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Diagnosis and Current Treatment of Strokes
Diagnosis and Current 'freatment of Strokes ROBERT G. SIEKERT CLARK H. MILLIKAN JACK P. WHISNANT
years have witnessed a renewed interest in diseases of the arteries in all parts of the body and, in particular, those to the brain. This interest has included re-examination of our methods of treatment for the various types of vascular disorders. This article will present a review of current treatment as it applies to the common diseases of the arteries supplying the brain. A stroke may be defined as an alteration in the blood supply to a particular region of the brain, with the production of focal neurologic symptoms or signs or both. These manifestations may be permanent or transitory, severe or minimal, depending on the cause and on the degree and duration that such cause is operative. The vessels themselves may be the site of primary changes which include inflammatory, degenerative, and congenital conditions, for example, syphilis, atherosclerosis and berry aneurysm, respectively. The disease may be primary elsewhere with secondary cerebral effects; that is, an embolus arising from a diseased cardiac valve and traveling to and blocking a cerebral artery. A combination of these may exist as, for instance, in surgical shock that portion of the brain supplied by a narrowed artery may be infarcted. It is to be appreciated that the various types of strokes may require different methods of treatment. To this end, then, careful diagnosis is important, and we will deal briefly with certain aspects of it. Despite the· multitude of causes that may be involved in cerebral vascular disease, two basic pathologic effects occur in the brain: (1) ischemia with or without infarction, and (2) hemorrhage. We will use this basic framework in our discussion. The outline is useful not only from the aspect of diagnosis but from the practical standpoint of treatment. RECENT
939
940
Robert G. Siekert, (}lark H. Millikan, Jack P. Whisnant CLASSIFICATION
I. Ischemia (focal) A. Without known infarction (intermittent ischemia) 1. Vertebral-basilar arterial system 2. Carotid arterial system B. Infarction 1. Thrombosis (vertebral-basilar and carotid arterial systems) 2. Embolism (vertebral-basilar and carotid arterial systems) 11. Hemorrhage A. Intracerebral B. Subarachnoid
The wide range of possibilities in any given syndrome should be noted, but in this brief review only the more common manifestations can be mentioned. Particular attention will be paid to the ischemic type because this is so common. No attempt will be made to review the more unusual causes or varieties of cerebral vascular disease. FOCAL CEREBRAL ISCHEMIA
Decrease or absence of arterial blood supply to a particular region of the brain results in focal cerebral ischemia (or anemia). If the decrease is minimal or rather transitory, no apparent infarction occurs. If the decrease is sufficiently great and persists long enough, a cerebral infarct results. Thus, on the one hand, neurologic abnormalities appear only transiently (intermittent insufficiency; sometimes called "spasm"), while on the other hand, neurologic abnormalities occur and remain to a greater or lesser degree. There obviously is some overlap between these two extremes. The amount of residual or permanent neurologic abnormality will depend on the severity of the ischemia, length of time this remains, surrounding edema, amount of collateral circulation, arterial blood pressure, cardiac output, and status of the dynamic clotting mechanism of the blood. The last three factors listed may be involved in the initiation of the ischemia. Even though a stroke is described as a single event under the appropriate heading, it is well to recall that an individual may suffer multiple strokes. A single one may be minimal, yet an increasing deficit may accrue with many such strokelets. The onset of focal cerebral ischemia may be abrupt or gradual. In the case of thrombosis the neurologic deficit usually develops over minutes or hours. The maximal deficit destined to occur may be reached within five or ten minutes, or occasionally within six to 12 hours, rarely longer. Progressive loss of focal cerebral function over a period exceeding four days is often the result of other causes than thrombosis. A stroke which consumes one or two days to develop has been termed a "slow stroke" and, if studied during this time, "a stroke in evolution" (Fischer). If an embolus is the basis of the focal cerebral anemia, the onset is
Diagnosis and Current Treatment of Strokes
941
abrupt. The diagnosis is dependent, of course, on a likely source of the embolic material and is aided by the appearance of embolic phenomena elsewhere. The anatomic syndromes produced by thrombosis and embolism are otherwise the same. Intermittent Insufficiency Within the Vertebral-Basilar Arterial System. 7, 12 This syndrome consists of transient attacks of neurologic abnormalities, the result of ischemia in this arterial field, with well-being between the episodes. The episodes last minutes to several hours, 10 to 20 minutes being the usual duration. The symptoms include vertigo, slurred speech, dysphagia, perioral numbness, bilateral decrease in vision and diplopia, and weakness or numbness of one or both limbs of a side, in various combinations. If the numbness or weakness shifts from side to side in separate attacks, this is characteristic. During an attack, appropriate neurologic abnormalities will be observed, while between attacks the neurologic examination reveals normal findings. I ntermittent I nsufficiency Within the Carotid A rterial System. 8 This syndrome also consists of transient episodes like those already mentioned which are manifested by various degrees of weakness and numbness or both, involving the limbs of one side. Aphasic abnormalities will occur if the dominant hemisphere is involved. A transient decrease in vision in only the eye on the side of the involved artery, with or without persistently lowered ophthalmodynamometric pressure,14 will occur in some instances. Examination during an episode will reveal appropriate abnormalities, while between attacks the examination shows normal findings. In some instances pulsation in the carotid artery in the neck will be decreased or absent. However, only when the pulsation on the appropriate side is markedly reduced, particularly as compared to that on the opposite side, or absent, have we found this sign to be of much aid in the diagnosis. The pulse of the carotid artery in the pharynx is too variable to be of help in diagnosis. In both of these syndromes of intermittent arterial insufficiency, a single episode may not be diagnostic. When a number of such episodes occur over weeks or months, the diagnosis can usually be made on clinical grounds. The diagnosis is made largely on the basis of the history unless an attack is observed. Occasionally, the differentiation between these two syndromes of insufficiency cannot be made. Thrombosis Within the Vertebral-Basilar Arterial System. Thrombosis of the basilar artery itself is characterized by quadriplegia, dysarthria, dysphagia, pupillary and oculorotatory abnormalities, decrease in vision, extensor spasms, marked sensory deficits over the face and limbs, and in later stages by coma and hyperpyrexia. Fragments of this syndrome are frequent early in the course of this condition, and over succeeding days or weeks the neurologic abnormalities may appear in steplike fashion presumably as the thrombus extends to occlude more arteries. A high
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Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
percentage of patients who die as a result of thrombosis of the basilar artery has previously had an insufficiency syndrome. ll The diagnosis is dependent on evidence that the lesion is in the field of supply of the vertebral-basilar complex which includes structures in the posterior cranial fossa, the posterior thalamus, and the calcarine area of the occipital lobes. Evidence that is useful in ascertaining that the lesion is in the territory of the vertebral and basilar arteries includes such signs as palsy of one or several of the muscles of ocular rotation, nystagmus, pupillary inequality or nonreaction, weakness of one entire side of the face (peripheral facial palsy), weakness of the masticatory muscles, loss of pain sensation in the face, cerebellar ataxia of the limbs, and palatal or lingual weakness. Thrombosis Within the Carotid A rterial System. Weakness or paralysis and sensory loss of one or both limbs of a side, weakness of the lower half of the face, and homonymous hemianopsia, all opposite to the side of the lesion, characterize this syndrome. The full picture is not necessarily present. Indeed, occlusive disease' of the carotid arterial system is extremely variable as to the degree of the abnormalities produced; one internal carotid artery might be completely closed without evident neurologic abnormality, or massive cerebral infarction may ensue with coma and death. If the lesion involves the dominant cerebral hemisphere, aphasic defects will be seen. Decrease in the pressure of the homolateral central retinal artery as measured by the ophthalmodynamometer may be present. Many patients who have occlusion of the internal carotid artery have had previously an insufficiency syndrome. 3 In some instances it may not be possible to distinguish between thrombosis in the vertebral-basilar and carotid arterial systems. In these four varieties of ischemia, results of laboratory studies are largely normal or provide no diagnostic aid except by their normalcy. Evidence of atherosclerosis elsewhere in the body is frequent but not universal. The skull itself appears normal in roentgenograms. Although evidence of calcification of the carotid artery may be seen, this may be seen also in patients with no cerebral symptoms. The spinal fluid is normal, although a slight increase in the protein level to 75mg. p~r 100 m!. is not infrequent. Values of more than 125 mg. per 100 ml. should suggest a need for caution in the diagnosis of cerebral ischemia. The electroencephalographic tracings will usually be abnormal in instances in which extensive infarction has occurred recently. However, there is not a direct relation between the clinical and the electroencephalographic findings. A normal or a minimally abnormal record is ordinarily seen in the syndromes of episodic arterial insufficiency. HEMORRHAGE
The abrupt onset of neurologic abnormalities-often severe and rapidly progressive-characterizes intracerebral or subarachnoid hemorrhage.
Diagnosis and Current Treatment of Strokes
943
Intracerebral. Massive bleeding into the substance of the brain is a common sequela of arterial hypertension. With the sudden appearance of such focal neurologic signs, as hemiplegia, there is usually some discomfort in the head and frequently altered consciousness. Within hours the abnormalities may progress and unconsciousness may supervene. The spinal fluid will be grossly bloody in about 75 per cent of the cases. Examination shows prominent neurologic deficits, hypertension, and hypertensive changes in the ocular fundus. Subarachnoid (Ruptured Berry Aneurysm). l"he onset is abrupt with severe pain in the head and neck, nausea and vomiting, and, in certain instances, focal neurologic signs and alteration in consciousness. Palsies of the cranial nerves, particularly those to the extraocular muscles, are common. Examination reveals evidence of focal neurologic deficit, stiff neck and often preretinal hemorrhages due to the sudden increase in intracranial pressure. The spinal fluid is uniformly bloody. DIFFERENTIAL DIAGNOSIS
The list of conditions that may have to be considered in the differential diagnosis of the various types of cerebral vascular disease can be extensive. When episodes of arterial insufficiency occur, convulsive disorders of various causes are the most prominent conditions to be considered in the differential diagnosis. With convulsive disorders the onset tends to be abrupt, awareness or consciousness usually is altered, and convulsive movements may occur. In general, the ischemic attack is characterized by the absence of something, such as strength, whereas the seizure is characterized by positive components, such as convulsive movements. The electroencephalogram may be helpful in distinguishing between these. Labyrinthitis, Meniere's disease, postural vertigo, tension or fatigue states, episodic metabolic disorders, expanding intracranial mass lesions and demyelinating diseases may need to be considered in the differential diagnosis at times. A careful history, examination, and appropriate laboratory studies will usually permit the correct diagnosis to be made. When permanent damage is evolving or has occurred, the list would include mass lesions such as tumor, epidural or subdural hematoma, and abscess, infectious processes such as encephalitis and meningitis, trauma, postictal state, and metabolic or electrolytic imbalance. By careful study the diagnosis can usually be established. Occasionally pneumoencephalography, ventriculography, and cerebral arteriography will have to be performed. Usually roentgenograms of the skull are normal in patients with strokes, and the pineal gland is in the midline. Rarely after a recent massive stroke, the involved hemisphere may be swollen and push the pineal body to the opposite side, in which instance differentiation be-
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Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
tween a stroke and an acutely expanding glioma may be extremely difficult. In patients who have had infarction some years ago with subsequent shrinkage of a cerebral hemisphere, the pineal body may be shifted to the side of the lesion. Electroencephalography may be of value to some extent in the over-all appraisal of a patient. A focal area of slow waves may be produced by any acute destructive lesion, regardless of the cause. With advancing lesions such as a mass lesion, the electroencephalographic abnormality worsens. Following infarctions, abnormal electrical activity may be present for weeks or months. Episodic insufficiency ordinarily produces little or no abnormality in the electroencephalogram which lends credence to the view that there is only minimal, if any, permanent structural damage to the brain. Other episodic disorders such as seizures due to a brain tumor often produce an abnormal electroencephalogram. Examinations of the blood and urine usually do not aid in differentiating the type of stroke. They do, however, aid in the general evaluation and subsequent management. of the patient. Electrolytic derangements, inflammatory conditions, anemia, polycythemia vera and diabetes mellitus may coexist with cerebral vascular disease. The apparent simultaneous onset of a cerebral and a myocardial infarction must be kept in mind. A patient who is concerned primarily with his hemiplegia may minimize previous or current cardiac symptoms. In addition to physical examination, the electrocardiogram should be employed in certain instances.
MANAGEMENT Associated Conditions
For patients with episodic cerebral vascular insufficiency, the usual methods of treatment should be employed for coexisting or associated conditions, such as obesity, diabetes mellitus, and cardiac disease. True or secondary polycythemia may be treated by venesection with cautious reduction of the volume of erythrocytes to between 50 and 55 per cent. Results of this procedure are frequently gratifying. Although the effect of hyperlipemia on the cerebral circulation is not known specifically, nonetheless, treatment directed toward the reduction of the fat content of the blood, if elevated, should be considered. A diet low in fat or foods containing unsaturated fatty acids and extremely large d05es of nicotinic acid may be employed in various combinations. These measures will not always reduce hyperlipemia. Other measures for these patients include the administration of papaverine hydrochloride and nicotinic acid in vasodilating dosages. If emotional tension appears to be associated with the episodes, mild sedation with phenobarbital or mephobarbital (Mebaral) will usually suffice. Tranquilizing drugs are rarely needed. Alcohol in moderate
Diagnosis and Current Treatment of Strokes
945
amounts is not interdicted. When excessive smoking seems associated with the occurrence of attacks, it should be curtailed. Two New Specific Measures
Two specific measures have been introduced recently for the management of the episodic syndromes. These are long-term anticoagulant therapy for both vertebral-basilar and carotid insufficiency and surgical procedures when the carotid artery is involved. Anticoagulant medication is effective in a high percentage of these patients and will be discussed separately later. Various surgical procedures on the carotid artery are being studied. These include thrombo-endarterectomy, excision of the diseased portion of the carotid artery with primary anastomosis or reconstruction with an arterial homograft or synthetic prosthesis, and bypass procedures using similar materials. 6 • 10 The type of operation will depend on the conditions present in each individual patient. Primary attention has been placed on the cervical portion of the carotid artery because of its accessibility. However, surgical procedures for the treatment of occlusive processes of the intracranial portion probably will be developed. Currently the most desirable patients for surgical treatment are those who present little or no evidence of brain damage, have only focal narrowing of the carotid artery at an accessible site, and are having frequent attacks. Carotid arteriography is needed to identify the site of the occlusive process and to indicate the status of the whole vascular tree. When complete occlusion near the bifurcation of the carotid artery is determined by angiography, the extent of the occlusion is almost impossible to ascertain. Operative intervention in these instances may not be as successful as in those in which focal narrowing is present in a currently accessible portion of the artery. The various surgical procedures are relatively new, and although the results cannot be stated as yet, there is great hope for the future. These procedures, however, will not restore already infarcted brain tissue. General Measures
If the neurologic deficit resulting from the cerebral infarction is minor, little general care is needed. Patients are ambulatory and able to care for themselves, and complications are nil. When hemiplegia, severe aphasia, and alteration in consciousness or mentality are present, careful attention to the general condition of the patient and the use of the usual therapeutic measures for the seriously ill are required. These are well known and only brief comment will be made. Adequate respiratory exchange with maintenance of an airway is essential. Frequent turning to aid expansion of the lungs and prevent hypostatic pneumonia, coupled with frequent suctioning, is the basic procedure. Insertion of the suctioning catheter into the upper reaches of
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Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
the larynx may stimulate coughing even in stuporous patients and thus aid in keeping the bronchial tree clear. Tracheotomy may be required when results of suctioning through the pharynx are inadequate and respiratory exchange is embarrassed. Occasionally plugs of mucus will have to be aspirated through a bronchoscope. Oxygen given by mask or tent is needed for patients with cyanosis, particularly when cardiac disease is also present. Atropine sulfate may be useful for an occasional patient with excessive secretion. An adequate caloric and electrolytic balance should be maintained. Intravenous administration of fluids will be adequate for several days, but after that administration of a balanced formula through a small plastic catheter passed through the nose into the stomach can be used. Urinary retention or incontinence or both in patients with altered sensorium or speech are best managed by an indwelling urinary catheter. Straight drainage is adequate for about a week, but if the catheter is to be left in place longer, intermittent clamping or tidal drainage should be employed. It is appropriate to use urinary disinfectants, such as sulfisoxazole (Gantrisin) and sulfamethoxypyridazine (Kynex), at the same time. The catheter should be irrigated daily and changed frequently. Attention must be paid to the bowels. Tap water enemas usually suffice when bowel action is inadequate. Oral cathartics frequently lead to soiling of the bed and maceration of the skin. Magnesium sulfate enemas may be used to reduce cerebral edema. Good nursing care with frequent turning and massage is essential in the attempt to prevent breakdown of the skin. Only rarely will sedatives be required for restlessness. We have found chloral hydrate and paraldehyde adequate. Appropriate antimicrobial therapy is employed if and when infection is present. Its routine use is not necessary. Mobilization of the patient and physical therapy should be started just as soon as possible. The involved limbs should be put through a normal range of movement three times a day. Unless contraindicated by associated conditions, patients are gotten up within a day, at first sitting on the edge of the bed, then in a chair and eventually standing, and if possible, in a few days, walking. Specific Measures
The specific treatment of strokes, of course, will depend on the type of abnormality noted. Efforts toward restoring the edge of an infarct (marginal zone) to function by such methods as stellate ganglion block and administration of histamine, papaverine, and nicotinic acid have been less effective than desired but may be tried. The inhalation of a mixture of 5 per cent carbon dioxide and 95 per cent oxygen may be of value. 6 Anticoagulant medication is indicated when the infarction is in the vertebral-basilar arterial system, in cases of actively advancing
Diagnosis and Current Treatment of Strokes
947
thrombosis with a steadily increasing deficit while under observation and when recurrent cerebral embolization occurs from associated heart disease. 16 Patients with intracerebral hemorrhage are treated by such general measures as already noted with the exception that mobilization of the patient is delayed for several days or until the neurologic defect and general condition appear stabilized. The administration of antihypertensive drugs is needed for those patients whose blood pressure is extremely high. Only rarely will it be possible to carry out surgical evacua.. tion of an intracerebral clot. The care of patients with subarachnoid hemorrhage includes conservative and surgical methods. Rest in bed for several weeks after active bleeding has stopped is the cardinal principle of the conservative regimen. To this are added, as necessary, mild sedation, adequate analgesia for headache, and tranquilizing drugs for nausea and vomiting. Straining should be avoided. Periodic drainage of the spinal fluid with cautious reduction of the pressure by a fourth to a half when it is elevated may help relieve headache. The fluid removed provides an index of any further bleeding. Hypothermia! and hypotension4 have been suggested as treatment of patients with subarachnoid hemorrhage. Hypothermia has been combined with early surgical attack on the aneurysm. Hypotension has been employed when bleeding continues. Whether an arteriogram should be performed immediately has not been decided. Most authorities delay this diagnostic procedure for several days. If an aneurysm is demonstrated in the arteriograms, a decision between surgical and conservative treatment will depend on multiple factors including the general condition of the patient, location of the aneurysm, number of previous bleedings, and extent of the neurologic deficit. Various types of surgical techniques are used, such as direct attack on the aneurysm by trapping, primary ligation or clipping, or an indirect attack by ligation of the major feeding vessel, as the carotid artery. The choice will be dictated by the situation. An aneurysm is not always demonstrated by carotid arteriography, and when no aneurysm is shown conservative care is used. Anticoagulant Medication
We have pointed out that anticoagulant medication can be used in certain carefully chosen categories of cerebrovascular diseases. It must be emphasized that the diagnosis should be as accurate as possible. Such medication would not be indicated when intracranial bleeding is present. Since anticoagulant therapy does not restore infarcted cerebral tissue, its value is nil after a completed stroke, that is, when the maximal deficit of function (hemiplegia) has already occurred. Anticoagulant medication is in a sense preventative-either prevention of the first infarction in
948
Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
insufficiency syndromes or prevention of extension of a developing infarct associated with basilar thrombosis or stroke in evolution. The indications for anticoagulant medication in cerebral vascular disease are as follows: 9 , 13 (1) the syndrome of intermittent insufficiency of the vertebral-basilar arterial system; (2) the syndrome of intermittent insufficiency of the carotid arterial system; (3) thrombosis within the vertebral-basilar arterial system; (4) slow stroke (stroke in evolution), and (5) thrombo-embolic disorders (Wright and McDevitt). Elsewhere 9 we have presented data to indicate the usefulness of anticoagulants in the first four categories (indications) just listed. The ischemic attacks ceased in approximately 95 per cent of the patients in both of the groups having insufficiency states who were given anticoagulant therapy. The mortality rate in a group of patients with thrombosis within the vertebral-basilar arterial system was 8 per cent when they were treated with anticoagulants; in a contrast group (not treated with anticoagulants) the mortality rate was 58 per cent. Six per cent of a group of patients with a stroke in evolution, that is, actively advancing while being observed, developed hemiplegia or died while receiving anticoagulant medication as compared to a contrast group without such treatment in whom 35 per cent developed hemiplegia or died. Our experience with the use of anticoagulant medication for patients having thrombo-embolic episodes secondary to cardiac disease is inadequate. However, on the basis of the work by Wright and McDevitt we include this category in the list of indications for anticoagulant therapy. When the diagnosis of one of the insufficiency syndromes is established, anticoagulant medication is begun except in those patients who have had only one episode of insufficiency. In these latter patients provisions for such treatment are made in the event that further attacks occur. Ordinarily 900 to 1200 mg. of ethyl biscoumacetate (Tromexan Ethyl Acetate) and 200 to 300 mg. of bishydroxycoumarin (Dicumarol) are given the first day and subsequently only Dicumarol, with the dosage adjusted to the prothrombin time. When attacks are occurring in rapid succession, the treatment is started on an emergency basis with the intravenous administration of heparin (50 mg. every four hours) for the first 36 to 48 hours in addition to Tromexan and Dicumarol. Patients who have only minor neurologic deficits on the basis of infarction are observed carefully over the next few hours. If no further increase in neurologic deficit takes place, anticoagulants are not used. If the abnormalities increase but are still not absolute, anticoagulant therapy is instituted with all three drugs. These are the strokes in evolution. When the diagnosis of infarction within the vertebral-basilar system is made, anticoagulation is begun immediately. The outlook for these patients is grim without treatment and, furthermore, the development
Diagnosis and Current Treatment of Strokes
949
of these strokes is not always smooth but irregularly cumulative, so that further observation delays institution of treatment. The cooperation of the patient, experience of the physician, and proper laboratory assistance in determination of prothrombin times are essential for long-term anticoagulant therapy. The optimal duration of this treatment is unknown. It is our current practice to evaluate each patient individually, but in general to discontinue the medication after six to 12 months. At this time adequate provision is made for reinstitution of the medication should further difficulty ensue. Contraindications to anticoagulant therapy include blood dyscrasias, disease of the liver or kidneys and potential bleeding sites. Such contraindications are relative, and each case has to be decided on its merits. Subacute bacterial endocarditis is, of course, a definite contraindication to anticoagulant therapy. REFERENCES 1. Botterell, E. H., Lougheed, W. M., Scott, J. W. and Vandewater, S. L.: Hypothermia and-Interruption of Carotid, or Carotid and Vertebral Circulation, in the Surgical Management of Intracranial Aneurysms. J. Neurosurg. 13: 1-42 (Jan.) 1956. 2. Fischer, C. Miller: Personal communication to the authors. 3. Johnson, H. C. and Walker, A. E.: The Angiographic Diagnosis of Spontaneous Thrombosis of the Internal and Common Carotid Arteries. J. Neurosurg. 8: 631-659 (Nov.) 1951. 4. Little, D. M.: "Controlled Hypotension" in Anesthesia and Surgery. Springfield, Illinois, Charles C Thomas, 1956, 159 pp. 5. Lyons, Champ and Galbraith, J. G.: Surgical Treatment of Internal Carotid Occlusion. J.M.A. Alabama 27: 1-4 (July) 1957. 6. Millikan, C. H.: Evaluation of Carbon Dioxide Inhalation for Acute Focal Cerebral Infarction. A.M.A. Arch. Neurol. & Psychiat. 73: 324-328 (March) 1955. 7. Millikan, C. H. and Siekert, R. G.: Studies in Cerebrovascular Disease. T. The Syndrome of Intermittent Insufficiency of the Basilar Arterial System. Proc. Staff Meet., Mayo Clin. 30: 61-68 (Feb. 23) 1955. 8. Millikan, C. H. and Siekert, R. G.: Studies in Cerebrovascular Disease. IV. The Syndrome of Intermittent Insufficiency of the Carotid Arterial System. Proc. Staff Meet., Mayo Clin. 30: 186-191 (May 4) 1955. 9. Millikan, C. H., Siekert, R. G. and Whisnant, J. P.: Anticoagulant Therapy in Cerebral Vascular Disease: Current Status. J.A.M.A. 166: 587-592 (Feb. 8) 1958. 10. Rob, Charles and Wheeler, E. B.: Thrombosis of Internal Carotid Artery Treated by Arterial Surgery. Brit. M. J. 2: 264-266 (Aug. 3) 1957. 11. Siekert, R. G. and Millikan, C. H.: Studies in Cerebrovascular Disease. II. Some Clinical Aspects of Thrombosis of the Basilar Artery. Proc. Staff Meet., Mayo Clin. 30: 93-100 (March 9) 1955. 12. Siekert, R. G. and Millikan, C. H.: Syndrome of Intermittent Insufficiency of the Basilar Arterial System. Neurology 5: 625-630 (Sept.) 1955. 13. Siekert, R. G., Millikan, C. H. and Shick, R. M.: Current Indications for the Use of Anticoagulant Drugs in Cerebrovascular Disease. Circulation 13: 725728 (May) 1956. 14. Svien, H. J. and Hollenhorst, R. W_: Pressure in Retinal Arteries After Ligation or Occlusion of the Carotid Artery. Proe. Staff Meet., Mayo Clin. 31: 684692 (Dec. 26) 1956. 15. Wright, I. S. and McDevitt, Ellen: Cerebral Vascular Diseases: Their Significance, Diagnosis and Present Treatment, Including the Selective Use of Anticoagulant Substances. Ann. Int. Med. 4.1: 682-698 (Oct.) 1954.
years have witnessed a renewed interest in diseases of the arteries in all parts of the body and, in particular, those to the brain. This interest has included re-examination of our methods of treatment for the various types of vascular disorders. This article will present a review of current treatment as it applies to the common diseases of the arteries supplying the brain. A stroke may be defined as an alteration in the blood supply to a particular region of the brain, with the production of focal neurologic symptoms or signs or both. These manifestations may be permanent or transitory, severe or minimal, depending on the cause and on the degree and duration that such cause is operative. The vessels themselves may be the site of primary changes which include inflammatory, degenerative, and congenital conditions, for example, syphilis, atherosclerosis and berry aneurysm, respectively. The disease may be primary elsewhere with secondary cerebral effects; that is, an embolus arising from a diseased cardiac valve and traveling to and blocking a cerebral artery. A combination of these may exist as, for instance, in surgical shock that portion of the brain supplied by a narrowed artery may be infarcted. It is to be appreciated that the various types of strokes may require different methods of treatment. To this end, then, careful diagnosis is important, and we will deal briefly with certain aspects of it. Despite the· multitude of causes that may be involved in cerebral vascular disease, two basic pathologic effects occur in the brain: (1) ischemia with or without infarction, and (2) hemorrhage. We will use this basic framework in our discussion. The outline is useful not only from the aspect of diagnosis but from the practical standpoint of treatment. RECENT
939
940
Robert G. Siekert, (}lark H. Millikan, Jack P. Whisnant CLASSIFICATION
I. Ischemia (focal) A. Without known infarction (intermittent ischemia) 1. Vertebral-basilar arterial system 2. Carotid arterial system B. Infarction 1. Thrombosis (vertebral-basilar and carotid arterial systems) 2. Embolism (vertebral-basilar and carotid arterial systems) 11. Hemorrhage A. Intracerebral B. Subarachnoid
The wide range of possibilities in any given syndrome should be noted, but in this brief review only the more common manifestations can be mentioned. Particular attention will be paid to the ischemic type because this is so common. No attempt will be made to review the more unusual causes or varieties of cerebral vascular disease. FOCAL CEREBRAL ISCHEMIA
Decrease or absence of arterial blood supply to a particular region of the brain results in focal cerebral ischemia (or anemia). If the decrease is minimal or rather transitory, no apparent infarction occurs. If the decrease is sufficiently great and persists long enough, a cerebral infarct results. Thus, on the one hand, neurologic abnormalities appear only transiently (intermittent insufficiency; sometimes called "spasm"), while on the other hand, neurologic abnormalities occur and remain to a greater or lesser degree. There obviously is some overlap between these two extremes. The amount of residual or permanent neurologic abnormality will depend on the severity of the ischemia, length of time this remains, surrounding edema, amount of collateral circulation, arterial blood pressure, cardiac output, and status of the dynamic clotting mechanism of the blood. The last three factors listed may be involved in the initiation of the ischemia. Even though a stroke is described as a single event under the appropriate heading, it is well to recall that an individual may suffer multiple strokes. A single one may be minimal, yet an increasing deficit may accrue with many such strokelets. The onset of focal cerebral ischemia may be abrupt or gradual. In the case of thrombosis the neurologic deficit usually develops over minutes or hours. The maximal deficit destined to occur may be reached within five or ten minutes, or occasionally within six to 12 hours, rarely longer. Progressive loss of focal cerebral function over a period exceeding four days is often the result of other causes than thrombosis. A stroke which consumes one or two days to develop has been termed a "slow stroke" and, if studied during this time, "a stroke in evolution" (Fischer). If an embolus is the basis of the focal cerebral anemia, the onset is
Diagnosis and Current Treatment of Strokes
941
abrupt. The diagnosis is dependent, of course, on a likely source of the embolic material and is aided by the appearance of embolic phenomena elsewhere. The anatomic syndromes produced by thrombosis and embolism are otherwise the same. Intermittent Insufficiency Within the Vertebral-Basilar Arterial System. 7, 12 This syndrome consists of transient attacks of neurologic abnormalities, the result of ischemia in this arterial field, with well-being between the episodes. The episodes last minutes to several hours, 10 to 20 minutes being the usual duration. The symptoms include vertigo, slurred speech, dysphagia, perioral numbness, bilateral decrease in vision and diplopia, and weakness or numbness of one or both limbs of a side, in various combinations. If the numbness or weakness shifts from side to side in separate attacks, this is characteristic. During an attack, appropriate neurologic abnormalities will be observed, while between attacks the neurologic examination reveals normal findings. I ntermittent I nsufficiency Within the Carotid A rterial System. 8 This syndrome also consists of transient episodes like those already mentioned which are manifested by various degrees of weakness and numbness or both, involving the limbs of one side. Aphasic abnormalities will occur if the dominant hemisphere is involved. A transient decrease in vision in only the eye on the side of the involved artery, with or without persistently lowered ophthalmodynamometric pressure,14 will occur in some instances. Examination during an episode will reveal appropriate abnormalities, while between attacks the examination shows normal findings. In some instances pulsation in the carotid artery in the neck will be decreased or absent. However, only when the pulsation on the appropriate side is markedly reduced, particularly as compared to that on the opposite side, or absent, have we found this sign to be of much aid in the diagnosis. The pulse of the carotid artery in the pharynx is too variable to be of help in diagnosis. In both of these syndromes of intermittent arterial insufficiency, a single episode may not be diagnostic. When a number of such episodes occur over weeks or months, the diagnosis can usually be made on clinical grounds. The diagnosis is made largely on the basis of the history unless an attack is observed. Occasionally, the differentiation between these two syndromes of insufficiency cannot be made. Thrombosis Within the Vertebral-Basilar Arterial System. Thrombosis of the basilar artery itself is characterized by quadriplegia, dysarthria, dysphagia, pupillary and oculorotatory abnormalities, decrease in vision, extensor spasms, marked sensory deficits over the face and limbs, and in later stages by coma and hyperpyrexia. Fragments of this syndrome are frequent early in the course of this condition, and over succeeding days or weeks the neurologic abnormalities may appear in steplike fashion presumably as the thrombus extends to occlude more arteries. A high
942
Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
percentage of patients who die as a result of thrombosis of the basilar artery has previously had an insufficiency syndrome. ll The diagnosis is dependent on evidence that the lesion is in the field of supply of the vertebral-basilar complex which includes structures in the posterior cranial fossa, the posterior thalamus, and the calcarine area of the occipital lobes. Evidence that is useful in ascertaining that the lesion is in the territory of the vertebral and basilar arteries includes such signs as palsy of one or several of the muscles of ocular rotation, nystagmus, pupillary inequality or nonreaction, weakness of one entire side of the face (peripheral facial palsy), weakness of the masticatory muscles, loss of pain sensation in the face, cerebellar ataxia of the limbs, and palatal or lingual weakness. Thrombosis Within the Carotid A rterial System. Weakness or paralysis and sensory loss of one or both limbs of a side, weakness of the lower half of the face, and homonymous hemianopsia, all opposite to the side of the lesion, characterize this syndrome. The full picture is not necessarily present. Indeed, occlusive disease' of the carotid arterial system is extremely variable as to the degree of the abnormalities produced; one internal carotid artery might be completely closed without evident neurologic abnormality, or massive cerebral infarction may ensue with coma and death. If the lesion involves the dominant cerebral hemisphere, aphasic defects will be seen. Decrease in the pressure of the homolateral central retinal artery as measured by the ophthalmodynamometer may be present. Many patients who have occlusion of the internal carotid artery have had previously an insufficiency syndrome. 3 In some instances it may not be possible to distinguish between thrombosis in the vertebral-basilar and carotid arterial systems. In these four varieties of ischemia, results of laboratory studies are largely normal or provide no diagnostic aid except by their normalcy. Evidence of atherosclerosis elsewhere in the body is frequent but not universal. The skull itself appears normal in roentgenograms. Although evidence of calcification of the carotid artery may be seen, this may be seen also in patients with no cerebral symptoms. The spinal fluid is normal, although a slight increase in the protein level to 75mg. p~r 100 m!. is not infrequent. Values of more than 125 mg. per 100 ml. should suggest a need for caution in the diagnosis of cerebral ischemia. The electroencephalographic tracings will usually be abnormal in instances in which extensive infarction has occurred recently. However, there is not a direct relation between the clinical and the electroencephalographic findings. A normal or a minimally abnormal record is ordinarily seen in the syndromes of episodic arterial insufficiency. HEMORRHAGE
The abrupt onset of neurologic abnormalities-often severe and rapidly progressive-characterizes intracerebral or subarachnoid hemorrhage.
Diagnosis and Current Treatment of Strokes
943
Intracerebral. Massive bleeding into the substance of the brain is a common sequela of arterial hypertension. With the sudden appearance of such focal neurologic signs, as hemiplegia, there is usually some discomfort in the head and frequently altered consciousness. Within hours the abnormalities may progress and unconsciousness may supervene. The spinal fluid will be grossly bloody in about 75 per cent of the cases. Examination shows prominent neurologic deficits, hypertension, and hypertensive changes in the ocular fundus. Subarachnoid (Ruptured Berry Aneurysm). l"he onset is abrupt with severe pain in the head and neck, nausea and vomiting, and, in certain instances, focal neurologic signs and alteration in consciousness. Palsies of the cranial nerves, particularly those to the extraocular muscles, are common. Examination reveals evidence of focal neurologic deficit, stiff neck and often preretinal hemorrhages due to the sudden increase in intracranial pressure. The spinal fluid is uniformly bloody. DIFFERENTIAL DIAGNOSIS
The list of conditions that may have to be considered in the differential diagnosis of the various types of cerebral vascular disease can be extensive. When episodes of arterial insufficiency occur, convulsive disorders of various causes are the most prominent conditions to be considered in the differential diagnosis. With convulsive disorders the onset tends to be abrupt, awareness or consciousness usually is altered, and convulsive movements may occur. In general, the ischemic attack is characterized by the absence of something, such as strength, whereas the seizure is characterized by positive components, such as convulsive movements. The electroencephalogram may be helpful in distinguishing between these. Labyrinthitis, Meniere's disease, postural vertigo, tension or fatigue states, episodic metabolic disorders, expanding intracranial mass lesions and demyelinating diseases may need to be considered in the differential diagnosis at times. A careful history, examination, and appropriate laboratory studies will usually permit the correct diagnosis to be made. When permanent damage is evolving or has occurred, the list would include mass lesions such as tumor, epidural or subdural hematoma, and abscess, infectious processes such as encephalitis and meningitis, trauma, postictal state, and metabolic or electrolytic imbalance. By careful study the diagnosis can usually be established. Occasionally pneumoencephalography, ventriculography, and cerebral arteriography will have to be performed. Usually roentgenograms of the skull are normal in patients with strokes, and the pineal gland is in the midline. Rarely after a recent massive stroke, the involved hemisphere may be swollen and push the pineal body to the opposite side, in which instance differentiation be-
944
Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
tween a stroke and an acutely expanding glioma may be extremely difficult. In patients who have had infarction some years ago with subsequent shrinkage of a cerebral hemisphere, the pineal body may be shifted to the side of the lesion. Electroencephalography may be of value to some extent in the over-all appraisal of a patient. A focal area of slow waves may be produced by any acute destructive lesion, regardless of the cause. With advancing lesions such as a mass lesion, the electroencephalographic abnormality worsens. Following infarctions, abnormal electrical activity may be present for weeks or months. Episodic insufficiency ordinarily produces little or no abnormality in the electroencephalogram which lends credence to the view that there is only minimal, if any, permanent structural damage to the brain. Other episodic disorders such as seizures due to a brain tumor often produce an abnormal electroencephalogram. Examinations of the blood and urine usually do not aid in differentiating the type of stroke. They do, however, aid in the general evaluation and subsequent management. of the patient. Electrolytic derangements, inflammatory conditions, anemia, polycythemia vera and diabetes mellitus may coexist with cerebral vascular disease. The apparent simultaneous onset of a cerebral and a myocardial infarction must be kept in mind. A patient who is concerned primarily with his hemiplegia may minimize previous or current cardiac symptoms. In addition to physical examination, the electrocardiogram should be employed in certain instances.
MANAGEMENT Associated Conditions
For patients with episodic cerebral vascular insufficiency, the usual methods of treatment should be employed for coexisting or associated conditions, such as obesity, diabetes mellitus, and cardiac disease. True or secondary polycythemia may be treated by venesection with cautious reduction of the volume of erythrocytes to between 50 and 55 per cent. Results of this procedure are frequently gratifying. Although the effect of hyperlipemia on the cerebral circulation is not known specifically, nonetheless, treatment directed toward the reduction of the fat content of the blood, if elevated, should be considered. A diet low in fat or foods containing unsaturated fatty acids and extremely large d05es of nicotinic acid may be employed in various combinations. These measures will not always reduce hyperlipemia. Other measures for these patients include the administration of papaverine hydrochloride and nicotinic acid in vasodilating dosages. If emotional tension appears to be associated with the episodes, mild sedation with phenobarbital or mephobarbital (Mebaral) will usually suffice. Tranquilizing drugs are rarely needed. Alcohol in moderate
Diagnosis and Current Treatment of Strokes
945
amounts is not interdicted. When excessive smoking seems associated with the occurrence of attacks, it should be curtailed. Two New Specific Measures
Two specific measures have been introduced recently for the management of the episodic syndromes. These are long-term anticoagulant therapy for both vertebral-basilar and carotid insufficiency and surgical procedures when the carotid artery is involved. Anticoagulant medication is effective in a high percentage of these patients and will be discussed separately later. Various surgical procedures on the carotid artery are being studied. These include thrombo-endarterectomy, excision of the diseased portion of the carotid artery with primary anastomosis or reconstruction with an arterial homograft or synthetic prosthesis, and bypass procedures using similar materials. 6 • 10 The type of operation will depend on the conditions present in each individual patient. Primary attention has been placed on the cervical portion of the carotid artery because of its accessibility. However, surgical procedures for the treatment of occlusive processes of the intracranial portion probably will be developed. Currently the most desirable patients for surgical treatment are those who present little or no evidence of brain damage, have only focal narrowing of the carotid artery at an accessible site, and are having frequent attacks. Carotid arteriography is needed to identify the site of the occlusive process and to indicate the status of the whole vascular tree. When complete occlusion near the bifurcation of the carotid artery is determined by angiography, the extent of the occlusion is almost impossible to ascertain. Operative intervention in these instances may not be as successful as in those in which focal narrowing is present in a currently accessible portion of the artery. The various surgical procedures are relatively new, and although the results cannot be stated as yet, there is great hope for the future. These procedures, however, will not restore already infarcted brain tissue. General Measures
If the neurologic deficit resulting from the cerebral infarction is minor, little general care is needed. Patients are ambulatory and able to care for themselves, and complications are nil. When hemiplegia, severe aphasia, and alteration in consciousness or mentality are present, careful attention to the general condition of the patient and the use of the usual therapeutic measures for the seriously ill are required. These are well known and only brief comment will be made. Adequate respiratory exchange with maintenance of an airway is essential. Frequent turning to aid expansion of the lungs and prevent hypostatic pneumonia, coupled with frequent suctioning, is the basic procedure. Insertion of the suctioning catheter into the upper reaches of
946
Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
the larynx may stimulate coughing even in stuporous patients and thus aid in keeping the bronchial tree clear. Tracheotomy may be required when results of suctioning through the pharynx are inadequate and respiratory exchange is embarrassed. Occasionally plugs of mucus will have to be aspirated through a bronchoscope. Oxygen given by mask or tent is needed for patients with cyanosis, particularly when cardiac disease is also present. Atropine sulfate may be useful for an occasional patient with excessive secretion. An adequate caloric and electrolytic balance should be maintained. Intravenous administration of fluids will be adequate for several days, but after that administration of a balanced formula through a small plastic catheter passed through the nose into the stomach can be used. Urinary retention or incontinence or both in patients with altered sensorium or speech are best managed by an indwelling urinary catheter. Straight drainage is adequate for about a week, but if the catheter is to be left in place longer, intermittent clamping or tidal drainage should be employed. It is appropriate to use urinary disinfectants, such as sulfisoxazole (Gantrisin) and sulfamethoxypyridazine (Kynex), at the same time. The catheter should be irrigated daily and changed frequently. Attention must be paid to the bowels. Tap water enemas usually suffice when bowel action is inadequate. Oral cathartics frequently lead to soiling of the bed and maceration of the skin. Magnesium sulfate enemas may be used to reduce cerebral edema. Good nursing care with frequent turning and massage is essential in the attempt to prevent breakdown of the skin. Only rarely will sedatives be required for restlessness. We have found chloral hydrate and paraldehyde adequate. Appropriate antimicrobial therapy is employed if and when infection is present. Its routine use is not necessary. Mobilization of the patient and physical therapy should be started just as soon as possible. The involved limbs should be put through a normal range of movement three times a day. Unless contraindicated by associated conditions, patients are gotten up within a day, at first sitting on the edge of the bed, then in a chair and eventually standing, and if possible, in a few days, walking. Specific Measures
The specific treatment of strokes, of course, will depend on the type of abnormality noted. Efforts toward restoring the edge of an infarct (marginal zone) to function by such methods as stellate ganglion block and administration of histamine, papaverine, and nicotinic acid have been less effective than desired but may be tried. The inhalation of a mixture of 5 per cent carbon dioxide and 95 per cent oxygen may be of value. 6 Anticoagulant medication is indicated when the infarction is in the vertebral-basilar arterial system, in cases of actively advancing
Diagnosis and Current Treatment of Strokes
947
thrombosis with a steadily increasing deficit while under observation and when recurrent cerebral embolization occurs from associated heart disease. 16 Patients with intracerebral hemorrhage are treated by such general measures as already noted with the exception that mobilization of the patient is delayed for several days or until the neurologic defect and general condition appear stabilized. The administration of antihypertensive drugs is needed for those patients whose blood pressure is extremely high. Only rarely will it be possible to carry out surgical evacua.. tion of an intracerebral clot. The care of patients with subarachnoid hemorrhage includes conservative and surgical methods. Rest in bed for several weeks after active bleeding has stopped is the cardinal principle of the conservative regimen. To this are added, as necessary, mild sedation, adequate analgesia for headache, and tranquilizing drugs for nausea and vomiting. Straining should be avoided. Periodic drainage of the spinal fluid with cautious reduction of the pressure by a fourth to a half when it is elevated may help relieve headache. The fluid removed provides an index of any further bleeding. Hypothermia! and hypotension4 have been suggested as treatment of patients with subarachnoid hemorrhage. Hypothermia has been combined with early surgical attack on the aneurysm. Hypotension has been employed when bleeding continues. Whether an arteriogram should be performed immediately has not been decided. Most authorities delay this diagnostic procedure for several days. If an aneurysm is demonstrated in the arteriograms, a decision between surgical and conservative treatment will depend on multiple factors including the general condition of the patient, location of the aneurysm, number of previous bleedings, and extent of the neurologic deficit. Various types of surgical techniques are used, such as direct attack on the aneurysm by trapping, primary ligation or clipping, or an indirect attack by ligation of the major feeding vessel, as the carotid artery. The choice will be dictated by the situation. An aneurysm is not always demonstrated by carotid arteriography, and when no aneurysm is shown conservative care is used. Anticoagulant Medication
We have pointed out that anticoagulant medication can be used in certain carefully chosen categories of cerebrovascular diseases. It must be emphasized that the diagnosis should be as accurate as possible. Such medication would not be indicated when intracranial bleeding is present. Since anticoagulant therapy does not restore infarcted cerebral tissue, its value is nil after a completed stroke, that is, when the maximal deficit of function (hemiplegia) has already occurred. Anticoagulant medication is in a sense preventative-either prevention of the first infarction in
948
Robert G. Siekert, Clark H. Millikan, Jack P. Whisnant
insufficiency syndromes or prevention of extension of a developing infarct associated with basilar thrombosis or stroke in evolution. The indications for anticoagulant medication in cerebral vascular disease are as follows: 9 , 13 (1) the syndrome of intermittent insufficiency of the vertebral-basilar arterial system; (2) the syndrome of intermittent insufficiency of the carotid arterial system; (3) thrombosis within the vertebral-basilar arterial system; (4) slow stroke (stroke in evolution), and (5) thrombo-embolic disorders (Wright and McDevitt). Elsewhere 9 we have presented data to indicate the usefulness of anticoagulants in the first four categories (indications) just listed. The ischemic attacks ceased in approximately 95 per cent of the patients in both of the groups having insufficiency states who were given anticoagulant therapy. The mortality rate in a group of patients with thrombosis within the vertebral-basilar arterial system was 8 per cent when they were treated with anticoagulants; in a contrast group (not treated with anticoagulants) the mortality rate was 58 per cent. Six per cent of a group of patients with a stroke in evolution, that is, actively advancing while being observed, developed hemiplegia or died while receiving anticoagulant medication as compared to a contrast group without such treatment in whom 35 per cent developed hemiplegia or died. Our experience with the use of anticoagulant medication for patients having thrombo-embolic episodes secondary to cardiac disease is inadequate. However, on the basis of the work by Wright and McDevitt we include this category in the list of indications for anticoagulant therapy. When the diagnosis of one of the insufficiency syndromes is established, anticoagulant medication is begun except in those patients who have had only one episode of insufficiency. In these latter patients provisions for such treatment are made in the event that further attacks occur. Ordinarily 900 to 1200 mg. of ethyl biscoumacetate (Tromexan Ethyl Acetate) and 200 to 300 mg. of bishydroxycoumarin (Dicumarol) are given the first day and subsequently only Dicumarol, with the dosage adjusted to the prothrombin time. When attacks are occurring in rapid succession, the treatment is started on an emergency basis with the intravenous administration of heparin (50 mg. every four hours) for the first 36 to 48 hours in addition to Tromexan and Dicumarol. Patients who have only minor neurologic deficits on the basis of infarction are observed carefully over the next few hours. If no further increase in neurologic deficit takes place, anticoagulants are not used. If the abnormalities increase but are still not absolute, anticoagulant therapy is instituted with all three drugs. These are the strokes in evolution. When the diagnosis of infarction within the vertebral-basilar system is made, anticoagulation is begun immediately. The outlook for these patients is grim without treatment and, furthermore, the development
Diagnosis and Current Treatment of Strokes
949
of these strokes is not always smooth but irregularly cumulative, so that further observation delays institution of treatment. The cooperation of the patient, experience of the physician, and proper laboratory assistance in determination of prothrombin times are essential for long-term anticoagulant therapy. The optimal duration of this treatment is unknown. It is our current practice to evaluate each patient individually, but in general to discontinue the medication after six to 12 months. At this time adequate provision is made for reinstitution of the medication should further difficulty ensue. Contraindications to anticoagulant therapy include blood dyscrasias, disease of the liver or kidneys and potential bleeding sites. Such contraindications are relative, and each case has to be decided on its merits. Subacute bacterial endocarditis is, of course, a definite contraindication to anticoagulant therapy. REFERENCES 1. Botterell, E. H., Lougheed, W. M., Scott, J. W. and Vandewater, S. L.: Hypothermia and-Interruption of Carotid, or Carotid and Vertebral Circulation, in the Surgical Management of Intracranial Aneurysms. J. Neurosurg. 13: 1-42 (Jan.) 1956. 2. Fischer, C. Miller: Personal communication to the authors. 3. Johnson, H. C. and Walker, A. E.: The Angiographic Diagnosis of Spontaneous Thrombosis of the Internal and Common Carotid Arteries. J. Neurosurg. 8: 631-659 (Nov.) 1951. 4. Little, D. M.: "Controlled Hypotension" in Anesthesia and Surgery. Springfield, Illinois, Charles C Thomas, 1956, 159 pp. 5. Lyons, Champ and Galbraith, J. G.: Surgical Treatment of Internal Carotid Occlusion. J.M.A. Alabama 27: 1-4 (July) 1957. 6. Millikan, C. H.: Evaluation of Carbon Dioxide Inhalation for Acute Focal Cerebral Infarction. A.M.A. Arch. Neurol. & Psychiat. 73: 324-328 (March) 1955. 7. Millikan, C. H. and Siekert, R. G.: Studies in Cerebrovascular Disease. T. The Syndrome of Intermittent Insufficiency of the Basilar Arterial System. Proc. Staff Meet., Mayo Clin. 30: 61-68 (Feb. 23) 1955. 8. Millikan, C. H. and Siekert, R. G.: Studies in Cerebrovascular Disease. IV. The Syndrome of Intermittent Insufficiency of the Carotid Arterial System. Proc. Staff Meet., Mayo Clin. 30: 186-191 (May 4) 1955. 9. Millikan, C. H., Siekert, R. G. and Whisnant, J. P.: Anticoagulant Therapy in Cerebral Vascular Disease: Current Status. J.A.M.A. 166: 587-592 (Feb. 8) 1958. 10. Rob, Charles and Wheeler, E. B.: Thrombosis of Internal Carotid Artery Treated by Arterial Surgery. Brit. M. J. 2: 264-266 (Aug. 3) 1957. 11. Siekert, R. G. and Millikan, C. H.: Studies in Cerebrovascular Disease. II. Some Clinical Aspects of Thrombosis of the Basilar Artery. Proc. Staff Meet., Mayo Clin. 30: 93-100 (March 9) 1955. 12. Siekert, R. G. and Millikan, C. H.: Syndrome of Intermittent Insufficiency of the Basilar Arterial System. Neurology 5: 625-630 (Sept.) 1955. 13. Siekert, R. G., Millikan, C. H. and Shick, R. M.: Current Indications for the Use of Anticoagulant Drugs in Cerebrovascular Disease. Circulation 13: 725728 (May) 1956. 14. Svien, H. J. and Hollenhorst, R. W_: Pressure in Retinal Arteries After Ligation or Occlusion of the Carotid Artery. Proe. Staff Meet., Mayo Clin. 31: 684692 (Dec. 26) 1956. 15. Wright, I. S. and McDevitt, Ellen: Cerebral Vascular Diseases: Their Significance, Diagnosis and Present Treatment, Including the Selective Use of Anticoagulant Substances. Ann. Int. Med. 4.1: 682-698 (Oct.) 1954.