CEREBRAL BLOOD FLOW AND OXYGEN CONSUMPTION IN

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1 CEREBRAL BLOOD FLOW AND OXYGEN CONSUMPTION IN NEUROSYPHILIS By JOHN L. PATTERSON, JR., ALBERT HEYMAN, AND FENWICK T. NICHOLS, JR. (From the Departments of Physiology and Medicine, Emory University School of Medicine, and the Clinic for Genito-infectious Diseases, Grady Memorial Hospital and the Georgia Department of Public Health, Atlanta, Ga.) (Submitted for publication February 1, 195; accepted, July 1, 195) The blood vessels of the brain are involved to a major extent in the pathologic changes of late neurosyphilis. Narroing or obliteration of the vascular lumen frequently results. In dementia paralytica the smaller blood vessels, particularly the capillaries, sho the more marked changes, hile the medium-sie and larger arteries are principally affected in meningovascular syphilis (1). Nerve cell destruction and cortical atrophy occur in both conditions, but are usually more striking and idespread in dementia paralytica. Functional changes in the cerebral circulation and metabolism ould be expected to accompany such anatomical alterations. A diminution in total intracranial blood flo has been found in severely demented patients ith general paresis (2), but the method used is no believed to yield abnormally lo values. It very probably gives a correct indication, hoever, of the direction of change in flo. Himich and Faekas (3) reported a definite reduction in the cerebral arteriovenous oxygen difference in a patient ith dementia paralytica, hile Wortis, Boman and Goldfarb (4) found only a slight diminution of questionable significance in a series of 18 patients. The recent development of Kety and Schmidt (5) of the nitrous oxide method for the determination of cerebral blood flo (CBF) has provided a reasonably accurate technique for the study of the cerebral circulation and metabolism. The present report presents studies ith this technique on 58 patients ith various types of neurosyphilis and on 16 control subjects. METHODS The majority of patients ith paresis had moderately or far advanced dementia, the duration of hich varied from to to 18 months, and averaged 1 months. Most of the patients ith meningovascular syphilis ere studied ithin a fe eeks after the occurrence of an acute vascular syndrome, such as hemiplegia or cranial nerve palsy. The duration of the infection in the patients ith asymptomatic neurosyphilis varied from to to 28 years. The only evidences of neurosyphilis on physical examination in this latter group of patients ere pupillary abnormalities in to individuals. All of the patients ith neurosyphilis had abnormal spinal fluid findings, consisting of increased cell counts, elevated protein content, and a strongly positive Wassermann reaction. The average ages in the different groups ere: dementia paralytica, 46 years; meningovascular syphilis, 44 years; and asymptomatic neurosyphilis, 38 years. The control group of 16 subjects had an average age of 34 years and consisted of patients ho ere convalescing from various acute illnesses, such as pneumonia and gonococcal arthritis. There as no evidence of intracranial complication in any of these patients. In the patients ith neurosyphilis, the determinations ere carried out either before penicillin or fever therapy as begun or ithin a fe days after the beginning of treatment. All subjects ere afebrile at the time of study and the determinations ere made ith the patients in the supine position. If the patient shoed undue anxiety or visible hyperventilation during the procedure, the determination as rejected as invalid. The effects of penicillin and fever therapy ere studied in 17 patients ith neurosyphilis. Six patients ith dementia paralytica and one ith meningovascular syphilis ere given malarial fever therapy combined ith penicillin, hile five patients ith dementia paralytica and five ith meningovascular syphilis received penicillin alone. Fever therapy for each case consisted of an average of 1 malarial paroxysms ith approximately 5 hours of temperature above 13 F. The total dosage of penicillin as 4.8 to 6. million units given in divided doses every three hours for a period of eight to 12 days. A complete neurologic and mental The subjects ith neurosyphilis ere either patients status examination as done on each patient before and on the ards of Grady Memorial Hospital or out-patients in the Genito-infectious Disease Clinic. There The cerebral blood flo as determined by the method after treatnent. ere 26 patients ith dementia paralytica, nine ith of Kety and Schmidt, ith minor modifications. The meningovascular syphilis, and 23 ith asymptomatic blood sampling procedure as simplified by connecting neurosyphilis. the sampling syringes directly to the needle in the in- 1327

2 1328 JOHN L. PATTERSON, JR., ALBERT HEYMAN, AND FENWICK T. NICHOLS, JR. ternal jugular vein and to the needle in the femoral artery. The area beteen the arterial and venous nitrous oxide curves as measured by use of a planimeter rather than by calculation ith the trapeoid rule. The difference beteen the results obtained by the to methods as found to be negligible, and the planimetric method as used because of its simplicity. The arterial and venous oxygen and carbon dioxide contents ere obtained from samples dran just before and at the end of the flo procedure. If the arteriovenous difference of these gases had changed during the procedure by more than 2 volumes per cent, the test as rejected as invalid. The cerebral oxygen consumption (CMRO2) as obtained from the product of the blood flo and the arteriovenous oxygen difference. The analyses of blood for nitrous oxide ere done by the method of Orcutt and Waters (6), as modified by Kety and Schmidt, and for carbon dioxide and oxygen by the Van Slyke-Neill manometric techniques (7), also as modified by Kety and Schmidt for blood containing nitrous oxide. Recent studies in this laboratory suggest that the use of Baker saponin together ith the modifications, published in 1943, of the original method of Van Slyke and Neill for oxygen analysis may account for the slightly lo value for cerebral arteriovenous oxygen difference noted in the control subjects. The partition coefficient of nitrous oxide beteen the blood and the brain in paresis as found to be the same as in normal brain (8). The original method of calculating the amount of nitrous oxide taken up by the brain as therefore used ithout change. In order to rule out the possibility of increased contamination of internal jugular blood by extracerebral venous blood, the period of inhalation of nitrous oxide as increased to 14 minutes in 14 patients ith paresis. The differences beteen the blood flos calculated for 14 minutes and for 1 minutes did not indicate excessive admixture. Mean arterial pressure as obtained from a damped mercury manometer connected to the femoral arterial needle. The cerebral vascular resistance (CVR) as calculated by dividing the average arterial pressure during the flo procedure by the cerebral blood flo. It represents the mean perfusion pressure required to produce a flo of 1 cc. of blood through 1 Gm. of brain per minute. RESULTS The mean values and standard deviations obtained in the control subjects and in the various groups of patients ith neurosyphilis are given in Table I. Cerebral blood flo. The mean value for cerebral blood flo in the control subjects as 58 cc./ 1 Gm. brain/min. (Figure 1). In the patients ith asymptomatic neurosyphilis the distribution of the cerebral blood flo values and the mean ere not significantly different from those found in the control subjects (p >.1). In the subjects ith meningovascular syphilis the mean CBF as 38 cc./1 Gm. brain/min., or 66 per cent of normal. This reduction as statistically significant (p <.1). The reduction of blood flo did not correlate ith the clinical state. Some of the patients ith the loest flo values had only mild meningovascular manifestations, such as a transient ophthalmoplegia, hereas patients ho had had hemiplegia and coma sometimes shoed CBF values approaching normal. The larger group of patients ith dementia paralytica shoed a similar reduction in CBF TABLE I Mean values and standard deviations in control subjects and in patients ith untreated neurosyphilis Control Asymptomatic Meningovascular Dementia subjects (16) neurosyphilis (23) syphilis (9) paralytica (26) Mean* Mean a Mean Mean Cerebral blood flo 58 :1: 7 55 t1 38 A : 9 cc./1 Gm./min. Cerebral oxygen consumption :1: L :.7 cc./1 Gm./min. Cerebral vascular resistance 1.8 t mm. Hg/cc./1 Gm./min. A-V oxygen difference :1 1.3 volumes % Respiratory quotientt :1:.24 Mean arterial blood pressure 15 d :414 mm. Hg Hematocrit * All mean values have been calculated from the data on individual patients. t This function as determined in 13 of the control subjects, 1 patients ith asymptomatic neurosyphilis, six ith meningovascular-syphilis, and 15 ith dementia paralytica. Figures in parenthesis indicate number of patients in each group.

3 CEREBRAL BLOOD FLOW AND 2 CONSUMPTION IN NEUROSYPHILIS I 7 ; : 45 IL a 25 j 2 15 S 1 I * * - u-* e. t v s~ p<.o 4~~~ ~~~ p<.oo too 9 s 8 i c) NORMAL ASYMPTO- MENINGO- PARESIS MATIC VASCLAR FIG. 1. THE VALUES OBTAINED FOR CEREBRAL BLOOD FLO IN THE INDIVIDUAL PATIENTS IN THIS STUDY The arros point to the mean value in each group. mean value in the control subjects O The broken line indicates the 1-3- S2 8 43o Os D OW9e t * *y4p -o * - ** 1~~~ E 8 2 7I 6 ' 4 II 3 p>.8 p<.oi p<ooi 2 1 NORMAL ASYMPT- MENINGO- PARESIS MATIC VASCULAR FIG. 2. VALUES FOR CEREBAL OXYGEN CONSUMPTION IN THE INDMDUAL PATIENTS IN THIS STUDY The arros indicate the mean value in each group. The broken line indicates the mean value in the control subjects.

4 -133 JOHN L. PATTERSON, JR., ALBERT HEYMAN, AND FENWICK T. NICHOLS, JR. ith a mean value of 42 cc./1 Gm. brain/min., or 72 per cent of normal. The distribution of these values and the mean reduction in CBF ere statistically significant (p <.1). The greatest reduction in CBF usually occurred in patients ith the most advanced degree of dementia, but in general there as poor correlation beteen the cerebral blood flo and the degree of mental deterioration. The hematocrit reading in the various groups of patients as not significantly different and ould not be expected to influence the mean CBF values (Table I). Cerebral oxygen consumption. The mean CMRO2 in the control subjects as 3.1 cc./1 Gm. brain/min. (Table I, Figure 2), a value agreeing ith the figure of 3.3 obtained by Kety and Schmidt. The average CMRO2 and the distribution of the results in the patients ith asymptomatic neurosyphilis ere very similar to those obtained in the control group. The patients ith meningovascular syphilis, hoever, shoed a diminished cerebral oxygen uptake ith an average of 2.4 cc., or 77 per cent of normal. The distribution of these values is significantly different from that of the controls (p <.1). The patients ith dementia paralytica exhibited a similar diminution in oxygen consumption, the mean value being 2.2 cc./1 Gm. brain/min., or 73 per cent of normal. Marked reductions in CMRO2 ere noted in several patients ith paresis, the values in these instances being less than 4 per cent of normal. In one patient ith far advanced dementia, the oxygen consumption as only.76 cc./1 Gm. brain/min., or 24 per cent of the normal mean. A definite correlation could usually be made beteen the degree of mental deterioration and the reduction in the cerebral oxygen consumption in these patients. The CMRO2 in seven patients ith moderate degrees of mental deterioration as 2.7 cc., hile 12 patients ith marked dementia and six ith extreme degrees of dementia had values of 2.3 and 1.6 cc., respectively. The cerebral respiratory quotient (carbon dioxide arteriovenous difference divided by oxygen arteriovenous difference) in the control subjects, as ell as the various groups of neurosyphilitic patients, as approximately unity (Table I). Other orkers (5, 9) have also obtained similar values in normal individuals. Cerebral vascular resistance. In the control subjects, the average value for the CVR as 1.8 mm. Hg/cc./1 Gm. brain/min. (Table I). In the patients ith asymptomatic neurosyphilis the mean CVR as not significantly different (p > TABLE II Changes folloing treatment of six patients ith meningovascular syphilis CBF CMRO2 CVR cc./1 Gm./ cc./1 Gm./ mm. Hg/cc./ Illness min. min. 1 Gm./min. Patient Clinical state duration Therapy Clinical outcome (days) Before After Before After Before After therapy therapy* therapy therapy* therapy therapy* J. H. Sudden syncope; tem- 5 Penicillin Complete recovery porary confusion Fever J. W. Chronic headache; sud- 15 Penicillin Complete recovery den confusion; transient nerve palsies B. B. Ophthalmoplegia; 44 Penicillin Complete recovery fixed pupils A. J. Progressive abducens? Penicillin No change palsy; fixed pupils R. L. Hemiplegia; abducens 5 Penicillin Paralysis improved palsy but developed paresis R. D. Repeated attacks of 21 Penicillin Developed another hemiplegia vascular accident Mean Mean change % 18t lot -lit * Post-treatment studies performed an average of three months after treatment completed. t Difference beteen means before and after treatment not statistically significant.

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6 1332 JOHN L. PATTERSON, JR., ALBERT HEYMAN, AND FENWICK T. NICHOLS, JR..3). Hoever, in meningovascular syphilis and in dementia paralytica, a significant increase in the CVR as found, the mean values being 2.8 (p <.1) and 2.4 (p <.1), respectively. The levels of the mean arterial pressure shoed only small differences in the various groups of subjects. The effect of treatment in meningovascular syphilis and dementia paralytica. In six patients ith meningovascular syphilis, cerebral blood flo determinations ere repeated at an average interval of three months folloing treatment. At this time four of them shoed an appreciable increase in CBF, one shoed a slight fall, hile one patient had no significant change. In to patients the CMRO2 increased considerably; in one, it decreased; there ere only slight changes in the remaining three cases (Table II). In general, the correlation beteen the changes in the CBF and CMRO2 and the clinical course folloing therapy in this group of patients as not striking. Studies ere also repeated in 11 of the patients ith dementia paralytica an average of four _. ss, 5 months folloing treatment (Table III). The changes in the cerebral blood flo ere not consistent. The cerebral oxygen consumption, hoever, generally shoed a marked increase folloing therapy in the patients ith lo pre-treatment values. In patients ith relatively high values before treatment, the response of the CMRO2 as variable (Figure 3). These studies ere repeated in six of the 11 patients at a mean interval of nine months folloing treatment, at hich time little further change as found in most patients in either CBF or CMRO2. One patient (D. W), hoever, exhibited a considerable increase in CBF, hile another patient (C. C.) shoed a marked rise in CMRO2 over the first post-treatment value. The change in cerebral oxygen consumption in the individual patient could be correlated to some extent ith change in mental state. Each of the three patients ith dementia paralytica ho shoed little or no clinical improvement had a small decrease in CMRO2. Of the eight patients ith definite improvement, six had a considerable C. 5 c1. cr cd SH JD BP JF AO PARES IS FIG. 3. THE EFFECT OF TREATMENT ON THE CEREBRAL OXYGEN CONSUMP- TION IN PATIENTS WITH PARESIS The solid columns represent the pre-treatment and the stippled columns the post-treatment determinations. The numbers above the columns indicate the interval in months beteen the determinations.

7 CEREBRAL BLOOD FLOW AND 2 CONSUMPTION IN NEUROSYPHILIS increase in CMRO2, one shoed no change, and one had a moderate decrease in oxygen consumption. Figure 4 shos the changes in oxygen consumption in the first and second post-treatment studies plotted against the changes in blood flo observed at these times. The correlation beteen these changes as definite but of rather lo order (r =.68). Several of the patients ho had marked increases in oxygen consumption shoed only minor changes in blood flo. In only one patient as there a definite decrease in CBF ithout a corresponding alteration in CMRO2. It is evident that the changes in oxygen consumption ere proportionately much greater than those in blood flo. a.q U) LiJO CD>x I m-j (. PARESIS a r= ,+) ' *.5.5 (H) 1. j4 *1 o I* (-) (+) CHANGE IN CEREBRAL BLOOD FLOW FIG. 4. CORRELATION BETWEEN CHANGES IN CERE- BRAL BLOOD FLOW AND CHANGES IN CEREBRAL OXYGEN CONSUMPTION FOLLOWING TREATMENT OF PATIENTS WITH PARSIS The numbers in the abscissa and ordinate indicate the change in cc. of blood and oxygen, respectively, per 1 Gm. brain/min. The solid dots represent the change observed in the first post-treatment determination, hile the circles represent changes in the second post-treatment determination. DISCUSSION 1333 The decrease in cerebral blood flo observed in patients ith dementia paralytica and meningovascular syphilis is consistent ith the reduction in lumen of the cerebral vessels knon to occur in these conditions. The cerebral blood flo, as determined by the nitrous oxide technique, represents principally the flo through perfused brain and does not account for cerebral tissue hich is completely devoid of blood supply. If such tissue ere taken into consideration, the CBF per unit of total brain substance might, in some individuals, be loer than that indicated by our study. Patients ith advanced dementia paralytica often sho a considerable degree of cortical atrophy ith a loss in brain substance, amounting to 1 Gm. or more (1). In such individuals. the reduction in total cerebral blood flo should be somehat greater than that indicated by the reduction in flo per unit eight of brain. The total intracranial blood flo in dementia paralytica as indeed found to be reduced by Rosenbaum and his associates (2). These orkers, hoever, could not be certain hether this diminution in flo as the result of a decrease in the cerebral vascular bed associated ith decrease in brain volume or hether the blood flo per unit of brain substance as impaired. The results of our studies indicate that both factors may be operative. The patients ith asymptomatic neurosyphilis shoed mean CBF and CMRO2 values in the normal range. The average duration of syphilis as found to be less than nine years in the 12 patients in hom this factor could be determined. It seems probable that in most of these patients there ere only minimal changes in the cerebral vessels and parenchyma, hich ere evidently insufficient to produce alterations in cerebral circulation and metabolism. There as a tendency for the patients ith longer duration of neurosyphilis to have loer CBF values. Five of the seven patients ith the loer blood flos ere knon to have had the disease for 1 years or more. The to patients ith the loest CMRO2 values of 1.8 and 2 cc./1 Gm. brain/min. developed prompt relief of headaches and nervousness folloing penicillin treatment -and may, in retrospect, have been cases of symptomatic, possibly early paretic, neurosyphilis. The results of these studies have some bearing

8 1334 JOHN L. PATTERSON, JR., ALBERT HEYMAN, AND FENWICK T. NICHOLS, JR. on the problem of the pathogenesis of cortical atrophy in dementia paralytica. Merritt, Putnam and Campbell (11) have suggested that the degenerative changes in the cortex of the paretic brain are secondary to ischemia produced by disease of the cerebral vessels. The fact that the mean percentile reduction in blood flo before treatment in the patients ith dementia paralytica as almost identical ith that found in oxygen consumption (73 per cent vs. 72 per cent) may be evidence in support of this hypothesis. On the other hand, four patients shoed considerable improvement in CMRO2 and to others had a moderate decrease in CMRO2 ith very little or no change in cerebral blood flo. This dissociation of CBF and CMRO2 suggests that disease of the cerebral vessels may not be the sole cause of changes in nerve cell function. The nature and distribution of pathologic processes in the brain, as ell as the overall rate of cerebral metabolism, appear to be important factors in determining alterations in mental function. A reduction of cerebral oxygen consumption to 2. cc./1 Gm./min. is usually associated ith coma in patients ith diabetic acidosis, insulin shock and brain tumor (12). In contrast, six of our patients had CMRO2 values belo this level and, although greatly deteriorated, these individuals ere nevertheless conscious and capable of simple mental functions. SUMMARY 1. The cerebral blood flo (CBF), oxygen consumption (CMRO2), and vascular resistance (CVR) ere determined by the nitrous oxide technique in 58 patients ith neurosyphilis and 16 control subjects. 2. In patients ith dementia paralytica and meningovascular syphilis the mean CBF and CMRO2 ere significantly reduced, hile the mean CVR as significantly increased. In asymptomatic neurosyphilis these functions ere ithin the normal range. 3. In patients ith dementia paralytica, a definite correlation as found beteen the degree of mental deterioration and the reduction in cerebral oxygen consumption. 4. In patients ith meningovascular syphilis, treatment as usually folloed by a rise in CBF, hile the CMRO, shoed a variable response, 5. Treatment ith penicillin and fever as folloed by a rise in the CMRO2 in those patients ith dementia paralytica ho had lo pre-treatment values. This increase in CMRO2 as accompanied by improvement in mental state. ACKNOWLEDGMENT We are indebted to Dr. Seymour S. Kety for instruction in the technique utilied in this paper and to Misses Mary McPhaul, Fransetta Vinson, Ann Payne, Voncile Williams, and Eloise Cavin for their technical assistance. BIBLIOGRAPHY 1. Scheinker, I. M., Neuropathology in its Clinicopathologic Aspects. Charles C. Thomas, Springfield, Ill., Rosenbaum, M., Roseman, E., Aring, C. D., and Ferris, E. B., Jr., Intracranial blood flo in dementia paralytica, cerebral atrophy and schiophrenia. Arch. Neurol. & Psychiat., 1942, 47, Himich, H. E., and Faekas, F., The oxygen content of cerebral blood in patients ith acute symptomatic psychoses and acute destructive brain lesions. Am. J. Psychiat., 1944, 1, Wortis, J., Boman, K. M., and Goldfarb, W., Human brain metabolism. Normal values and values in certain clinical states. Am. J. Psychiat., 194, 97, Kety, S. S., and Schmidt, C. F., The nitrous oxide method for the quantitative determinations of cerebral blood flo in man: theory, procedure and normal values. J. Clin. Invest., 1948, 27, Orcutt, F. S., and Waters, R. M., A method for the determination of cyclopropane, ethylene, and nitrous oxide in the blood ith the Van Slyke-Neill manometric apparatus. J. Biol. Chem., 1937, 117, Peters, J. P., and Van Slyke, D. D., Quantitative Clinical Chemistry, Vol. II, Methods. Williams & Wilkins, Baltimore, (Emended Editon.) 8. Kety, S. S., Harmel, M. H., Broomell, H. T., and Rhode. C. B., The solubility of nitrous oxide in blood and brain. J. Biol. Chem., 1948, 173, Lennox, W. G., The cerebral circulation. 'XIV. The respiratory quotient of the brain and of the extremities in man. Arch. Neurol. & Psychiat., 1931, 26, Merritt, H. H., Adams, R. D., and Solomon, H. C., Neurosyphilis. Oxford University Press, Ne York, Merritt, H. H., Putnam, T. J., and Campbell, A. C. P., Pathogenesis of the cortical atrophy observed in dementia paralytica. Arch. Neurol. & Psychiat., 1937, 37, Kety, S. S., Circulation and metabolism of the human brain in health and disease. Am. J. Med., 195, 8, 25,