided to operate with Dr Mahels Molins, performing an excision of the affected arterial segment and an end-to-end anastomosis of the external to the internal carotid arteries. During surgery, "the internal carotid was cut 5 mm above the abnormal area, the external carotid was also cut at the same level and the proximal portion of the external carotid was anastomosed end to end to the distal portion of the internal carotid." Patency of the artery was confirmed postoperatively, and the patient, who remained blind but improved his strength on the right side, was followed for 27 years. Carrea published this case in the Acta Neurologica Latinoamericana 4 years later in 1955.17
In 1954, Eastcott, Pickering, and Robb18 published a report of a similar operation in Lancet. They resected a 3-cm thrombosed segment of the internal carotid artery origin and performed a direct end-to-end anastomosis between the common and the internal carotid arteries. Their patient, a 66-year-old woman who had suffered a total of 33 attacks of hemiparesis, aphasia, and amaurosis fugax, did not have any further episodes after surgery. To the question of how Eastcott in England thought of surgical reconstruction when the pathophysiology of carotid disease was not well known, Dr Fisher answered, "Well, I was at Queen's Square in July 1951 and made rounds with Sir Charles Symonds, who asked me, `Are you the one that wrote the paper on blocked carotid artery and transient blindness?' So he knew about it! It is not surprising that Eastcott knew as well. Robb had begun his surgical training in Montreal. Also, around that time, an English surgeon visited me in Montreal after touring most major surgical centers in the United States. The chief of surgery at McGill sent him to see me about my work on the carotids. From the comments of others I learned that this surgeon was quite impressed with the work I had been doing."
On the basis of the technique of endarterectomy introduced by Cid dos Santos19 in 1947 for atherosclerotic disease of the aortoiliac system, the first carotid endarterectomy was performed by Strully, Hurwitt, and Blankenberg20 on January 28, 1953, at the Montefiore Hospital in New York on a patient who had suffered a severe stroke 2 weeks earlier. Since no retrograde flow could be obtained from the cranial end, the vessel was ligated to prevent the risk of cerebral embolism. On August 7, 1953, DeBakey performed the first successful endarterectomy, but the operation was reported 22 years later.21 The patient was a 53-year-old man with TIAs who did not have angiography before surgery "because clinical suspicion of the stenosis was strong." The patient did not have recurrence of cerebrovascular disease until his death from a myocardial infarction 19 years later. In 1956, Cooley, Al-Naaman, and Carton22 performed and published the first report of a carotid endarterectomy.
In this first publication, Dr Fisher made a crucial step in permanently establishing the neglected concept of extracranial CAD as a cause of stroke. However, he could not define the mechanism of stroke and remained partially faithful to the "vasospasm" theory. Dr Fisher considered embolism as a possible mechanism, especially in "the rare cases in which hemiplegia has occurred during massage of the carotid sinus," and concluded that "unexplained cerebral embolism may arise from thrombotic material lying in the carotid sinus."
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1952—Clinical Findings: `Transient Monocular Blindness Associated With Hemiplegia' |
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In this detailed analysis of clinical and pathological data, Dr Fisher studied 7 patients with TMB to definitely settle the issue of "a sort of warning that disaster threatened."12 He also described 150 cases collected from the literature in which TMB was attributed to different causes (arteriosclerosis, spasm, migraine, Raynaud's disease, heart disease, reflex amaurosis, and arteritis) but was not related to CAD, although this was mentioned as a coexisting finding by a few authors. He attributed the perpetuation of wrong theories to the lack of pathological examinations and follow-up studies.
Under his clinical comments, Dr Fisher noted that upper retinal vessels were more prone to emboli than their lower counterparts. He again questioned the usefulness of auscultation, with only one of all the examined patients revealing a neck bruit. It is important to stress that all patients studied had carotid artery occlusions, a scenario that not infrequently presents without a bruit. Probably, in some of these cases consistent auscultation of the eyes could have revealed an ocular bruit opposite to the carotid occlusion. Dr Fisher suggested that a rough estimate of the decreased retinal artery pressure on the side of CAD could be obtained by gently pressing the lateral aspect of the eye globe with the index finger until blood flow ceased. Not believing that it was sufficiently safe, Dr Fisher cautioned against the routine use of cerebral angiography to confirm the clinical diagnosis of CAD, especially "after a cerebrovascular disaster has occurred."
Trying to elucidate the mechanism of TMB, Dr Fisher felt that there was "abundant" evidence against temporary interruption of blood flow to the eye and brain from a severely diseased carotid artery. The main arguments he enumerated were as follows: (1) if occlusion was responsible, then both eye and brain symptoms should occur at the same time, and (2) there were many reports in the literature of ligation of the internal and common carotid arteries without associated visual symptoms.
Dr Fisher concluded that "the physiologic concept which seems best to fit the clinical picture is vasospasm." This notion originated almost 100 years earlier, when Jackson12 used the term "retinal epilepsy" to label one of his patients suffering what retrospectively seems to be an episode of TMB that he attributed to vasospasm. Dr Fisher remained puzzled, however, about why vasospasm should show itself for long periods only in the central retinal artery and with the close relationship between vasospasm and the imminent occlusion that resulted in hemiplegia weeks or a few months after TMB. In a final remark he stated that "the exact relation of the carotid occlusion to the transient phenomena is far from clear."
In different paragraphs, Dr Fisher acknowledged that the natural history of CAD was highly variable. He therefore contributed to the epidemiology of cerebrovascular disease by recognizing the possibility of asymptomatic stenosis or occlusion of the carotid artery. In 1951, Johnson and Walker23 also reported that among 500 angiographic studies, six patients had total carotid artery occlusion and some were asymptomatic. In 1963, Faris et al24 added to these concepts with an angiographic study of healthy inmates in a Kansas prison, finding that approximately 50% had variable degrees of asymptomatic CAD.
Dr Fisher's 1952 article expands the basic theory of CAD, emphasizing its relation to TMB. It is interesting to note that the actual mechanism of transient phenomena in relation to CAD is almost in Dr Fisher's hands (he actually rejects it), but that the strong influence of older theories prevails in his analysis.
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1953—A (Very Special) Case Report: `Concerning Cerebral Vasospasm' |
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A 70-year-old woman described multiple, at times daily, episodes over a few months, which included tetraparesis, perioral numbness, dizziness, vomiting, and loss of vision.25 The clinical diagnosis was thrombosis of the basilar artery. In an attempt to arrest the attacks, anticoagulation was started with phenindione administered orally and heparin administered intramuscularly the first 24 hours. Not a single attack occurred for 33 days while she was on the medication. Three days after the medication was discontinued, she started having new episodes. Again, treatment completely controlled the attacks during 15 days, but the anticoagulation was stopped because of the limitations for good laboratory control of the prothrombin time after discharge. However, this time the patient was sent home with a placebo pill only to begin having episodes the same day that the prothrombin time became normal. The patient was again treated for 6 months, and because of her excellent response, anticoagulation was stopped with no recurrence of symptoms. The patient died 4 years later of a myocardial infarction. Occlusion of the basilar artery was confirmed at autopsy.
This study represents the first piece of evidence that strongly argued, in Dr Fisher's mind, against the vasospastic phenomenon. Dr Fisher stated, "Indeed it seems likely that the process in this case was related to the mechanism of coagulation or thrombosis of blood rather than to transient changes in the caliber of cerebral arteries." He linked transient episodes to the thrombotic process in contrast to embolism and cerebral hemorrhage, which "almost never occasion prodromal symptoms." Dr Fisher speculated on the role that thrombotic mechanisms, platelet aggregation, and erythrocytes could have had in the genesis of the patient's episodes. However, the final word had not arrived yet, as shown by the quasiparadoxical comment at the end of the article: "A case is presented in which attacks of cerebral vasospasm were clearly prevented by anticoagulant therapy. . . ."
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1954—The Mechanism: `Occlusion of the Carotid Arteries: Further Experiences' |
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In this article, Dr Fisher presented the study of 432 routine autopsies in which he detected a 9.5% incidence of severe CAD.10 Forty-five patients had occlusion of one or both carotid systems. However, Dr Fisher included a few cases that showed a "pinhole lumen" without total occlusion. He also reviewed 13 cases with severe stenosis but no associated symptoms and 4 cases of cerebral embolism (a subject he had reviewed with Dr Adams 3 years earlier) caused by dislodgment of material from ulcerated atherosclerotic plaques. The characteristics of the group analyzed contributed valuable information to the growing knowledge on CAD: (1) the concept of "stenosis" adds to the previously discussed 8 cases with occlusion; (2) asymptomatic stenosis is recognized as another possibility in the natural history of CAD; and (3) artery-to-artery embolism is documented.
Plaque behavior was one of the main subjects of interest in this study. Occlusion was felt to be the result of superimposed thrombosis or hemorrhage into the plaque. The difficulty in defining old embolus from plaque formation in situ, even under light microscopy, was recognized. When occlusion of the carotid artery occurred, thrombus from the plaque frequently extended to the cavernous sinus, at times even reaching the MCA or ACA. This could be differentiated pathologically from occlusions originating in the cavernous sinus with retrograde extension to the carotid bulb. A well-studied case gave evidence for the theory of embolism from ulcerated plaques: The patient had suffered a hemiplegia, and an embolus was found in the ipsilateral ACA. The carotid artery had a residual lumen of 0.5 mm, and the size of the embolus was greater than the artery's narrowed diameter; thus, the end of the plaque distal to the stenosis proved to be the origin of embolism. Dr Fisher extrapolated this previously unrecognized mechanism to other parts of the body in which emboli distal to arterial stenosis could affect organs such as the heart and limbs. His concern about plaque embolism led him to test for carotid sinus sensitivity "in a gentler fashion than is usually the case."
Dr Fisher arbitrarily proposed that a residual lumen of 0.5 mm was "significant" and that physiological studies on cerebral blood flow should be awaited to define this matter. He also posited that carotid artery occlusion was responsible for cases of "long, narrow infarctions" running from the frontal to occipital poles in the most distant territory of the MCA and ACA, accurately describing "watershed" or border zone infarctions.
Five of the 10 cases of bilateral carotid occlusion occurred in patients with senile dementia. It was a surprise to Dr Fisher that the arteries carrying most of the blood supply to both hemispheres had never been studied in relation to dementia. He felt that unilateral and bilateral carotid occlusions could explain some of the cases with senile dementia! The thorough knowledge achieved on the mechanisms of CAD during these first few years allowed a quantum leap into the treatment era.
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1958—Medical Treatment: `The Use of Anticoagulants in Cerebral Thrombosis' |
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Before Dr Fisher began to elucidate the mechanisms underlying carotid artery stroke, Hedenius,26 in 1941, reported "favorable" outcome in 5 of 18 patients treated with heparin for cerebral thrombosis. A prolonged gap followed these observations, until a few studies by different authors were completed on the basis of ideas reported by Dr Fisher in the 1951 article.27 28 29 After the previous successful experience with the patient with basilar artery thrombosis in 1953 and a few other anecdotal similar treatments, Dr Fisher planned a larger and more formal study. In 1958, he published the first controlled study of anticoagulation in cerebrovascular disease.30 He treated 58 patients belonging to different groups of (1) TIAs, (2) TIAs proceeding to permanent moderate sequelae, (3) TIAs following a permanent deficit, (4) progressing deficits, and (5) completed stroke. The mean duration of therapy was 6 months. Of 29 cases in the first three groups, TIAs ceased in 28 and attacks recurred in 12 of 20 cases in which anticoagulation was stopped. Satisfactory results were noted in 11 of 14 cases in group 4. Results in group 5 were "highly unsatisfactory." Aware of the limitations of a nonrandomized study, Dr Fisher thought that selecting a group of comparable patients as control subjects would serve as an "appraisal, albeit limited, of the efficacy of anticoagulant therapy." Thirty-seven patients with features of groups 1 to 5 were selected and did not receive treatment. When comparison of the groups was undertaken, results showed a far better outcome for the treated patients. The completion of "a large-scale systematic study of many more cases" needed to scientifically establish this issue, as suggested by Dr Fisher, is still awaited.
A few conclusions were drawn from the results obtained. Emphasis was placed on treating patients with increasing frequency of transient episodes and those with a less than maximal stroke (ie, with remaining territory at risk) where "trouble lies in store." Dr Fisher recommended early treatment to avoid delays that could result in vascular catastrophes unresponsive to anticoagulant treatment.
In another prophetic statement, Dr Fisher reported that anticoagulants did not cause hemorrhage in pale infarctions and that six cases of hemorrhagic infarctions were not aggravated by this treatment. These comments have had important implications for the tempo of embolic infarct treatment, since today any evidence of hemorrhagic conversion prompts discontinuation of anticoagulant treatment by many physicians. Dr Fisher concluded that "the data suggest that anticoagulant therapy abolishes transient ischemic attacks and prevents or postpones the arrival of the threatening stroke."
While large randomized, placebo-controlled trials were still in the future, Dr Fisher had a personal way to assign treatment to different patients with vascular disease. He carried a green and a red marble in the pocket of his lab coat, blindly selecting one to decide treatment based on green for yes, red for no. In 1961, he published a randomized study of anticoagulant treatment in patients with TIAs. The patients receiving anticoagulants experienced a total of 20 attacks, whereas those in the control group suffered 570 attacks.31
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1962—Further Clinical Thoughts: `Concerning Recurrent Transient Cerebral Ischemic Attacks' |
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"Straws which show how the intracranial wind is blowing": These words metaphorically reflected the transient deficits that could behave as the forerunners of disaster.32 Dr Fisher arbitrarily set the limit of 24 hours to define a cerebrovascular episode as a TIA and divided TIAs into three types: (1) single episode, (2) multiple stereotyped attacks, and (3) multiple attacks with different patterns. Thorough discussion was dedicated to the second type, which was attributed to atherosclerosis and thrombosis "reflecting repeated transient local ischemia." This type of TIA was distinguished from the other two types, which could be caused by other ischemic or hemorrhagic events.
A few clinical highlights of this article merit enumeration: (1) an early description of "limb shaking" as a result of CAD is given and differentiated from seizure activity; (2) anemia, hypertension, and postural hypotension are listed as precipitants of TIAs, although it seemed puzzling that "tilt-table testing failed to reproduce the attacks"; (3) TIAs are reported to occur more frequently in relation to activities when the patient is ambulating and stroke while the patient is sleeping; (4) TIAs occurring over a period of weeks or months are attributed to large-artery disease, and those spanning a few hours or days are more likely the result of penetrating artery disease; (5) the concept suggesting that the presence of symptoms and their extension over "days, weeks or months" depended to a significant extent on the development of efficient collateral circulation is expanded; and (6) clinical criteria for diagnosis of occlusion or stenosis of the carotid artery in "9 cases out of 10" are provided: (a) history of TMB, (b) absence of carotid pulse, and (c) a bruit over the ipsilateral carotid or contralateral orbit.
At this point, the theory of vasospasm had not only been abandoned, but a few arguments against it were considered, including the following: vasospasm associated with aneurysmal rupture, hyperventilation, and narrowing associated with arteritis never precipitate a TIA. Dr Fisher stated, "It is amazing how facts that today are readily obvious were ignored at that time." Reference to the patients' negligence in reporting transient deficits is made frequently in these articles. This could explain in part why TIAs preceding a stroke were rarely reported in the literature before Dr Fisher's articles.
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1976—The Mechanism Pendulum: `The Microembolic Theory of Transient Ischemic Attacks' |
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Controversy regarding the mechanisms causing carotid artery territory symptoms has persisted over the years. At one of the Princeton conferences, Dr Fisher was asked the following question by Dr Scheinberg: "Could I presume upon you to give us perhaps five reasons why TIAs are not embolic?" Dr Fisher answered, "I have for some time kept track of observations that are difficult to reconcile with fibrin-platelet emboli as the mechanism and have assembled 30-odd items, and here I am referring predominantly to recurrent TIAs lasting 10 minutes or less."33 A few examples are illustrative: even in a system with laminar blood flow, emboli from the heart do not follow a regular course; in vertebrobasilar TIAs with quadriplegia, an embolus should occlude the top of the basilar artery to provoke bilateral symptoms, and this would be unlikely without compromise of alertness and memory; shallow ulcerated carotid plaque lesions do not cause TIAs with the same pattern; the retina has been observed at the time of TMB without documentation of emboli; in bilateral vertebral artery occlusion, TIAs can occur for months or years without detection of a source for emboli; after a series of TIAs, if a stroke develops, it affects the parts involved by TIAs, suggesting a common mechanism for both; reports of personal cases with MCA or siphon stenosis show a marching numbness over the fingers with sharply changing symptoms from one finger to the next, which is unexpected in embolic mechanisms; longer duration of proven embolic TIAs versus short-lasting episodes (0.5 to 2 minutes) in hemodynamic deficits has been observed; TMB and a hemispheric TIA could be simultaneous, a circumstance against embolism; a patient with bilateral total carotid occlusion became bilaterally blind; a patient with 150 spells while on antihypertensive drugs had no episodes after the medication was discontinued; in the majority of cases, TIAs occur during activities such as walking and standing, which precipitate hemodynamic changes; in the subclavian steal syndrome (named by Dr Fisher), symptoms can occur by exercising the arm; arteriograms performed during the period of TIA occurrence have failed to show arterial embolic occlusions in some cases; the involvement of an arm in carotid stenosis TIA is consistent with a borderline, hemodynamic deficit; after carotid endarterectomy, the arterial surface is a bed of fibrin-platelet material but TIAs are almost unknown; in carotid dissection with a filiform lumen, TIAs occur in more than 75% of cases without visualization of a luminal thrombus; and when a proven embolus of cardiac origin gives rise to a flurry of stereotyped TIAs, it would be necessary to propose embolism from the embolus.
Dr Fisher ended by stating that this compilation of observations must not be construed as meaning that multiple TIAs are never embolic. However, his statements had been convincing enough, as suggested by the fact that the subject of the conversation after Dr Fisher's thorough presentation sharply changed to the American Aspirin Trial.
It was clear then that hemodynamic effects and embolism could be associated with transient and fixed carotid artery territory ischemia. It was also clear that the symptoms reflecting disease of the carotid artery did not predict the exact pathology but strongly suggested major occlusive disease.
Dr Fisher also pointed out the occurrence of asymptomatic internal carotid artery occlusion and contrasted it with MCA occlusion, which "is almost never without a prodrome." From these ideas derives the clinical observation that confronted with a patient who has head and eye deviation associated with hemiplegia and aphasia or neglect/anosognosia, suggesting extensive injury of the MCA territory, an etiology from internal CAD can be proposed only on the basis of embolus dislodgment with subsequent occlusion of the MCA stem. A case of internal carotid artery occlusion will not result in this extensive clinical presentation if occlusion of the MCA from artery-to-artery embolism does not also occur.
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1986—The Final Touch: `A Clinico-pathologic Study of Carotid Endarterectomy Plaques' |
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The management of nonstenotic, irregular lesions in the carotid artery has not been defined with the recently published studies on CAD. However, these lesions are frequently used as scapegoats when no other obvious cause for a cerebrovascular event is found. Unfortunately, these erroneous notions have been perpetuated by the finding of an "irregular, ugly" plaque at surgery that, many times, only proves to be innocent when symptoms recur after a successful endarterectomy is performed.
In his recent 1986 article with Ojemann, Dr Fisher studied 141 endarterectomy specimens of patients with different cerebrovascular syndromes, in which he performed 1000 to 3000 serial sections at a thickness of 8 to 10 µm.34 He analyzed the relationships among ulcers, mural thrombi, plaque hemorrhage, occlusion, near occlusion, and clinical findings. Dr Fisher concluded that in most cases large cavities were not associated with ulcerations and that mural thrombus and plaque hemorrhage were not commonly related to stroke.
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Conclusions |
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CAD is one of the best examples of clinical knowledge leading the way to a rational course of treatment.
We are indebted to Dr Fisher for reversing the nihilistic view of stroke. With clear, detailed observations he has unmasked the processes involved in CAD. It is no exaggeration to say that Dr Fisher's clinical observations provided the present guidelines for medical and surgical therapy in CAD.
Most of us have learned, from the literature or in person, the concepts born from his efforts. This is natural if we remember the words of Sir Isaac Newton: "If I have seen farther, it is by standing on the shoulders of giants."
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The teaching, advice, and guidance of Drs Lou Caplan and Mike Pessin during many years were the stimuli for this work. I am very grateful to Dr C. Miller Fisher for inspiring and reviewing this manuscript.
Received October 20, 1995; revision received November 27, 1995; accepted November 27, 1995.
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