CEREBRALBLOODFLOWANDOXYGENCONSUMPTIONINNEUROSYPHILIS

By JOHNL. PATTERSON,JR., ALBERTHEYMAN,ANDFENWICKT. 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 10, 1950; accepted, July 10, 1950)

The blood vessels of the brain are involved toa major extent in the pathologic changes of lateneurosyphilis. Narrowing or obliteration of thevascular lumen frequently results. In dementiaparalytica the smaller blood vessels, particularlythe capillaries, show the more marked changes,while the medium-size and larger arteries areprincipally affected in meningovascular syphilis(1). Nerve cell destruction and cortical atrophyoccur in both conditions, but are usually morestriking and widespread in dementia paralytica.

Functional changes in the cerebral circulationand metabolism would be expected to accompanysuch anatomical alterations. A diminution intotal intracranial blood flow has been found inseverely demented patients with general paresis(2), but the method used is now believed to yieldabnormally low values. It very probably givesa correct indication, however, of the direction ofchange in flow. Himwich and Fazekas (3) re-ported a definite reduction in the cerebral ar-teriovenous oxygen difference in a patient withdementia paralytica, while Wortis, Bowman andGoldfarb (4) found only a slight diminution ofquestionable significance in a series of 18 patients.

The recent development of Kety and Schmidt(5) of the nitrous oxide method for the determi-nation of cerebral blood flow (CBF) has provideda reasonably accurate technique for the study ofthe cerebral circulation and metabolism. Thepresent report presents studies with this techniqueon 58 patients with various types of neurosyphilisand on 16 control subjects.

METHODS

The subjects with neurosyphilis were either patientson the wards of Grady Memorial Hospital or out-pa-tients in the Genito-infectious Disease Clinic. Therewere 26 patients with dementia paralytica, nine withmeningovascular syphilis, and 23 with asymptomaticneurosyphilis.

The majority of patients with paresis had moderately orfar advanced dementia, the duration of which varied fromtwo to 18 months, and averaged 10 months. Most of thepatients with meningovascular syphilis were studiedwithin a few weeks after the occurrence of an acutevascular syndrome, such as hemiplegia or cranial nervepalsy. The duration of the infection in the patients withasymptomatic neurosyphilis varied from two to 28 years.The only evidences of neurosyphilis on physical exami-nation in this latter group of patients were pupillary ab-normalities in two individuals.

All of the patients with neurosyphilis had abnormalspinal fluid findings, consisting of increased cell counts,elevated protein content, and a strongly positive Wasser-mann reaction. The average ages in the different groupswere: dementia paralytica, 46 years; meningovascularsyphilis, 44 years; and asymptomatic neurosyphilis, 38years.

The control group of 16 subjects had an average ageof 34 years and consisted of patients who were con-valescing from various acute illnesses, such as pneumoniaand gonococcal arthritis. There was no evidence of in-tracranial complication in any of these patients. In thepatients with neurosyphilis, the determinations were car-ried out either before penicillin or fever therapy was be-gun or within a few days after the beginning of treat-ment. All subjects were afebrile at the time of study andthe determinations were made with the patients in the su-pine position. If the patient showed undue anxiety orvisible hyperventilation during the procedure, the de-termination was rejected as invalid.

The effects of penicillin and fever therapy were stud-ied in 17 patients with neurosyphilis. Six patientswith dementia paralytica and one with meningovascularsyphilis were given malarial fever therapy combinedwith penicillin, while five patients with dementia para-lytica and five with meningovascular syphilis receivedpenicillin alone. Fever therapy for each case consistedof an average of 10 malarial paroxysms with approxi-mately 50 hours of temperature above 103° F. Thetotal dosage of penicillin was 4.8 to 6.0 million unitsgiven in divided doses every three hours for a periodof eight to 12 days. A complete neurologic and mentalstatus examination was done on each patient before andafter treatnent.

The cerebral blood flow was determined by the methodof Kety and Schmidt, with minor modifications. Theblood sampling procedure was simplified by connectingthe sampling syringes directly to the needle in the in-

1327

JOHN L. PATTERSON, JR., ALBERT HEYMAN, AND FENWICK T. NICHOLS, JR.

ternal jugular vein and to the needle in the femoralartery. The area between the arterial and venous ni-trous oxide curves was measured by use of a planimeterrather than by calculation with the trapezoid rule. Thedifference between the results obtained by the twomethods was found to be negligible, and the planimetricmethod was used because of its simplicity.

The arterial and venous oxygen and carbon dioxidecontents were obtained from samples drawn just beforeand at the end of the flow procedure. If the arteriovenousdifference of these gases had changed during the procedureby more than 2 volumes per cent, the test was rejectedas invalid. The cerebral oxygen consumption (CMRO2)was obtained from the product of the blood flow and thearteriovenous oxygen difference.

The analyses of blood for nitrous oxide were done bythe method of Orcutt and Waters (6), as modified byKety and Schmidt, and for carbon dioxide and oxygenby the Van Slyke-Neill manometric techniques (7), alsoas modified by Kety and Schmidt for blood containing ni-trous oxide. Recent studies in this laboratory suggestthat the use of Baker saponin together with the modifi-cations, published in 1943, of the original method of VanSlyke and Neill for oxygen analysis may account for theslightly low value for cerebral arteriovenous oxygen dif-ference noted in the control subjects.

The partition coefficient of nitrous oxide between theblood and the brain in paresis was found to be the sameas in normal brain (8). The original method of calcu-lating the amount of nitrous oxide taken up by the brainwas therefore used without change. In order to ruleout the possibility of increased contamination of internaljugular blood by extracerebral venous blood, the periodof inhalation of nitrous oxide was increased to 14 minutesin 14 patients with paresis. The differences between theblood flows calculated for 14 minutes and for 10 minutesdid not indicate excessive admixture.

Mean arterial pressure was obtained from a dampedmercury manometer connected to the femoral arterialneedle. The cerebral vascular resistance (CVR) wascalculated by dividing the average arterial pressureduring the flow procedure by the cerebral blood flow.It represents the mean perfusion pressure required toproduce a flow of 1 cc. of blood through 100 Gm. ofbrain per minute.

RESULTS

The mean values and standard deviations ob-tained in the control subjects and in the variousgroups of patients with neurosyphilis are givenin Table I.

Cerebral blood flow. The mean value for cere-bral blood flow in the control subjects was 58 cc./100 Gm. brain/min. (Figure 1). In the patientswith asymptomatic neurosyphilis the distributionof the cerebral blood flow values and the meanwere not significantly different from those foundin the control subjects (p > .1).

In the subjects with meningovascular syphilisthe mean CBFwas 38 cc./100 Gm. brain/min., or66 per cent of normal. This reduction was statis-tically significant (p < .001). The reduction ofblood flow did not correlate with the clinical state.Some of the patients with the lowest flow valueshad only mild meningovascular manifestations,such as a transient ophthalmoplegia, whereas pa-tients who had had hemiplegia and coma some-times showed CBF values approaching normal.

The larger group of patients with dementiaparalytica showed a similar reduction in CBF

TABLE I

Mean values and standard deviations in control subjects and in patients with untreated neurosyphilis

Control Asymptomatic Meningovascular Dementiasubjects (16) neurosyphilis (23) syphilis (9) paralytica (26)

Mean* | Mean a Mean Mean

Cerebral blood flow 58 :1: 7 55 t10 38 A 8 42 4: 9cc./100 Gm./min.

Cerebral oxygen consumption 3.1 4 .4 3.1 :1: .6 2.4 L .5 2.2 : .7cc./100 Gm./min.

Cerebral vascular resistance 1.8 t .4 2.0 | .5 2.8 + .5 2.4 4 .7mm. Hg/cc./100 Gm./min.

A-V oxygen difference 5.5 + .9 5.7 + .1 6.5 + 1.5 5.4 :1 1.3volumes %

Respiratory quotientt 1.06 + .2 1.02 4 .18 .95 4 .27 1.03 :1: .24Mean arterial blood pressure 105 d22 106 414 104 413 96 :414

mm. HgHematocrit 38 4 4 41 4 5 43 4 5 39 4 4

* All mean values have been calculated from the data on individual patients.t This function was determined in 13 of the control subjects, 10 patients with asymptomatic neurosyphilis, six with

meningovascular-syphilis, and 15 with dementia paralytica.Figures in parenthesis indicate number of patients in each group.

1328

CEREBRALBLOODFLOWAND 02 CONSUMPTIONIN NEUROSYPHILIS

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with a mean value of 42 cc./100 Gm. brain/min.,or 72 per cent of normal. The distribution ofthese values and the mean reduction in CBF werestatistically significant (p < .001). The greatestreduction in CBF usually occurred in patientswith the most advanced degree of dementia, butin general there was poor correlation betweenthe cerebral blood flow and the degree of mentaldeterioration.

The hematocrit reading in the various groupsof patients was not significantly different andwould not be expected to influence the meanCBF values (Table I).

Cerebral oxygen consumption. The meanCMRO2in the control subjects was 3.1 cc./100Gm. brain/min. (Table I, Figure 2), a valueagreeing with the figure of 3.3 obtained by Ketyand Schmidt. The average CMRO2and the dis-tribution of the results in the patients with asymp-tomatic neurosyphilis were very similar to thoseobtained in the control group. The patients withmeningovascular syphilis, however, showed adiminished cerebral oxygen uptake with an aver-age of 2.4 cc., or 77 per cent of normal. The dis-tribution of these values is significantly differentfrom that of the controls (p < .01).

The patients with dementia paralytica exhibiteda similar diminution in oxygen consumption, the

mean value being 2.2 cc./100 Gm. brain/min., or73 per cent of normal. Marked reductions inCMRO2were noted in several patients with pare-sis, the values in these instances being less than40 per cent of normal. In one patient with faradvanced dementia, the oxygen consumption wasonly 0.76 cc./100 Gm. brain/min., or 24 per centof the normal mean. A definite correlation couldusually be made between the degree of mentaldeterioration and the reduction in the cerebraloxygen consumption in these patients. TheCMRO2in seven patients with moderate degreesof mental deterioration was 2.7 cc., while 12 pa-tients with marked dementia and six with ex-treme degrees of dementia had values of 2.3 and1.6 cc., respectively.

The cerebral respiratory quotient (carbon di-oxide arteriovenous difference divided by oxygenarteriovenous difference) in the control subjects,as well as the various groups of neurosyphiliticpatients, was approximately unity (Table I).Other workers (5, 9) have also obtained similarvalues in normal individuals.

Cerebral vascular resistance. In the controlsubjects, the average value for the CVRwas 1.8mm. Hg/cc./100 Gm. brain/min. (Table I). Inthe patients with asymptomatic neurosyphilis themean CVR was not significantly different (p >

TABLE II

Changes following treatment of six patients with meningovascular syphilis

CBF CMRO2 CVRcc./100 Gm./ cc./100 Gm./ mm. Hg/cc./

Illness min. min. 100 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 51 55 2.9 3.5 2.0 1.9 Complete recoveryporary confusion Fever

J. W. Chronic headache; sud- 15 Penicillin 45 36 2.7 1.6 2.2 3.5 Complete recoveryden confusion; trans-ient nerve palsies

B. B. Ophthalmoplegia; 44 Penicillin 42 52 1.7 3.0 2.6 2.1 Complete recoveryfixed pupils

A. J. Progressive abducens ? Penicillin 36 43 2.7 3.2 3.7 3.2 No changepalsy; fixed pupils

R. L. Hemiplegia; abducens 5 Penicillin 31 47 3.0 2.4 2.9 1.9 Paralysis improvedpalsy but developed

paresisR. D. Repeated attacks of 21 Penicillin 28 44 1.7 2.8 3.1 2.1 Developed another

hemiplegia vascular accident

Mean 39 46 2.5 2.7 2.8 2.5

Mean change % 18t lot -lit

* Post-treatment studies performed an average of three months after treatment completed.t Difference between means before and after treatment not statistically significant.

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.3). However, in meningovascular syphilis andin dementia paralytica, a significant increase inthe CVR was found, the mean values being 2.8(p < .01) and 2.4 (p < .001), respectively. Thelevels of the mean arterial pressure showed onlysmall differences in the various groups of subjects.

The effect of treatment in meningovascularsyphilis and dementia paralytica. In six patientswith meningovascular syphilis, cerebral blood flowdeterminations were repeated at an average in-terval of three months following treatment. Atthis time four of them showed an appreciable in-crease in CBF, one showed a slight fall, while onepatient had no significant change. In two pa-tients the CMRO2increased considerably; in one,it decreased; there were only slight changes inthe remaining three cases (Table II). In gen-eral, the correlation between the changes in theCBF and CMRO2and the clinical course follow-ing therapy in this group of patients was notstriking.

Studies were also repeated in 11 of the patientswith dementia paralytica an average of four

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months following treatment (Table III). Thechanges in the cerebral blood flow were not con-sistent. The cerebral oxygen consumption, how-ever, generally showed a marked increase follow-ing therapy in the patients with low pre-treatmentvalues. In patients with relatively high valuesbefore treatment, the response of the CMRO2was variable (Figure 3). These studies were re-peated in six of the 11 patients at a mean intervalof nine months following treatment, at which timelittle further change was found in most patients ineither CBF or CMRO2. One patient (D. W),however, exhibited a considerable increase inCBF, while another patient (C. C.) showed amarked rise in CMRO2over the first post-treat-ment value.

The change in cerebral oxygen consumption inthe individual patient could be correlated to someextent with change in mental state. Each of thethree patients with dementia paralytica whoshowed little or no clinical improvement had asmall decrease in CMRO2. Of the eight patientswith definite improvement, six had a considerable

FIG. 3. THE EFFECT OF TREATMENTON THE CEREBRALOXYGENCONSUMP-TION IN PATIENTS WITH PARESIS

The solid columns represent the pre-treatment and the stippled columnsthe post-treatment determinations. The numbers above the columns indicatethe interval in months between the determinations.

1332

CEREBRALBLOODFLOWAND 02 CONSUMPTIONIN NEUROSYPHILIS

increase in CMRO2, one showed no change, andone had a moderate decrease in oxygen con-sumption.

Figure 4 shows the changes in oxygen con-sumption in the first and second post-treatmentstudies plotted against the changes in blood flowobserved at these times. The correlation betweenthese changes was definite but of rather low order(r = .68). Several of the patients who hadmarked increases in oxygen consumption showedonly minor changes in blood flow. In only onepatient was there a definite decrease in CBFwith-out a corresponding alteration in CMRO2. It isevident that the changes in oxygen consumptionwere proportionately much greater than those inblood flow.

PARESIS

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The numbers in the abscissa and ordinate indicate thechange in cc. of blood and oxygen, respectively, per 100Gm. brain/min. The solid dots represent the change ob-served in the first post-treatment determination, whilethe circles represent changes in the second post-treatmentdetermination.

DISCUSSION

The decrease in cerebral blood flow observed inpatients with dementia paralytica and meningo-vascular syphilis is consistent with the reductionin lumen of the cerebral vessels known to occur inthese conditions. The cerebral blood flow, asdetermined by the nitrous oxide technique, repre-sents principally the flow through perfused brainand does not account for cerebral tissue which iscompletely devoid of blood supply. If such tis-sue were taken into consideration, the CBF perunit of total brain substance might, in some indi-viduals, be lower than that indicated by our study.

Patients with advanced dementia paralyticaoften show a considerable degree of corticalatrophy with a loss in brain substance, amountingto 100 Gm. or more (10). In such individuals.the reduction in total cerebral blood flow shouldbe somewhat greater than that indicated by thereduction in flow per unit weight of brain. Thetotal intracranial blood flow in dementia paralyticawas indeed found to be reduced by Rosenbaumand his associates (2). These workers, however,could not be certain whether this diminution inflow was the result of a decrease in the cerebralvascular bed associated with decrease in brainvolume or whether the blood flow per unit ofbrain substance was impaired. The results of ourstudies indicate that both factors may be operative.

The patients with asymptomatic neurosyphilisshowed mean CBF and CMRO2values in thenormal range. The average duration of syphiliswas found to be less than nine years in the 12 pa-tients in whom this factor could be determined.It seems probable that in most of these patientsthere were only minimal changes in the cerebralvessels and parenchyma, which were evidentlyinsufficient to produce alterations in cerebral cir-culation and metabolism. There was a tendencyfor the patients with longer duration of neuro-syphilis to have lower CBF values. Five of theseven patients with the lower blood flows wereknown to have had the disease for 10 years ormore. The two patients with the lowest CMRO2values of 1.8 and 2 cc./100 Gm. brain/min. de-veloped prompt relief of headaches and nervous-ness following penicillin treatment -and may, inretrospect, have been cases of symptomatic, pos-sibly early paretic, neurosyphilis.

The results of these studies have some bearing

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on the problem of the pathogenesis of corticalatrophy in dementia paralytica. Merritt, Putnamand Campbell (11) have suggested that the de-generative changes in the cortex of the pareticbrain are secondary to ischemia produced by dis-ease of the cerebral vessels. The fact that themean percentile reduction in blood flow beforetreatment in the patients with dementia paralyticawas almost identical with that found in oxygenconsumption (73 per cent vs. 72 per cent) may beevidence in support of this hypothesis. On theother hand, four patients showed considerableimprovement in CMRO2and two others had amoderate decrease in CMRO2with very little orno change in cerebral blood flow. This dissociationof CBF and CMRO2suggests that disease of thecerebral vessels may not be the sole cause ofchanges in nerve cell function.

The nature and distribution of pathologic proc-esses in the brain, as well as the overall rate ofcerebral metabolism, appear to be important fac-tors in determining alterations in mental func-tion. A reduction of cerebral oxygen consump-tion to 2.0 cc./100 Gm./min. is usually associatedwith coma in patients with diabetic acidosis, insu-lin shock and brain tumor (12). In contrast, sixof our patients had CMRO2values below thislevel and, although greatly deteriorated, these in-dividuals were nevertheless conscious and capableof simple mental functions.

SUMMARY

1. The cerebral blood flow (CBF), oxygen con-sumption (CMRO2), and vascular resistance(CVR) were determined by the nitrous oxidetechnique in 58 patients with neurosyphilis and16 control subjects.

2. In patients with dementia paralytica andmeningovascular syphilis the mean CBF andCMRO2were significantly reduced, while themean CVRwas significantly increased. In asymp-tomatic neurosyphilis these functions were withinthe normal range.

3. In patients with dementia paralytica, a defi-nite correlation was found between the degree ofmental deterioration and the reduction in cerebraloxygen consumption.

4. In patients with meningovascular syphilis,treatment was usually followed by a rise in CBF,while the CMRO, showed a variable response,

5. Treatment with penicillin and fever was fol-lowed by a rise in the CMRO2in those patientswith dementia paralytica who had low pre-treat-ment values. This increase in CMRO2was ac-companied by improvement in mental state.

ACKNOWLEDGMENT

We are indebted to Dr. Seymour S. Kety for in-struction in the technique utilized in this paper and toMisses Mary McPhaul, Fransetta Vinson, Ann Payne,Voncile Williams, and Eloise Cavin for their technicalassistance.

BIBLIOGRAPHY

1. Scheinker, I. M., Neuropathology in its Clinico-pathologic Aspects. Charles C. Thomas, Spring-field, Ill., 1947.

2. Rosenbaum, M., Roseman, E., Aring, C. D., andFerris, E. B., Jr., Intracranial blood flow in de-mentia paralytica, cerebral atrophy and schizo-phrenia. Arch. Neurol. & Psychiat., 1942, 47,793.

3. Himwich, H. E., and Fazekas, F., The oxygen con-tent of cerebral blood in patients with acute sympto-matic psychoses and acute destructive brain lesions.Am. J. Psychiat., 1944, 100, 648.

4. Wortis, J., Bowman, K. M., and Goldfarb, W., Hu-man brain metabolism. Normal values and valuesin certain clinical states. Am. J. Psychiat., 1940,97, 552.

5. Kety, S. S., and Schmidt, C. F., The nitrous oxidemethod for the quantitative determinations ofcerebral blood flow in man: theory, procedure andnormal values. J. Clin. Invest., 1948, 27, 476.

6. Orcutt, F. S., and Waters, R. M., A method for thedetermination of cyclopropane, ethylene, and ni-trous oxide in the blood with the Van Slyke-Neillmanometric apparatus. J. Biol. Chem., 1937, 117,509.

7. Peters, J. P., and Van Slyke, D. D., QuantitativeClinical Chemistry, Vol. II, Methods. Williams &Wilkins, Baltimore, 1943. (Emended Editon.)

8. Kety, S. S., Harmel, M. H., Broomell, H. T., andRhode. C. B., The solubility of nitrous oxide inblood and brain. J. Biol. Chem., 1948, 173, 487.

9. Lennox, W. G., The cerebral circulation. 'XIV. Therespiratory quotient of the brain and of the ex-tremities in man. Arch. Neurol. & Psychiat., 1931,26, 719.

10. Merritt, H. H., Adams, R. D., and Solomon, H. C.,Neurosyphilis. Oxford University Press, NewYork, 1946.

11. Merritt, H. H., Putnam, T. J., and Campbell, A. C.P., Pathogenesis of the cortical atrophy observedin dementia paralytica. Arch. Neurol. & Psy-chiat., 1937, 37, 75.

12. Kety, S. S., Circulation and metabolism of the hu-man brain in health and disease. Am. J. Med.,1950, 8, 205,

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