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The Pathologic Physiology of Cerebral Metabolic Disease
THE PATHOLOGIC PHYSIOLOGY OF CEREBRAL METABOLIC DISEASE JOSEPH F. FAZEKAS,
M.D.*
AND RALPH
W.
ALMAN,
M.D.t
IT IS agreed that the application of physiological principles to problems of clinical medicine permits a better understanding of the etiology' of various disease processes and that their treatment then becomes rational rather than empirical. Metabolic disturbances of the central nervous system have been poorly understood in the past, mainly because of the lack of reliable procedures by which brain metabolism could be studied in vivo. A great deal of miscellaneous and presumptive evidence regarding the brain had been obtained from in vivo studies which provided information regarding the uptake or release of oxygen and various metabolites by cerebral tissue, as indicated by differences in concentration in cerebral arterial and venous blood. More recently, Kety and co-workersl have introduced a method by which the cerebral blood flow may be quantitatively determined, thus permitting a correlation of previous observations and hence a more accurate estimation of the cerebral metabolic capacity. Their method has since been modified and simplified by Scheinberg. 2 The application of these procedures to a variety of conditions associated with disturbances of function of the central nervous system has been among our outstanding advances in this field. 3 However, it should be recognized that studies of total cerebral metabolism do not differentiate the many complex reactions involved in intermediate metabolic processes nor do they give much information regarding the nature of local disturbances or of the fundamental etiology of the more diffuse brain abnormalities. It is generally believed that the variable richness of blood supply to the various parts of the brain and the individual metabolic patterns of different brain areas are important factors in the production of certain selective lesions of the central nervous system. 4 For example, asphyxia and hypoglycemia tend to damage most the cerebral cortex while carbon monoxide damages the corpus striatum. With certain dietary deficiencies the histological changes are most marked in the periventricular gray matter of the brain stem. As From the Cerebral-Metabolic Laboratory, Gallinger Municipal Hospital and the Department of Medicine, Georgetown University School of Medicine, Washington, D. C. * Chief-of-Staff, Gallinger Municipal Hospital; Adjunct Clinical Professor of Medicine, Georgetown University and Gcorge Washington University Schools of Medicine. t Resident-in-Medicine, Gallinger Municipal Hospital. 1801
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
previously indicated, in these and in other clinical states the local changes in blood flow and metabolism may not necessarily be revealed by investigation of the total cerebral metabolic rate and total blood flow of the brain. Such studies, however, supplemented by in vitro and clinical observations help considerably in the formulation of definite concepts regarding the metabolic characteristics of the central nervous system. In order to perform their various functions and to maintain their structure, cells require energy which is obtained from the oxidation of • various foodstuffs. Cerebral cells require a large and constant supply of energy and any significant interruption of its flow will result in chemical and histological changes in the cells and in functional changes reflected by the development of neurological and psychological aberrations. It should be evident that the metabolic rate of nervous tissue, as with any other tissue, is dependent upon both the metabolizing mechTABLE 1 CLASSIFICATION OF CEREBRAL METABOLIC DISTURBANCES
-
.-
Disturbances Due to Changes in Substrate Supply
--
Hypoglycemia
~~~
Disturbances Due to Changes in Intracellular Enzyme Activity Acceleration of enzyme activity Inhibition of enzyme activity Lack of enzymes
Disturbances Due to Changes in Oxygen Availability Hypoxic anoxia Anemic anoxia Stagnant anoxia a. General b. Local
..
anisms and the availability of metabolites; therefore, a system having a completely adequate metabolic capacity may yet demonstrate a reduction in metabolic rate due simply to an insufficient supply of substrate. Similarly, with a completely adequate supply of substrate an impairment or deficiency of intracellular enzymes may depress the metabolic rate because of inadequate utilization of the substrate. Finally, although oxygen is usually separately considered, it is quite as significant a metabolite as are the substrates. It is acted upon by the cytochrome-oxidase system to an equally important extent although in the final analysis it functions primarily as an acceptor for hydrogen or carbon. A classification of metabolic disturbances of the central nervous system based on such a concept is illustrated in Table 1. In this review we should like to discuss the pathophysiology of various metabolic disturbances of the central nervous system, citing where possible clinical examples of the classification outlined.
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CHANGES IN SUBSTRATE SUPPLY
Hypoglycemia. The brain has special metabolic characteristics which differentiate it from most other organs. It is unique in that it obtains its energy practically exclusively from the oxidation of carbohydrate; it has been repeatedly demonstrated that the respiratory quotient of the brain is unity.5. 6, 7 Since it is an aerobic organ for the most part and since its glycogen supplies are inadequate to support its high metabolic requirements for any appreciable length of time, the brain must obtain the glucose it needs from the circulating blood. 8 The oxygen consumption of the brain can be completely accounted for by the oxidation of the glucose removed from the peripheral blood. 9 It may be anticipated, therefore, that hypoglycemia, however induced, will cause a marked disturbance in the functions of the central nervous system. Studies on patients in whom hypoglycemia was induced by the injection of insulin have disclosed a decrease in the cerebral metabolic rate and a slowing of the cerebral electrical activity but a normal blood flow. 9,10 The cerebral arteriovenous oxygen difference decreases because of a gradually increasing oxygen tension of the cerebral venous blood. The latter finding indicates a decrease in substrate oxidation, the obvious result of the inadequate substrate supply. The specific parts of the brain most involved are indicated by the neurological and electrical changes which make their appearance in a definite order beginning with those referable to the newer portions of the brain and descending through the various phylogenetic layers. The administration of glucose which alone supplies the energy for brain metabolism usually reverses the biochemical, electrical and clinical abnormalities observed in hypoglycemia,u· 12 Apparently more energy is required to maintain the function of the cerebral cells than to maintain their structure, and disturbances of function are the first to be manifested as a result of hypoglycemia. If, however, hypo glycemia is too prolonged, irreversible Rtructural damage will result, and the cerebral metabolic rate, electrical activity, and function will not return to normal after the administration of glucose. la, 14. 15 Hyperglycemia has not been noted to cause any changes in cerebral metabolism, presumably because cerebral metabolism is normally maximal and not dependent upon insulin, as will be discussed. CHANGES IN INTRACELLULAR ENZYME ACTIVITY
If we accept the fact that glucose is the only important substrate of the central nervous system, it might reasonably be supposed that alterations in concentration or activity of the physiological substancesenzymes, vitamins, or hormones-governing its oxidation would produce changes remarkably similar to those resulting from hypoglycemia 20
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of equivalent degree and comparable duration, or accelerate the oxidation of glucose. However, as we shall point out in this review, although it is not unusual to find a cerebral metabolic rate decreased below the normal value, there is no conclusive evidence to show that it may be elevated to levels above the normal. Temperature. One might anticipate an acceleration of cerebral enzyme activity by fever, and it is true that in vitro studies have demonstrated for brain tissue an increasing oxygen requirement with rising temperatures. 16 . 17 It should be understood, however, that in these experiments the maximum oxygen consumption of the excised cerebral tissue was not compared with the normal metabolic rate of the intact brain. Earlier in vivo studies17 made during fever demonstrated an increase in the cerebral arteriovenous oxygen difference; this admittedly may have been, at least in part, due to a decrease in cerebral blood flow, which unfortul'ately was not simultaneously investigated. Heyman, Patterson and Nicholas18 studied the effects of pyrogeninduced fever on the cerebral blood flow and oxygen consumption in thirteen patients with asymptomatic neurosyphilis and fourteen patients with dementia paralytica. The mean elevation of temperature in both groups of patients was 3.9 0 F. In the patients with asymptomatic neurosyphilis, the mean cerebral blood flow and oxygen consumption were normal in the afebrile state and showed no significant changes during fever. In the patients with dementia paralytica the mean cerebral blood flow and oxygen consumption, which were abnormally low in the afebrile state, increased by 30 per cent and 23 per cent respectively during fever. The final values approached but did not exceed the normal. The authors concluded that, during induced fever, the brain in asymptomatic neurosyphilis does not share in the increases in cardiac output and total oxygen consumption which are known to occur. By contrast, the brain in dementia paralytica shares to some extent in the increases in both of these functions, perhaps by virtue of a demonstrable proportional decrease in the elevated cerebral vascular resistance. The beneficial effect of fever therapy in dementia paralytica may have some relation to these findings. It was tentatively assumed that the normal brain has a response to fever similar to that of the asymptomatic patients.l 8 However, it is recognized that hyperpyrexia may cause exhaustion or destruction of cerebral enzyme systems, and it is therefore essential that the critical temperature level above which these injurious effects occur be identified so that the physiological limitations of fever can be quantitatively evaluated. The effects of hypothermia on the cerebral metabolic rate of experimental animals reveal a much better agreement between in vitr019 and in viv0 20 studies. As the body temperature drops below normal, there is a progressive decrease in cerebral blood flow as indicated by rather
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crude methods. The cerebral electrical activity is also reduced. These results probably reflect the depression of all enzymatic activity as a result of hypothermia. Smith and Fay used hypothermia for the treatment of patients with terminal carcinoma. The changes in central nervous system function which he described may well be attributed to the decreased cerebral metabolic rate. Pharmacological Stimulants. There is a large group of drugs and toxic agents which "stimulate" the central nervous system; our experimental methods are not yet sensitive enough to indicate with certainty that the mechanism of such stimulation is associated with an appreciable increase in the cerebral metabolic rate unless there is previous cerebral depression. 21 Under normal conditions, stimulation by analeptics may be due to alterations in membrane potential of the neurone with resulting changes in conduction and discharge characteristics; the small energy requirement for these alterations would hardly be evident in the face of the very large energy requirements for maintenance of the structural integrity of nerve-cell cytoplasm. The analeptic agents would certainly not be indicated in those states in which cerebral depression resulted from either substrate deprivation or oxygen lack (to be discussed). Neither could they be expected to be of any value where cerebral depression is due to insufficiency of specific enzyme systems. Central stimulants are only indicated when the depression is caused by aliphatic agents since the latter afford protection against the convulsant effects of the analeptics. Their promiscuous use may cause an additive depression presumably by exhaustion of the remaining enzyme systems. Pharmacological Depressants. An entire medical specialty is devoted to control of the depression of the nervous system by anesthetic agents. The essential difference between the clinical effects of these drugs and of those substances usually considered noxious is that the effects of anesthetics may be controlled and are normally reversible. The precise mechanism through which depressants exert their effects has never been clearly elucidated. However, the effects of the barbiturates may probably be typical of many of the depressants. The depression observed following the injection or ingestion of large amounts of the barbiturates is believed to be due to an inhibition of cerebral intracellular enzymes (dehydrogenase). Quastej22 demonstrated many years ago that the barbiturates inhibit the oxidation of glucose, lactic aNd pyruvic acids by excised cerebral tissue. This inhibition is reversible. More recently it has been demonstrated in man that the cerebral metabolic rate is diminished during pentothal narcosis and that the rate of oxidation by cerebral cortex is depressed earlier and more profoundly than that of the rest of the brain. 23]'Lately more rational attempts at therapy of pharmacological central nervous system depression by the use of sodium succinate24 and cytochrome C25 have
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been made; however, the effectiveness of such treatment is still highly controversial. Hormones. The influence of hormones on the cerebral metabolic mechanism has received considerable attention, but the only studies the results of which are reasonably conclusive are those concerning insulin and the thyroid hormone. Insulin may be summarily dismissed with the remark that the effects of hyperinsulinism on cerebral function are those of hypoglycemia, the mechanism for which resides in sites far removed from the brain. The familiar observation that cerebral function is not altered in uncomplicated diabetes, as well as careful experimental studies, demonstrate that the brain does not require insulin in its metabolism of glucose. The laboratory evidence for this statement is embodied in the fact that a respiratory quotient of unity for the brain has been obtained in completely depancreatized animals and in isolated cerebral tissues deprived of insulin. 26 , 27 It has been assumed from clinical observations that the motor and psychological aberrations observed in hyper- and hypothyroid states reflect alterations in cerebral metabolism due directly to local excess or deficiency of the thyroid hormone. Such reasoning derives its major support from analogy to the well-known response characteristic:s of many widely different tissues. Critical analysis of in vivo and in vitro studies of brain metabolism indicates that such an assumption is not justified. Brain tissues excised from adult rats made hyper- or hypothyroid have failed to disclose a metabolic rate significantly different from the normal.2 8 In the developing rat the only observed difference has been an acceleration toward maturity caused by the hyperthyroid state. Hypothyroidism in the developing rat has been without apparent effect on the cerebral metabolic rate. In vivo studies by Scheinberg29 support these findings in that the cerebral oxygen consumption is not increased in human hyperthyroids; and the decrease which he observed in myxedema might well be accounted for by the reduction in oxygen availability caused by accompanying anemia and the decreased cerebral blood flow, the latter perhaps partly aggravated by subclinical cerebral arteriosclerosis, so common in the age group most subject to myxedema. The similarity in the depression of the cerebral metabolic rate in myxedema and cardiac failure, in both of which cerebral blood flow is decreased because of diminished cardiac output and increased cerebral vascular resistance, should be noted. From the teleological point of view, it should not be surprising that upon close examination the brain demonstrates a lack of enzyme response to changes in hormone concentration, in exception to the findings in most other tissues. It is difficult to conceive of survival of a complex
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organism, highly dependent upon optimal function of a governing structure, if such a structure were more than minimally influenced by fluctuations in endocrine activity. Endogenous Depression. Even though changes in hormone concentration do not appreciably affect cerebral metabolism, coma is nevertheless a fairly frequent complication of uncontrolled diabetes. Studies by Kety and co-workers30 of the cerebral metabolism and blood flow of patients in diabetic coma have demonstrated an adequate oxygen saturation of the blood going to the brain, a normal or slightly increased cerebral blood flow despite general dehydration, but a significant fall in the cerebral metabolic rate. Particularly noteworthy is the observation that if the cerebral metabolic rate is below 2 cc. of oxygen per 100 gm of brain per minute, recovery of the patient is unlikely regardless o. the nature of the therapy employed.
Certainly one cannot attribute the cerebral metabolic depression to hyperglycemia. If anything, one might expect that hyperglycemia would tend to counteract the depression by accelerating toward normal the oxidation of glucose through a mass action effect. 31 The cause of the decreased cerebral metabolic rate in diabetic coma is unknown. The available evidence would seem to indicate that the impairment of activity of intracellular cerebral enzymes is due to the acidosis and ketosis,32 although such evidence is not sufficient to arrive at an unquestionable conclusion. In any case, all therapeutic efforts should be primarily directed toward alleviating as rapidly as possible the acidosis and ketosis. Therefore, on such theoretical grounds the importance of early intensive insulin therapy is again emphasized and should put an end to the fruitless discussion of the necessity for giving or not giving glucose to the patient in diabetic coma. Certainly claims for either procedure will mean very little in the future unless data is available to indicate the cerebral metabolic rates of the patients reported. Unfortunately adequate studies attempting to elucidate the mechanism for the endogenous depressions associated with other metabolic states (hepatic and uremic coma) have not as yet been made, and rational therapy must await the results of careful investigation. Deficiency of Enzymes. The many clinical syndromes associated with a deficiency of thiamine are well known. It should not be too surprising that the tissue most frequently affected by vitamin Bl deficiency is the central nervous system in view of this structure's dependence on glucose and the fact that vitamin Bl is essential for the oxidative decarboxylation of pyruvic acid which is a necessary intermediate in the metabolism of glucose. 33 In the absence of thiamine, therefore, glucose oxidation in the central nervous system can be expected to proceed only as far as pyruvic acid. In fact, the studies on cerebral tissue ex-
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
cised from animals with vitamin BI deficiency reveal a decrease in oxygen consumption, a respiratory quotient below unity, and the expected accumulation of pyruvic acid. 34 Detailed studies of cerebral metabolism of patients with Wernicke's disease have as yet not been performed. In this condition, the clouding of consciousness, varying ophthalmoplegias, and the ataxia have been attributed to damage confined for the most part to the periventricular gray matter. The syndrome is probably a combination of several nutritional deficiencies, but the observed disturbances in pyruvic acid metabolism and the response to thiamine pyrophosphate would seem to indicate that Wernicke's syndrome is invariably associated with a thiamine deficiency.35 Cerebral metabolic disturbances associated with vitamin deficiencies other than of thiamine should also be expected in view of the fact that the oxidation of glucose involves co-enzymes requiring nicotinic acid and riboflavin. Unfortunately adequate studies of cerebral metabolism have not been reported in patients exhibiting the dementia of pellagra and the acute nicotinic acid encephalopathy described by Jollife. 36 Because pure deficiency states involving individual members of the B group are rarely, if ever, observed clinically, it is very likely that artificial induction of such states will be required for their investigation. Although functional and eventually permanent structural spinal cord changes in pernicious anemia have long been recognized to be due to deficiency of some necessary specific vitamin rather than to the anemia itself, it is relatively recently that histological changes in the brain due to this disease have been identified. 37 That this is a deficiency disease in which permanent functional changes with or without obvious mental aberrations are also present may have been demonstrated by Scheinberg,29 who has reported in pernicious anemia a moderate to marked depression in cerebral oxygen consumption persisting indefinitely in many cases, even after therapy has rendered the patient hematologically normal. The validity of this conclusion is subject to the qualification that cerebral arteriosclerosis, not evident clinically, must not have been present in his subjects; pernicious anemia is most common in the age group wherein cerebral arteriosclerosis is also most frequent. CHANGES IN THE AVAILABILITY OF OXYGEN
The extreme dependence of the central nervous system upon oxygen has long been recognized. Brief episodes of anoxia are poorly tolerated and result in functional and structural changes within a very short period of time. This fact was well illustrated by the experiments of Kabat 38 in which he deprived the human brain of oxygen by causing acute complete arrest of the cerebral circulation. Following this procedure, he noted in normal young men that consciousness was lost in from 6 to
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7 seconds. Restoration of the cerebral circulation after 100 seconds was followed by a rapid recovery of consciousness with no objective evidence of injury. In normal adult dogs, sudden and complete arrest of the circulation to the brain for periods longer than six minutes uniformly results in permanent coma, presumably due to a functional decortication. The marked sensitivity of mature cerebral cells to anoxia may to a large extent be related to their high oxygen requirement, which is indicated by the utilization by the normal adult brain of approximately one-fifth of the total oxygen uptake of the individual.2 The remarkable resistance of newborn animals to anoxia has been shown to be directly related to their low cerebral metabolic rate 39 and perhaps also to the fact that the newborn of certain species may obtain sufficient energy from anaerobic processes to maintain the functions of the vital centers. 40 For example, a newborn rat with a cerebral oxygen uptake of 1.25 cc. of oxygen per 100 gm. of brain per minute can survive in an atmosphere of pure nitrogen for about forty minutes. This is in marked contrast to the very short survival period after the cerebral oxygen uptake approaches the value found for the adult animal. At 15 days of age, the rat is unable to tolerate an atmosphere of pure nitrogen for periods longer than two minutes. Since the normal adult brain for the most part is an aerobic organ and cannot contract an oxygen debt, it must depend entirely on the circulating blood for a constant supply of oxygen. There are numerous clinical states in which, for one reason or another, an adequate supply of oxygen is not readily available to the cerebral cells. These states may best be depicted by Yandell Henderson's classification of anoxiaY Hypoxic anox1:a will result whenever there is lack of oxygen in the environment or an impairment in the diffusion of oxygen across the alveolar membranes. Anemic anoxia refers to those states in which the oxygencarrying capacity of the blood is reduced by either a lack of hemoglobin or interference by toxic agents with the formation or dissociation of oxyhemoglobin. The cerebral cells will suffer from stagnant anoxia whenever the cardiac output becomes inadequate to maintain the cerebral circulation or if there is a local obstruction to the flow of blood to any part of the brain. The cerebral blood flow in the adult normal individual in the supine position averages 65 cc. per 100 gm. of brain per minute. 2 Thus the amoullt of blood diverted to the brain represents approximately 14 per cent of the total cardiac output. In view of the high oxygen requirement of the central nervous system and its dependence on the circulating blood for its oxygen needs, adequacy of the circulation to the brain must be zealously guarded. There are certain compensatory mechanisms operating to correct, at least in part, any deficiency of the oxygen supply to the brain cells. These mechanisms are as follows: Peripherally there
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
may be reflex elevation of the blood pressure, changes in the cardiac output, and shunting of blood away from the less important viscera. Locally there are reflex and chemical influences that regulate the rate of the cerebral blood flow by changing the caliber and resistance of the cerebral vessels. Finally the chemical dissociation of oxyhemoglobin is increased in the presence of a low pH or high carbon dioxide concentration. Whenever the organism is threatened by hypoxia, it may attempt to assure the brain of an adequate oxygen supply by increasing the cerebral TABLE 2 CONDITIONS TENDING TO IMPAIR CEREBRAL BLOOD FLOW AND/OR OXYGENATION --
Condition
Cerebral Blood Flow
Cerebral 0, Consumption
Cerebral Vascular Resistance
--.-".~-----
Normal', 2 . . • . . ........ . ..........
Hyperoxemia (85-100% O2)4 •. ... Systemic hypoxia (10% O2)'6. ... . . Polycythemia'6 .. ............ . . Anemia 29 . . . ..... . ..... . . ........ Cardiac decompensation 47 . • . . . . • . Myxedema 29 . . • . . ................. Iner. intracran. pressure's' .. ...... Upright posture 2 . . . . . . . . . . . . . . . . . . Cerebral vasc. disease 49 . .... -
cc. 1.3-1.6 mm. 54-65 cc. per 3.3-3.8 100 gm. per per 100 gm. Hg per cc. per 100 gm. per min. per. min. min.
-13·5% +35·2% -53·7% +46·3% -36·5% -38·0% -37·0% -20·8% -36·5%
+3·2% -5·9% -9·1% Normal -13·2% -27·0% -15·3% Normal -24·3%
+29·4% -35·3% +169·0% -37·5% +98·5%* +92'0%* +117·0% -15·8% +154·0%
* The possibility must be considered that the increased cerebral vascular resistance, with secondary reduction of cerebral blood flow and oxygen consumption, is partly due to subclinical cerebral arteriosclerosis in the subjects investigated. blood flow, decreasing the cerebral vascular resistance, or increasing the dissociation of oxyhemoglobin. If a disease state interferes with the compensatory mechanisms tending to maintain a normal cerebral blood flow or if their physiological limitations render them inadequate, there results a decrease in cerebral oxygenation unless the remaining mechanisms are sufficiently active. Examples of abnormal states and their general cerebral effects, sometimes permitting full compensation of hypoxic tendencies, are listed'in the following table (Table 2). Occlusion of a cerebral vessel following thrombosis or embolism exemplifies the severest form of stagnant anoxia. After such an event, there is a deficiency of all substances necessary to maintain normal
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metabolism, as well as the accumulation of metabolic and abnormal waste products. In addition to the varying susceptibility of different portions of the brain, there are local factors that influence the extent of the damage resulting from the ischemia; namely, edema of neighboring tissues and spasm of adjacent vessels. Necrosis of tissue may be expected within a very short period of time unless the collateral circulation can correct the local stagnant anoxia. Clinicians have for quite some time concerned themselves with this problem and have been advocating the use of various drugs and stellate ganglion block to improve the cerebral circulation in such states. Unfortunately the efficacy of the various drugs recommended has not been proved except by observing the clinical response of the patient, frequently an unreliable index (Table 3). TABLE 3 RESPONSE OF CEREBRAL BLOOD FLOW TO VARIOUS AGENTS
Agents Nicotinic acid 60 .. CO2, 5-7%61 .................. . Aminophylline 62 . . . . • • . . . . . . . . . MgSO•............. Papaverine 63 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histamine .............................. . Stellate block" ......................... . 85-100% Oxygen 46 • • • . . . • • . . • . . . • • . • • • . . . .
Cerebral Blood Flow % Change +19·0 +88·0 -20·0 ? ? 0 -13·5
Cerebral Vasc. Resistance % Change -25·0 -30·0 ? ? ? 0 +3·2
The above table deserves some comment. It may be observed that as yet there are no studies to substantiate the efficacy of magnesium sulfate, papaverine and histamine as cerebral vasodilators. Rather interesting is the fact that aminophylline, a well-known peripheral vasodilator, causes a decrease in cerebral blood flow and an increase in the cerebral vascular resistance. One cannot conclude, therefore, that simply because a drug is a peripheral vasodilator it will have similar effects centrally. The value given for nicotinic acid was obtained by Aring using an indirect method of cerebral blood flow determination, employing displacement of spinal fluid after sudden compression of the neck veins.' Nicotinic acid causes such marked dilatation of extra cranial vessels that the nitrous oxide method of determining cerebral blood flow is rendered invalid. 29 The same objection may equally apply to future studies on histamine. In spite of the extreme optimism regarding stellate ganglion block, attempts at careful objective evaluation of its efficacy so far have failed
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
to yield a definite conclusion. Scheinberg and co-workers,42 have examined the effects of unilateral and bilateral sympathetic block on cerebral blood flow in normal subjects and in patients suffering from cerebral thrombosis. They were unable to observe any significant change in the total blood flow through the brain following even bilateral stellate ganglion block. One might well argue that there may be regional changes in cerebral blood flow which might not be detectable by their total blood flow studies, since the early work of Talbott, W olff, and Cobb 43 on animals demonstrated that cervical sympathectomy was followed by a slight but significant increase in the cerebral capillary bed. The increase in blood flow following this procedure seemed to be localized to various areas of the central nervous system and was not necessarily generalized. The variation of response in the different areas, however, calls for comment. Stohr44 inferred from his investigations that there are several routes for cerebral vasomotor nerves at the base of the brain. "All the brain vessels are not necessarily supplied by anyone nerve, ana anyone vessel may, in fact, be supplied from several sources. Therefore, after unilateral section of the cervical sympathetic nerve it is unlikely that all parts of the brain on that side will be equally affected or even that any vessel will be permanently or seriously altered. It would seem reasonable to assume that one portion would be most affected, an intermediate portion less affected, and other portions perhaps not affected at all." In view of the questionable effectiveness of stellate ganglion block and the certain knowledge that carbon dioxide is the most potent cerebral vasodilator known, one wonders why more complicated and far less efficient procedures are resorted to when a simple, nontoxic, inexpensive, physiologicat, and experimentally highly effective agent is readily available. SUMMARY AND CONCLUSIONS
In vivo experimental methods now available supplement previous observations and afford more accurate information regarding total cerebral metabolism and blood flow in a variety of clinical states. These studies complemented by in vitro and clinical observations permit the formulation of certain fundamental concepts concerning cerebral tissue. The cerebral metabolic rate depends upon the integrity of (1) the intracellular metabolizing mechanisms (enzymes), (2) the substrate supply, and (3) the availability of oxygen. Interference with any of these divisions, if of sufficient magnitude and duration, will result in functional and structural changes in the central nervous system. Clinical examples of diseases causing such disturbances are cited. The results of studies to date permit several hypotheses to be formulated:
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1. Cerebral metabolism probably proceeds normally at a maximal rate. Although it may be depressed with relative ease by substrate deprivation, by inhibition or deficiency of intracellular enzymes, or by oxygen lack, there is no conclusive evidence that the normal adult cerebral metabolic rate may be accelerated. Such factors as elevated temperature and pharmacological stimulants at least do not cause a detectable increase in normal cerebral metabolism. An increase or decrease in the concentrations of hormones (insulin and thyroxin) does not appear to affect the cerebral metabolic rate. 2. The graded sensitivity of various parts of the central nervous . system to impairment of energy supply reflects local differences in metabolic requirements and therefore in metabolic rate. 3. There are compensatory mechanisms which tend to maintain an adequate supply of oxygen to the brain in the face of systemic hypoxia; such mechanisms are least efficient in local stagnant hypoxia and are subject to moderate or marked impairment by diseases. The compensatory mechanism of local cerebral vasodilatation may best be stimulated by the inhalation of carbon dioxide; other "cerebral vasodilators" are of questionable value. REFERENCES 1. Kety, S. S. and Schmidt, C. F.: The Nitrous Oxide Method for the Quantitative Determination of Cerebral Blood Flow in Man: Theory, Procedure and Normal Values. J. Clin. Investigation 27:476-514,1948. 2. Scheinberg, Peritz and Stead, E. A. Jr.: The Cerebral Blood Flow in Male Subjects as Measured by the Nitrous Oxide Technique. Normal Values for Blood Flow, Oxygen Utilization, Glucose Utilization, and Peripheral Resistance, with Observations on the Effect of Tilting and Anxiety. J. Clin. Investigation 28:1163-1171,1949. 3. Kety, S. S.: Circulation and Metabolism of the Human Brain in Health and Disease. Am. J. Med. 8:205-218, 1950. 4. Hicks, Samuel P.: Brain Metabolism in Vivo. Arch. Path. 49:111-137, 1950. 5. Himwich, H. E. and Nahum, L. H.: Respiratory Quotient of the Brain. Proc. Soc. Exper. BioI. Med. 26:496-497,1929. 6. Himwich, H. E. and Nahum, L. H.: The Respiratory Quotient of the Brain. Am. J. PhysioI. 101 :446-453, 1932. 7. Himwich, H. E. and Fazekas, J. F.: Respiratory Quotient of Various Parts of the Brain. Proc. Soc. Exper. BioI. Med. 30:366,1932. 8. Himwich, H. E. and Fazekas, J. F.: Anaerobic Survival of Adult Animals. Am. J. PhysioI. 139:366-370, 1943. 9. Kety, S. S., Woodford, R. B., Harmel, M. H., Freyhan, F. A., Appel, K. E. and Schmidt, C. F.: Cerebral Blood Flow and Metabolism in Schizophrenia. The Effects of Barbiturate Semi-narcosis, Insulin Coma and . Electroshock. Am. J. Psychiat. 104:765-769, 1948. 10. Himwich, H. E., Frostig, J. P., Fazekas, J. F. and Hadidian, Z.: The Mechanism of the Symptoms of Insulin Hypoglycemia. Am. J. Psychiat. 96:371385, 1939. 11. Maddock, S., Hawkins, J. E., Jr. and Holmes, E.: Inadequacy of Substances of "Glucose Cycle" for Maintenance of Normal Cortical Potentials During Hypoglycemia Produced by Hepatectomy with Abdominal Evisceration. Am. J. Physiol. 125:551-565, 1939.
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
12. Hoagland, Hudson, Himwich, H. E., Campbell, Eldridge, Fazekas, J. F. and Hadidian, Zareh: Effects of Hypo;z;lycemia and Pentobarbital Sodium on Electrical Activity of Cerebral Cortex and Hypothalamus (Dogs). J. Neurophysiol 2:276-288, 1939. 13. Himwich, H. E., Bowman, K. M. and Fazekas, J. F.: Prolonged Coma and Cerebral Metabolism. Arch. Neurol. & Psychiat. 44:1098-1101, 1940. 14. Himwich, H. K, Fazekas, J. F., Bernstcin, A. 0., Campbell, K H. and Martin, S. J.: Syndromes Secondary to Prolonged Hypoglycemia. Proc. Soc. Exper. BioI. & Med. 39:244-245,1938. 15. Tanenberg, J.: Am. J. Path. 15:25, 1939. 16. Field, John (2d), Fuhrman, F. A. and Martin, A. W.: Effect of Tempcrature on the Oxygen Consumption of Brain Tissue. J. Neurophysiol. 7:117-126, 1944. 17. Himwich, H. K, Bowman, K. M., Fazekas, J. F. and Goldfarb, W.: Tempera- . ture and Brain Metabolism. Am. J. M. Sc. 200:537-538, 1939. 18. Heyman, Albert, Patterson, J. L., Jr. and Nichols, F. T., Jr.: The Effects of Pyrogen-induced Fever on Cerebral Function in Neurosyphilis. (In press.) 19. Fazekas, J. F. and Himwich, H. E.: Effect of Hypothermia on Cerebral Metabolism. Proc. Soc. Exper. BioI. & Med. 42:537-538, 1939. 20. Libet, B., Fazekas, J. F., Meirowsky, A. M., Campbell, E. H. and Himwich, H. E.: Control of Electrical and Oxidative Activity of Brain by Temperature. Am. J. Physiol. 129:404-405, 1940. 21. Eckenhoff, J. E., Schmidt, C. F., Dripps, Il. D. and Kety, S. S.: A Status Report on Analeptics. J.A.M.A. 139:780-785, 1949. 22. Quastel, J. H.: Respiration in the Central Nervous System. Physiol. Rev. 19:135-183, 1939. 23. Etsten, B., York, G. K and Himwich, H. E.: Pattern of Metabolic Depression Induced with Pentothal Sodium. Arch. Neurol. & Psychiat. 56:171184,1946. 24. Barrett, R. H.: Sodium Succinate-An Analeptic for Barbiturate Poisoning in Man. Ann. Int. Med. 31:739-750,1949. 25. Proger, Samuel: Some Effects of Injected Cytochrome C in Animals and Man. Bull. New England Med. Center 7:1-8,1945. 26. Fazckas, J. F. and Himwich, H. E.: Effect of Nicotine on the Oxidations of the Diabetic Brain. Am. J. Physiol. 116:46--47, 1936. 27. Baker, Z., Fazekas, J. F. and Himwich, H. E.: Carbohydrate Oxidation in Normal and Diabetic Cerebral Tissues. J. BioI. Chem. 125:545-556, 1938. 28. Fazekas, J. F.: Unpublished data. 29. Scheinberg, Peritz: Personal communication. 30. Kety, S. S., Polis, B. D., Nadler, C. S. and Schmidt, C. F.: The Blood Flow and Oxygen Consumption of the Human Brain in Diabetic Acidosis and Coma. J. Clin. Investigation 27:476--514, 1948. 31. Soskin, S. and Levine, R.: A Relationship Between the Blood Sugar Level and the Rate of Sugar Utilization Affecting the Theories of Diabetes. Am. J. Physiol. 120:761, 1937. 32. Schneider, R. and Droller, H.: Relative Importance of Ketosis and Acidosis in Production of Diabetic Coma. Quart. J. Exper. Physiol. 28:323, 1938. 33. Peters, R. A.: Biochemical Lesion in Vitamin Bl Deficiency; Application of Modern Biochemical Analysis in Its Diagnosis. Lancet 1 :1161-1165, 1936. 34. Banga, I., Ochoa, S. and Peters, It. A.: Pyruvate Oxidation in Brain: Some Dialyzable Components of Pyruvate Oxidation System. Biochem. J. 33:1980, 1939. 35. Wortis, Herman, Bueding, Ernest, Stein, M. H. and Jolliffe, Norman: Pyruvic Acid Studies in the Wernicke Syndrome. Arch. Neurol. & Psychiat. 47:215222,1942. 36. Joliffe, N., Bowman, K. M., Rosenblum, L. A. and Fein, H. D.: Nicotinic Acid Deficiency Encephalopathy. J.A.M.A. 114:307, 1940.
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37. Adams, R. D. and Kubik, C. S.: Subacute Degeneration of Brain in Pernicious Anemia. New England J. Med. 231 :1~9, 1944. 38. Rossen, Ralph (Lt.), Kabat, Herman and Anderson, J. P.: Acute Arrest of Cerebral Circulation in Man. 50:51O~529, 1943. 39. Himwich, H. E., Baker, Zelma and Fazekas, J. F.: The Respiratory Metabolism of Infant Brain. Am. J. Physiol. 125:601-606, 1939. 40. Himwich, H. E., Bernstein, A. 0., Herrlich, H., Chesler, A. and Fazekas, J. F.: Mechanisms for the Maintenance of Life in the Newborn During Anoxia. Am. J. Physiol. 135:387, 1942. 41. Henderson, Yandell: Adventures in Respiration. Baltimore, Williams & Wilkins Co., 1938. 42. Scheinberg, Peritz: Cerebral Blood Flow in Vascular Disease of the Brain. Am. J. Med. 8:139~152, 1950. 43. Talbott, J. H., Woltf, H. G. and Cobb, Stanley: The Cerebral Circulation. Arch. Neurol. & Psychiat. 21:1102~1106, 1929. 44. Stohr, P.: Ztschr. f. Anat. u. Entwicklungs Gesellsch. 63:562, 1922. 45. Kety, S. S. and Schmidt, C. F.: The Effects of Alterations in the Arterial Tensions of Carbon Dioxide and Oxygen on Cerebral Blood Flow and Cerebral Oxygen Consumption of Normal Young Men. J. Clin. Investigation 27:484, 1948. 46. Kety, S. S.: Unpublished observations. 47. Scheinberg, Peritz: Cerebral Circulation in Heart Failure. Am. J. Med. 8:148153, 1950. 48. Kety, S. S., Shenkin, H. A. and Schmidt, C. F.: The Effect of Increased Intracranial Pressure on Cerebral Circulatory Functions in Man. J. Clin. Investigation, 27:493,1948. 94. Freyhan, F. A., Woodford, R. B. and Kety, S. S.: The Blood Flow, Vascular Resistance and Oxygen Consumption of the Brain in the Psychoses of Senility. J. Nerv. & Ment. Dis. (in press). 50. Aring, C. D., Ryder, H. W., Roseman, Ephraim, Rosenbaum, Milton and Ferris, E. B., Jr.: Effect of Nicotinic Acid and Related Substances on the Intracranial Blood Flow of Man. Arch. Neurol. & Psychiat. 46:649~ 654, 1941. 51. Kety, S. S. and Schmidt, C. F.: The Effects of Altered Arterial Tensions of Carbon Dioxide and Oxygen on Cerebral Blood Flow and Cerebral Oxygen Consumption of Normal Young Men. J. Clin. Investigation 27:484492, 1948. 52. Wechsler, R. L., Kleiss, L. M. and Kety, S. S.: The Effects of Intravenously Administered Aminophylline on Cerebral Circulation and Metabolism in Man. J. Clin. Investigation 29:28~31, 1950. 53. de Takats, G.: The Use of Papaverine in Acute Arterial Occlusions. J.A.M.A. 106:1003, 1936.
M.D.*
AND RALPH
W.
ALMAN,
M.D.t
IT IS agreed that the application of physiological principles to problems of clinical medicine permits a better understanding of the etiology' of various disease processes and that their treatment then becomes rational rather than empirical. Metabolic disturbances of the central nervous system have been poorly understood in the past, mainly because of the lack of reliable procedures by which brain metabolism could be studied in vivo. A great deal of miscellaneous and presumptive evidence regarding the brain had been obtained from in vivo studies which provided information regarding the uptake or release of oxygen and various metabolites by cerebral tissue, as indicated by differences in concentration in cerebral arterial and venous blood. More recently, Kety and co-workersl have introduced a method by which the cerebral blood flow may be quantitatively determined, thus permitting a correlation of previous observations and hence a more accurate estimation of the cerebral metabolic capacity. Their method has since been modified and simplified by Scheinberg. 2 The application of these procedures to a variety of conditions associated with disturbances of function of the central nervous system has been among our outstanding advances in this field. 3 However, it should be recognized that studies of total cerebral metabolism do not differentiate the many complex reactions involved in intermediate metabolic processes nor do they give much information regarding the nature of local disturbances or of the fundamental etiology of the more diffuse brain abnormalities. It is generally believed that the variable richness of blood supply to the various parts of the brain and the individual metabolic patterns of different brain areas are important factors in the production of certain selective lesions of the central nervous system. 4 For example, asphyxia and hypoglycemia tend to damage most the cerebral cortex while carbon monoxide damages the corpus striatum. With certain dietary deficiencies the histological changes are most marked in the periventricular gray matter of the brain stem. As From the Cerebral-Metabolic Laboratory, Gallinger Municipal Hospital and the Department of Medicine, Georgetown University School of Medicine, Washington, D. C. * Chief-of-Staff, Gallinger Municipal Hospital; Adjunct Clinical Professor of Medicine, Georgetown University and Gcorge Washington University Schools of Medicine. t Resident-in-Medicine, Gallinger Municipal Hospital. 1801
1802
JOSEPH F. FAZEKAS, RALPH W. ALMAN
previously indicated, in these and in other clinical states the local changes in blood flow and metabolism may not necessarily be revealed by investigation of the total cerebral metabolic rate and total blood flow of the brain. Such studies, however, supplemented by in vitro and clinical observations help considerably in the formulation of definite concepts regarding the metabolic characteristics of the central nervous system. In order to perform their various functions and to maintain their structure, cells require energy which is obtained from the oxidation of • various foodstuffs. Cerebral cells require a large and constant supply of energy and any significant interruption of its flow will result in chemical and histological changes in the cells and in functional changes reflected by the development of neurological and psychological aberrations. It should be evident that the metabolic rate of nervous tissue, as with any other tissue, is dependent upon both the metabolizing mechTABLE 1 CLASSIFICATION OF CEREBRAL METABOLIC DISTURBANCES
-
.-
Disturbances Due to Changes in Substrate Supply
--
Hypoglycemia
~~~
Disturbances Due to Changes in Intracellular Enzyme Activity Acceleration of enzyme activity Inhibition of enzyme activity Lack of enzymes
Disturbances Due to Changes in Oxygen Availability Hypoxic anoxia Anemic anoxia Stagnant anoxia a. General b. Local
..
anisms and the availability of metabolites; therefore, a system having a completely adequate metabolic capacity may yet demonstrate a reduction in metabolic rate due simply to an insufficient supply of substrate. Similarly, with a completely adequate supply of substrate an impairment or deficiency of intracellular enzymes may depress the metabolic rate because of inadequate utilization of the substrate. Finally, although oxygen is usually separately considered, it is quite as significant a metabolite as are the substrates. It is acted upon by the cytochrome-oxidase system to an equally important extent although in the final analysis it functions primarily as an acceptor for hydrogen or carbon. A classification of metabolic disturbances of the central nervous system based on such a concept is illustrated in Table 1. In this review we should like to discuss the pathophysiology of various metabolic disturbances of the central nervous system, citing where possible clinical examples of the classification outlined.
CEREBRAL METABOLIC DISEASE
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CHANGES IN SUBSTRATE SUPPLY
Hypoglycemia. The brain has special metabolic characteristics which differentiate it from most other organs. It is unique in that it obtains its energy practically exclusively from the oxidation of carbohydrate; it has been repeatedly demonstrated that the respiratory quotient of the brain is unity.5. 6, 7 Since it is an aerobic organ for the most part and since its glycogen supplies are inadequate to support its high metabolic requirements for any appreciable length of time, the brain must obtain the glucose it needs from the circulating blood. 8 The oxygen consumption of the brain can be completely accounted for by the oxidation of the glucose removed from the peripheral blood. 9 It may be anticipated, therefore, that hypoglycemia, however induced, will cause a marked disturbance in the functions of the central nervous system. Studies on patients in whom hypoglycemia was induced by the injection of insulin have disclosed a decrease in the cerebral metabolic rate and a slowing of the cerebral electrical activity but a normal blood flow. 9,10 The cerebral arteriovenous oxygen difference decreases because of a gradually increasing oxygen tension of the cerebral venous blood. The latter finding indicates a decrease in substrate oxidation, the obvious result of the inadequate substrate supply. The specific parts of the brain most involved are indicated by the neurological and electrical changes which make their appearance in a definite order beginning with those referable to the newer portions of the brain and descending through the various phylogenetic layers. The administration of glucose which alone supplies the energy for brain metabolism usually reverses the biochemical, electrical and clinical abnormalities observed in hypoglycemia,u· 12 Apparently more energy is required to maintain the function of the cerebral cells than to maintain their structure, and disturbances of function are the first to be manifested as a result of hypoglycemia. If, however, hypo glycemia is too prolonged, irreversible Rtructural damage will result, and the cerebral metabolic rate, electrical activity, and function will not return to normal after the administration of glucose. la, 14. 15 Hyperglycemia has not been noted to cause any changes in cerebral metabolism, presumably because cerebral metabolism is normally maximal and not dependent upon insulin, as will be discussed. CHANGES IN INTRACELLULAR ENZYME ACTIVITY
If we accept the fact that glucose is the only important substrate of the central nervous system, it might reasonably be supposed that alterations in concentration or activity of the physiological substancesenzymes, vitamins, or hormones-governing its oxidation would produce changes remarkably similar to those resulting from hypoglycemia 20
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
of equivalent degree and comparable duration, or accelerate the oxidation of glucose. However, as we shall point out in this review, although it is not unusual to find a cerebral metabolic rate decreased below the normal value, there is no conclusive evidence to show that it may be elevated to levels above the normal. Temperature. One might anticipate an acceleration of cerebral enzyme activity by fever, and it is true that in vitro studies have demonstrated for brain tissue an increasing oxygen requirement with rising temperatures. 16 . 17 It should be understood, however, that in these experiments the maximum oxygen consumption of the excised cerebral tissue was not compared with the normal metabolic rate of the intact brain. Earlier in vivo studies17 made during fever demonstrated an increase in the cerebral arteriovenous oxygen difference; this admittedly may have been, at least in part, due to a decrease in cerebral blood flow, which unfortul'ately was not simultaneously investigated. Heyman, Patterson and Nicholas18 studied the effects of pyrogeninduced fever on the cerebral blood flow and oxygen consumption in thirteen patients with asymptomatic neurosyphilis and fourteen patients with dementia paralytica. The mean elevation of temperature in both groups of patients was 3.9 0 F. In the patients with asymptomatic neurosyphilis, the mean cerebral blood flow and oxygen consumption were normal in the afebrile state and showed no significant changes during fever. In the patients with dementia paralytica the mean cerebral blood flow and oxygen consumption, which were abnormally low in the afebrile state, increased by 30 per cent and 23 per cent respectively during fever. The final values approached but did not exceed the normal. The authors concluded that, during induced fever, the brain in asymptomatic neurosyphilis does not share in the increases in cardiac output and total oxygen consumption which are known to occur. By contrast, the brain in dementia paralytica shares to some extent in the increases in both of these functions, perhaps by virtue of a demonstrable proportional decrease in the elevated cerebral vascular resistance. The beneficial effect of fever therapy in dementia paralytica may have some relation to these findings. It was tentatively assumed that the normal brain has a response to fever similar to that of the asymptomatic patients.l 8 However, it is recognized that hyperpyrexia may cause exhaustion or destruction of cerebral enzyme systems, and it is therefore essential that the critical temperature level above which these injurious effects occur be identified so that the physiological limitations of fever can be quantitatively evaluated. The effects of hypothermia on the cerebral metabolic rate of experimental animals reveal a much better agreement between in vitr019 and in viv0 20 studies. As the body temperature drops below normal, there is a progressive decrease in cerebral blood flow as indicated by rather
CEREBRAL METABOLIC DISEASE
1805
crude methods. The cerebral electrical activity is also reduced. These results probably reflect the depression of all enzymatic activity as a result of hypothermia. Smith and Fay used hypothermia for the treatment of patients with terminal carcinoma. The changes in central nervous system function which he described may well be attributed to the decreased cerebral metabolic rate. Pharmacological Stimulants. There is a large group of drugs and toxic agents which "stimulate" the central nervous system; our experimental methods are not yet sensitive enough to indicate with certainty that the mechanism of such stimulation is associated with an appreciable increase in the cerebral metabolic rate unless there is previous cerebral depression. 21 Under normal conditions, stimulation by analeptics may be due to alterations in membrane potential of the neurone with resulting changes in conduction and discharge characteristics; the small energy requirement for these alterations would hardly be evident in the face of the very large energy requirements for maintenance of the structural integrity of nerve-cell cytoplasm. The analeptic agents would certainly not be indicated in those states in which cerebral depression resulted from either substrate deprivation or oxygen lack (to be discussed). Neither could they be expected to be of any value where cerebral depression is due to insufficiency of specific enzyme systems. Central stimulants are only indicated when the depression is caused by aliphatic agents since the latter afford protection against the convulsant effects of the analeptics. Their promiscuous use may cause an additive depression presumably by exhaustion of the remaining enzyme systems. Pharmacological Depressants. An entire medical specialty is devoted to control of the depression of the nervous system by anesthetic agents. The essential difference between the clinical effects of these drugs and of those substances usually considered noxious is that the effects of anesthetics may be controlled and are normally reversible. The precise mechanism through which depressants exert their effects has never been clearly elucidated. However, the effects of the barbiturates may probably be typical of many of the depressants. The depression observed following the injection or ingestion of large amounts of the barbiturates is believed to be due to an inhibition of cerebral intracellular enzymes (dehydrogenase). Quastej22 demonstrated many years ago that the barbiturates inhibit the oxidation of glucose, lactic aNd pyruvic acids by excised cerebral tissue. This inhibition is reversible. More recently it has been demonstrated in man that the cerebral metabolic rate is diminished during pentothal narcosis and that the rate of oxidation by cerebral cortex is depressed earlier and more profoundly than that of the rest of the brain. 23]'Lately more rational attempts at therapy of pharmacological central nervous system depression by the use of sodium succinate24 and cytochrome C25 have
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
been made; however, the effectiveness of such treatment is still highly controversial. Hormones. The influence of hormones on the cerebral metabolic mechanism has received considerable attention, but the only studies the results of which are reasonably conclusive are those concerning insulin and the thyroid hormone. Insulin may be summarily dismissed with the remark that the effects of hyperinsulinism on cerebral function are those of hypoglycemia, the mechanism for which resides in sites far removed from the brain. The familiar observation that cerebral function is not altered in uncomplicated diabetes, as well as careful experimental studies, demonstrate that the brain does not require insulin in its metabolism of glucose. The laboratory evidence for this statement is embodied in the fact that a respiratory quotient of unity for the brain has been obtained in completely depancreatized animals and in isolated cerebral tissues deprived of insulin. 26 , 27 It has been assumed from clinical observations that the motor and psychological aberrations observed in hyper- and hypothyroid states reflect alterations in cerebral metabolism due directly to local excess or deficiency of the thyroid hormone. Such reasoning derives its major support from analogy to the well-known response characteristic:s of many widely different tissues. Critical analysis of in vivo and in vitro studies of brain metabolism indicates that such an assumption is not justified. Brain tissues excised from adult rats made hyper- or hypothyroid have failed to disclose a metabolic rate significantly different from the normal.2 8 In the developing rat the only observed difference has been an acceleration toward maturity caused by the hyperthyroid state. Hypothyroidism in the developing rat has been without apparent effect on the cerebral metabolic rate. In vivo studies by Scheinberg29 support these findings in that the cerebral oxygen consumption is not increased in human hyperthyroids; and the decrease which he observed in myxedema might well be accounted for by the reduction in oxygen availability caused by accompanying anemia and the decreased cerebral blood flow, the latter perhaps partly aggravated by subclinical cerebral arteriosclerosis, so common in the age group most subject to myxedema. The similarity in the depression of the cerebral metabolic rate in myxedema and cardiac failure, in both of which cerebral blood flow is decreased because of diminished cardiac output and increased cerebral vascular resistance, should be noted. From the teleological point of view, it should not be surprising that upon close examination the brain demonstrates a lack of enzyme response to changes in hormone concentration, in exception to the findings in most other tissues. It is difficult to conceive of survival of a complex
CEREBRAL METABOLIC DISEASE
1807
organism, highly dependent upon optimal function of a governing structure, if such a structure were more than minimally influenced by fluctuations in endocrine activity. Endogenous Depression. Even though changes in hormone concentration do not appreciably affect cerebral metabolism, coma is nevertheless a fairly frequent complication of uncontrolled diabetes. Studies by Kety and co-workers30 of the cerebral metabolism and blood flow of patients in diabetic coma have demonstrated an adequate oxygen saturation of the blood going to the brain, a normal or slightly increased cerebral blood flow despite general dehydration, but a significant fall in the cerebral metabolic rate. Particularly noteworthy is the observation that if the cerebral metabolic rate is below 2 cc. of oxygen per 100 gm of brain per minute, recovery of the patient is unlikely regardless o. the nature of the therapy employed.
Certainly one cannot attribute the cerebral metabolic depression to hyperglycemia. If anything, one might expect that hyperglycemia would tend to counteract the depression by accelerating toward normal the oxidation of glucose through a mass action effect. 31 The cause of the decreased cerebral metabolic rate in diabetic coma is unknown. The available evidence would seem to indicate that the impairment of activity of intracellular cerebral enzymes is due to the acidosis and ketosis,32 although such evidence is not sufficient to arrive at an unquestionable conclusion. In any case, all therapeutic efforts should be primarily directed toward alleviating as rapidly as possible the acidosis and ketosis. Therefore, on such theoretical grounds the importance of early intensive insulin therapy is again emphasized and should put an end to the fruitless discussion of the necessity for giving or not giving glucose to the patient in diabetic coma. Certainly claims for either procedure will mean very little in the future unless data is available to indicate the cerebral metabolic rates of the patients reported. Unfortunately adequate studies attempting to elucidate the mechanism for the endogenous depressions associated with other metabolic states (hepatic and uremic coma) have not as yet been made, and rational therapy must await the results of careful investigation. Deficiency of Enzymes. The many clinical syndromes associated with a deficiency of thiamine are well known. It should not be too surprising that the tissue most frequently affected by vitamin Bl deficiency is the central nervous system in view of this structure's dependence on glucose and the fact that vitamin Bl is essential for the oxidative decarboxylation of pyruvic acid which is a necessary intermediate in the metabolism of glucose. 33 In the absence of thiamine, therefore, glucose oxidation in the central nervous system can be expected to proceed only as far as pyruvic acid. In fact, the studies on cerebral tissue ex-
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
cised from animals with vitamin BI deficiency reveal a decrease in oxygen consumption, a respiratory quotient below unity, and the expected accumulation of pyruvic acid. 34 Detailed studies of cerebral metabolism of patients with Wernicke's disease have as yet not been performed. In this condition, the clouding of consciousness, varying ophthalmoplegias, and the ataxia have been attributed to damage confined for the most part to the periventricular gray matter. The syndrome is probably a combination of several nutritional deficiencies, but the observed disturbances in pyruvic acid metabolism and the response to thiamine pyrophosphate would seem to indicate that Wernicke's syndrome is invariably associated with a thiamine deficiency.35 Cerebral metabolic disturbances associated with vitamin deficiencies other than of thiamine should also be expected in view of the fact that the oxidation of glucose involves co-enzymes requiring nicotinic acid and riboflavin. Unfortunately adequate studies of cerebral metabolism have not been reported in patients exhibiting the dementia of pellagra and the acute nicotinic acid encephalopathy described by Jollife. 36 Because pure deficiency states involving individual members of the B group are rarely, if ever, observed clinically, it is very likely that artificial induction of such states will be required for their investigation. Although functional and eventually permanent structural spinal cord changes in pernicious anemia have long been recognized to be due to deficiency of some necessary specific vitamin rather than to the anemia itself, it is relatively recently that histological changes in the brain due to this disease have been identified. 37 That this is a deficiency disease in which permanent functional changes with or without obvious mental aberrations are also present may have been demonstrated by Scheinberg,29 who has reported in pernicious anemia a moderate to marked depression in cerebral oxygen consumption persisting indefinitely in many cases, even after therapy has rendered the patient hematologically normal. The validity of this conclusion is subject to the qualification that cerebral arteriosclerosis, not evident clinically, must not have been present in his subjects; pernicious anemia is most common in the age group wherein cerebral arteriosclerosis is also most frequent. CHANGES IN THE AVAILABILITY OF OXYGEN
The extreme dependence of the central nervous system upon oxygen has long been recognized. Brief episodes of anoxia are poorly tolerated and result in functional and structural changes within a very short period of time. This fact was well illustrated by the experiments of Kabat 38 in which he deprived the human brain of oxygen by causing acute complete arrest of the cerebral circulation. Following this procedure, he noted in normal young men that consciousness was lost in from 6 to
CEREBRAL METABOLIC DISEASE
1809
7 seconds. Restoration of the cerebral circulation after 100 seconds was followed by a rapid recovery of consciousness with no objective evidence of injury. In normal adult dogs, sudden and complete arrest of the circulation to the brain for periods longer than six minutes uniformly results in permanent coma, presumably due to a functional decortication. The marked sensitivity of mature cerebral cells to anoxia may to a large extent be related to their high oxygen requirement, which is indicated by the utilization by the normal adult brain of approximately one-fifth of the total oxygen uptake of the individual.2 The remarkable resistance of newborn animals to anoxia has been shown to be directly related to their low cerebral metabolic rate 39 and perhaps also to the fact that the newborn of certain species may obtain sufficient energy from anaerobic processes to maintain the functions of the vital centers. 40 For example, a newborn rat with a cerebral oxygen uptake of 1.25 cc. of oxygen per 100 gm. of brain per minute can survive in an atmosphere of pure nitrogen for about forty minutes. This is in marked contrast to the very short survival period after the cerebral oxygen uptake approaches the value found for the adult animal. At 15 days of age, the rat is unable to tolerate an atmosphere of pure nitrogen for periods longer than two minutes. Since the normal adult brain for the most part is an aerobic organ and cannot contract an oxygen debt, it must depend entirely on the circulating blood for a constant supply of oxygen. There are numerous clinical states in which, for one reason or another, an adequate supply of oxygen is not readily available to the cerebral cells. These states may best be depicted by Yandell Henderson's classification of anoxiaY Hypoxic anox1:a will result whenever there is lack of oxygen in the environment or an impairment in the diffusion of oxygen across the alveolar membranes. Anemic anoxia refers to those states in which the oxygencarrying capacity of the blood is reduced by either a lack of hemoglobin or interference by toxic agents with the formation or dissociation of oxyhemoglobin. The cerebral cells will suffer from stagnant anoxia whenever the cardiac output becomes inadequate to maintain the cerebral circulation or if there is a local obstruction to the flow of blood to any part of the brain. The cerebral blood flow in the adult normal individual in the supine position averages 65 cc. per 100 gm. of brain per minute. 2 Thus the amoullt of blood diverted to the brain represents approximately 14 per cent of the total cardiac output. In view of the high oxygen requirement of the central nervous system and its dependence on the circulating blood for its oxygen needs, adequacy of the circulation to the brain must be zealously guarded. There are certain compensatory mechanisms operating to correct, at least in part, any deficiency of the oxygen supply to the brain cells. These mechanisms are as follows: Peripherally there
1810
JOSEPH F. FAZEKAS, RALPH W. ALMAN
may be reflex elevation of the blood pressure, changes in the cardiac output, and shunting of blood away from the less important viscera. Locally there are reflex and chemical influences that regulate the rate of the cerebral blood flow by changing the caliber and resistance of the cerebral vessels. Finally the chemical dissociation of oxyhemoglobin is increased in the presence of a low pH or high carbon dioxide concentration. Whenever the organism is threatened by hypoxia, it may attempt to assure the brain of an adequate oxygen supply by increasing the cerebral TABLE 2 CONDITIONS TENDING TO IMPAIR CEREBRAL BLOOD FLOW AND/OR OXYGENATION --
Condition
Cerebral Blood Flow
Cerebral 0, Consumption
Cerebral Vascular Resistance
--.-".~-----
Normal', 2 . . • . . ........ . ..........
Hyperoxemia (85-100% O2)4 •. ... Systemic hypoxia (10% O2)'6. ... . . Polycythemia'6 .. ............ . . Anemia 29 . . . ..... . ..... . . ........ Cardiac decompensation 47 . • . . . . • . Myxedema 29 . . • . . ................. Iner. intracran. pressure's' .. ...... Upright posture 2 . . . . . . . . . . . . . . . . . . Cerebral vasc. disease 49 . .... -
cc. 1.3-1.6 mm. 54-65 cc. per 3.3-3.8 100 gm. per per 100 gm. Hg per cc. per 100 gm. per min. per. min. min.
-13·5% +35·2% -53·7% +46·3% -36·5% -38·0% -37·0% -20·8% -36·5%
+3·2% -5·9% -9·1% Normal -13·2% -27·0% -15·3% Normal -24·3%
+29·4% -35·3% +169·0% -37·5% +98·5%* +92'0%* +117·0% -15·8% +154·0%
* The possibility must be considered that the increased cerebral vascular resistance, with secondary reduction of cerebral blood flow and oxygen consumption, is partly due to subclinical cerebral arteriosclerosis in the subjects investigated. blood flow, decreasing the cerebral vascular resistance, or increasing the dissociation of oxyhemoglobin. If a disease state interferes with the compensatory mechanisms tending to maintain a normal cerebral blood flow or if their physiological limitations render them inadequate, there results a decrease in cerebral oxygenation unless the remaining mechanisms are sufficiently active. Examples of abnormal states and their general cerebral effects, sometimes permitting full compensation of hypoxic tendencies, are listed'in the following table (Table 2). Occlusion of a cerebral vessel following thrombosis or embolism exemplifies the severest form of stagnant anoxia. After such an event, there is a deficiency of all substances necessary to maintain normal
1811
CEREBRAL METABOLIC DISEASE
metabolism, as well as the accumulation of metabolic and abnormal waste products. In addition to the varying susceptibility of different portions of the brain, there are local factors that influence the extent of the damage resulting from the ischemia; namely, edema of neighboring tissues and spasm of adjacent vessels. Necrosis of tissue may be expected within a very short period of time unless the collateral circulation can correct the local stagnant anoxia. Clinicians have for quite some time concerned themselves with this problem and have been advocating the use of various drugs and stellate ganglion block to improve the cerebral circulation in such states. Unfortunately the efficacy of the various drugs recommended has not been proved except by observing the clinical response of the patient, frequently an unreliable index (Table 3). TABLE 3 RESPONSE OF CEREBRAL BLOOD FLOW TO VARIOUS AGENTS
Agents Nicotinic acid 60 .. CO2, 5-7%61 .................. . Aminophylline 62 . . . . • • . . . . . . . . . MgSO•............. Papaverine 63 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histamine .............................. . Stellate block" ......................... . 85-100% Oxygen 46 • • • . . . • • . . • . . . • • . • • • . . . .
Cerebral Blood Flow % Change +19·0 +88·0 -20·0 ? ? 0 -13·5
Cerebral Vasc. Resistance % Change -25·0 -30·0 ? ? ? 0 +3·2
The above table deserves some comment. It may be observed that as yet there are no studies to substantiate the efficacy of magnesium sulfate, papaverine and histamine as cerebral vasodilators. Rather interesting is the fact that aminophylline, a well-known peripheral vasodilator, causes a decrease in cerebral blood flow and an increase in the cerebral vascular resistance. One cannot conclude, therefore, that simply because a drug is a peripheral vasodilator it will have similar effects centrally. The value given for nicotinic acid was obtained by Aring using an indirect method of cerebral blood flow determination, employing displacement of spinal fluid after sudden compression of the neck veins.' Nicotinic acid causes such marked dilatation of extra cranial vessels that the nitrous oxide method of determining cerebral blood flow is rendered invalid. 29 The same objection may equally apply to future studies on histamine. In spite of the extreme optimism regarding stellate ganglion block, attempts at careful objective evaluation of its efficacy so far have failed
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JOSEPH F. FAZEKAS, RALPH W. ALMAN
to yield a definite conclusion. Scheinberg and co-workers,42 have examined the effects of unilateral and bilateral sympathetic block on cerebral blood flow in normal subjects and in patients suffering from cerebral thrombosis. They were unable to observe any significant change in the total blood flow through the brain following even bilateral stellate ganglion block. One might well argue that there may be regional changes in cerebral blood flow which might not be detectable by their total blood flow studies, since the early work of Talbott, W olff, and Cobb 43 on animals demonstrated that cervical sympathectomy was followed by a slight but significant increase in the cerebral capillary bed. The increase in blood flow following this procedure seemed to be localized to various areas of the central nervous system and was not necessarily generalized. The variation of response in the different areas, however, calls for comment. Stohr44 inferred from his investigations that there are several routes for cerebral vasomotor nerves at the base of the brain. "All the brain vessels are not necessarily supplied by anyone nerve, ana anyone vessel may, in fact, be supplied from several sources. Therefore, after unilateral section of the cervical sympathetic nerve it is unlikely that all parts of the brain on that side will be equally affected or even that any vessel will be permanently or seriously altered. It would seem reasonable to assume that one portion would be most affected, an intermediate portion less affected, and other portions perhaps not affected at all." In view of the questionable effectiveness of stellate ganglion block and the certain knowledge that carbon dioxide is the most potent cerebral vasodilator known, one wonders why more complicated and far less efficient procedures are resorted to when a simple, nontoxic, inexpensive, physiologicat, and experimentally highly effective agent is readily available. SUMMARY AND CONCLUSIONS
In vivo experimental methods now available supplement previous observations and afford more accurate information regarding total cerebral metabolism and blood flow in a variety of clinical states. These studies complemented by in vitro and clinical observations permit the formulation of certain fundamental concepts concerning cerebral tissue. The cerebral metabolic rate depends upon the integrity of (1) the intracellular metabolizing mechanisms (enzymes), (2) the substrate supply, and (3) the availability of oxygen. Interference with any of these divisions, if of sufficient magnitude and duration, will result in functional and structural changes in the central nervous system. Clinical examples of diseases causing such disturbances are cited. The results of studies to date permit several hypotheses to be formulated:
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1. Cerebral metabolism probably proceeds normally at a maximal rate. Although it may be depressed with relative ease by substrate deprivation, by inhibition or deficiency of intracellular enzymes, or by oxygen lack, there is no conclusive evidence that the normal adult cerebral metabolic rate may be accelerated. Such factors as elevated temperature and pharmacological stimulants at least do not cause a detectable increase in normal cerebral metabolism. An increase or decrease in the concentrations of hormones (insulin and thyroxin) does not appear to affect the cerebral metabolic rate. 2. The graded sensitivity of various parts of the central nervous . system to impairment of energy supply reflects local differences in metabolic requirements and therefore in metabolic rate. 3. There are compensatory mechanisms which tend to maintain an adequate supply of oxygen to the brain in the face of systemic hypoxia; such mechanisms are least efficient in local stagnant hypoxia and are subject to moderate or marked impairment by diseases. The compensatory mechanism of local cerebral vasodilatation may best be stimulated by the inhalation of carbon dioxide; other "cerebral vasodilators" are of questionable value. REFERENCES 1. Kety, S. S. and Schmidt, C. F.: The Nitrous Oxide Method for the Quantitative Determination of Cerebral Blood Flow in Man: Theory, Procedure and Normal Values. J. Clin. Investigation 27:476-514,1948. 2. Scheinberg, Peritz and Stead, E. A. Jr.: The Cerebral Blood Flow in Male Subjects as Measured by the Nitrous Oxide Technique. Normal Values for Blood Flow, Oxygen Utilization, Glucose Utilization, and Peripheral Resistance, with Observations on the Effect of Tilting and Anxiety. J. Clin. Investigation 28:1163-1171,1949. 3. Kety, S. S.: Circulation and Metabolism of the Human Brain in Health and Disease. Am. J. Med. 8:205-218, 1950. 4. Hicks, Samuel P.: Brain Metabolism in Vivo. Arch. Path. 49:111-137, 1950. 5. Himwich, H. E. and Nahum, L. H.: Respiratory Quotient of the Brain. Proc. Soc. Exper. BioI. Med. 26:496-497,1929. 6. Himwich, H. E. and Nahum, L. H.: The Respiratory Quotient of the Brain. Am. J. PhysioI. 101 :446-453, 1932. 7. Himwich, H. E. and Fazekas, J. F.: Respiratory Quotient of Various Parts of the Brain. Proc. Soc. Exper. BioI. Med. 30:366,1932. 8. Himwich, H. E. and Fazekas, J. F.: Anaerobic Survival of Adult Animals. Am. J. PhysioI. 139:366-370, 1943. 9. Kety, S. S., Woodford, R. B., Harmel, M. H., Freyhan, F. A., Appel, K. E. and Schmidt, C. F.: Cerebral Blood Flow and Metabolism in Schizophrenia. The Effects of Barbiturate Semi-narcosis, Insulin Coma and . Electroshock. Am. J. Psychiat. 104:765-769, 1948. 10. Himwich, H. E., Frostig, J. P., Fazekas, J. F. and Hadidian, Z.: The Mechanism of the Symptoms of Insulin Hypoglycemia. Am. J. Psychiat. 96:371385, 1939. 11. Maddock, S., Hawkins, J. E., Jr. and Holmes, E.: Inadequacy of Substances of "Glucose Cycle" for Maintenance of Normal Cortical Potentials During Hypoglycemia Produced by Hepatectomy with Abdominal Evisceration. Am. J. Physiol. 125:551-565, 1939.
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12. Hoagland, Hudson, Himwich, H. E., Campbell, Eldridge, Fazekas, J. F. and Hadidian, Zareh: Effects of Hypo;z;lycemia and Pentobarbital Sodium on Electrical Activity of Cerebral Cortex and Hypothalamus (Dogs). J. Neurophysiol 2:276-288, 1939. 13. Himwich, H. E., Bowman, K. M. and Fazekas, J. F.: Prolonged Coma and Cerebral Metabolism. Arch. Neurol. & Psychiat. 44:1098-1101, 1940. 14. Himwich, H. K, Fazekas, J. F., Bernstcin, A. 0., Campbell, K H. and Martin, S. J.: Syndromes Secondary to Prolonged Hypoglycemia. Proc. Soc. Exper. BioI. & Med. 39:244-245,1938. 15. Tanenberg, J.: Am. J. Path. 15:25, 1939. 16. Field, John (2d), Fuhrman, F. A. and Martin, A. W.: Effect of Tempcrature on the Oxygen Consumption of Brain Tissue. J. Neurophysiol. 7:117-126, 1944. 17. Himwich, H. K, Bowman, K. M., Fazekas, J. F. and Goldfarb, W.: Tempera- . ture and Brain Metabolism. Am. J. M. Sc. 200:537-538, 1939. 18. Heyman, Albert, Patterson, J. L., Jr. and Nichols, F. T., Jr.: The Effects of Pyrogen-induced Fever on Cerebral Function in Neurosyphilis. (In press.) 19. Fazekas, J. F. and Himwich, H. E.: Effect of Hypothermia on Cerebral Metabolism. Proc. Soc. Exper. BioI. & Med. 42:537-538, 1939. 20. Libet, B., Fazekas, J. F., Meirowsky, A. M., Campbell, E. H. and Himwich, H. E.: Control of Electrical and Oxidative Activity of Brain by Temperature. Am. J. Physiol. 129:404-405, 1940. 21. Eckenhoff, J. E., Schmidt, C. F., Dripps, Il. D. and Kety, S. S.: A Status Report on Analeptics. J.A.M.A. 139:780-785, 1949. 22. Quastel, J. H.: Respiration in the Central Nervous System. Physiol. Rev. 19:135-183, 1939. 23. Etsten, B., York, G. K and Himwich, H. E.: Pattern of Metabolic Depression Induced with Pentothal Sodium. Arch. Neurol. & Psychiat. 56:171184,1946. 24. Barrett, R. H.: Sodium Succinate-An Analeptic for Barbiturate Poisoning in Man. Ann. Int. Med. 31:739-750,1949. 25. Proger, Samuel: Some Effects of Injected Cytochrome C in Animals and Man. Bull. New England Med. Center 7:1-8,1945. 26. Fazckas, J. F. and Himwich, H. E.: Effect of Nicotine on the Oxidations of the Diabetic Brain. Am. J. Physiol. 116:46--47, 1936. 27. Baker, Z., Fazekas, J. F. and Himwich, H. E.: Carbohydrate Oxidation in Normal and Diabetic Cerebral Tissues. J. BioI. Chem. 125:545-556, 1938. 28. Fazekas, J. F.: Unpublished data. 29. Scheinberg, Peritz: Personal communication. 30. Kety, S. S., Polis, B. D., Nadler, C. S. and Schmidt, C. F.: The Blood Flow and Oxygen Consumption of the Human Brain in Diabetic Acidosis and Coma. J. Clin. Investigation 27:476--514, 1948. 31. Soskin, S. and Levine, R.: A Relationship Between the Blood Sugar Level and the Rate of Sugar Utilization Affecting the Theories of Diabetes. Am. J. Physiol. 120:761, 1937. 32. Schneider, R. and Droller, H.: Relative Importance of Ketosis and Acidosis in Production of Diabetic Coma. Quart. J. Exper. Physiol. 28:323, 1938. 33. Peters, R. A.: Biochemical Lesion in Vitamin Bl Deficiency; Application of Modern Biochemical Analysis in Its Diagnosis. Lancet 1 :1161-1165, 1936. 34. Banga, I., Ochoa, S. and Peters, It. A.: Pyruvate Oxidation in Brain: Some Dialyzable Components of Pyruvate Oxidation System. Biochem. J. 33:1980, 1939. 35. Wortis, Herman, Bueding, Ernest, Stein, M. H. and Jolliffe, Norman: Pyruvic Acid Studies in the Wernicke Syndrome. Arch. Neurol. & Psychiat. 47:215222,1942. 36. Joliffe, N., Bowman, K. M., Rosenblum, L. A. and Fein, H. D.: Nicotinic Acid Deficiency Encephalopathy. J.A.M.A. 114:307, 1940.
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37. Adams, R. D. and Kubik, C. S.: Subacute Degeneration of Brain in Pernicious Anemia. New England J. Med. 231 :1~9, 1944. 38. Rossen, Ralph (Lt.), Kabat, Herman and Anderson, J. P.: Acute Arrest of Cerebral Circulation in Man. 50:51O~529, 1943. 39. Himwich, H. E., Baker, Zelma and Fazekas, J. F.: The Respiratory Metabolism of Infant Brain. Am. J. Physiol. 125:601-606, 1939. 40. Himwich, H. E., Bernstein, A. 0., Herrlich, H., Chesler, A. and Fazekas, J. F.: Mechanisms for the Maintenance of Life in the Newborn During Anoxia. Am. J. Physiol. 135:387, 1942. 41. Henderson, Yandell: Adventures in Respiration. Baltimore, Williams & Wilkins Co., 1938. 42. Scheinberg, Peritz: Cerebral Blood Flow in Vascular Disease of the Brain. Am. J. Med. 8:139~152, 1950. 43. Talbott, J. H., Woltf, H. G. and Cobb, Stanley: The Cerebral Circulation. Arch. Neurol. & Psychiat. 21:1102~1106, 1929. 44. Stohr, P.: Ztschr. f. Anat. u. Entwicklungs Gesellsch. 63:562, 1922. 45. Kety, S. S. and Schmidt, C. F.: The Effects of Alterations in the Arterial Tensions of Carbon Dioxide and Oxygen on Cerebral Blood Flow and Cerebral Oxygen Consumption of Normal Young Men. J. Clin. Investigation 27:484, 1948. 46. Kety, S. S.: Unpublished observations. 47. Scheinberg, Peritz: Cerebral Circulation in Heart Failure. Am. J. Med. 8:148153, 1950. 48. Kety, S. S., Shenkin, H. A. and Schmidt, C. F.: The Effect of Increased Intracranial Pressure on Cerebral Circulatory Functions in Man. J. Clin. Investigation, 27:493,1948. 94. Freyhan, F. A., Woodford, R. B. and Kety, S. S.: The Blood Flow, Vascular Resistance and Oxygen Consumption of the Brain in the Psychoses of Senility. J. Nerv. & Ment. Dis. (in press). 50. Aring, C. D., Ryder, H. W., Roseman, Ephraim, Rosenbaum, Milton and Ferris, E. B., Jr.: Effect of Nicotinic Acid and Related Substances on the Intracranial Blood Flow of Man. Arch. Neurol. & Psychiat. 46:649~ 654, 1941. 51. Kety, S. S. and Schmidt, C. F.: The Effects of Altered Arterial Tensions of Carbon Dioxide and Oxygen on Cerebral Blood Flow and Cerebral Oxygen Consumption of Normal Young Men. J. Clin. Investigation 27:484492, 1948. 52. Wechsler, R. L., Kleiss, L. M. and Kety, S. S.: The Effects of Intravenously Administered Aminophylline on Cerebral Circulation and Metabolism in Man. J. Clin. Investigation 29:28~31, 1950. 53. de Takats, G.: The Use of Papaverine in Acute Arterial Occlusions. J.A.M.A. 106:1003, 1936.