Journal of Clinical InvestigationVol. 41, No. 2, 1962

STUDIES ON THE PATHOGENESISOF MENINGITIS. II. DEVELOPMENTOF MENINGITIS DURING PNEUMOCOCCALBACTEREMIA*

By ROBERTG. PETERSDORF,DAVID R. SWARNERAND MANUELGARCIA

(From the Division of Allergy and Infectious Disease, Department of Medicine, Johns HopkinsSchool of Medicine Baltimore, and Department of Medicine, University of

Washington School of Medicine, Seattle, Wash.)

(Submitted for publication August 9, 1961; accepted October 19, 1961)

In a previous publication we described an ex-perimental form of pneumococcal meningitis indogs, which was produced by introduction of typeIII pneumococci into the subarachnoid spacethrough a small midline burr hole placed equi-distant between the coronal and occipital sutures(1). The infection produced in this manner in-volved the entire neuraxis and, with the exceptionof marked changes in the spinal cord, closely re-sembled that found in man. It seems unlikely,however, that entry from the external environ-ment is the only means by which bacteria enterthe subarachnoid space. An alternative possibilityis that the meninges are infected by way of theblood stream. The present paper is concernedwith the development of meningitis during pneu-mococcal bacteremia in dogs.

With the exception of the early report by Bull(2) that intravenous administration of pneumo-cocci to dogs was followed by meningitis, in moststudies intravenous injection of a variety of mi-croorganisms into rabbits, dogs, monkeys, andcats has not resulted in infection of the meninges(3-7). Weed, Wegeforth, Ayer and Felton (6,8), however, regularly observed meningitis whencats were subjected to lumbar puncture duringbacteremia with Aerobacter aerogenes, an en-capsulated, gram-negative bacillus. Control ani-mals given twice as many organisms but not sub-jected to lumbar puncture remained well. In-fection developed only when cerebrospinal fluid(CSF) was removed 30 minutes before or afterthe injection of bacteria, and meningitis did notdevelop when lumbar puncture was performedoutside this 30-minute interval. Infected animalsgenerally became sick within 24 hours and died24 to 48 hours later. A. aerogenes was used in

* Supported by a grant from the U. S. Public HealthService and grants from Parke, Davis & Co. and theUpjohn Co.

the majority of experiments and cats were themost commonly employed animals. However,cats could also be successfully infected withPseudomonas aeruginosa and Salmonella para-typhosa B, while in rabbits infection could be pro-duced with streptococci and meningococci. Theauthors postulated two requisites for developmentof infection: 1) the organisms had to be virulentfor the meninges, and 2) a sufficiently large num-ber of bacteria had to be inoculated.

The most obvious explanation for these re-sults is that trauma to small meningeal blood ves-sels at the time of lumbar or cisternal punctureprovided access for bacteria, but careful morpho-logical studies failed to substantiate this. Fur-thermore, injection of hypertonic sodium chloride,compression of the jugular veins, and transientcardiac standstill during bacteremia were also fol-lowed by meningeal infection, indicating that di-rect injury to the meninges was not a requirementfor the development of meningitis. Weed andco-workers hypothesized that occurrence of in-fection was facilitated by the transient fall inCSF pressure associated with these procedures(6, 8). However, accurate measurements of CSFpressure under these conditions were not made.Furthermore, the development of meningitis dur-ing jugular compression, a maneuver known toincrease CSF pressure, is inconsistent with thishypothesis.

The studies to be reported deal with some ofthe factors influencing the development of menin-geal infection during pneumococcal bacteremiawith emphasis on alterations in CSF pressure.

MATERIALS AND METHODS

Animals. All experiments were performed in mongreldogs weighing between 10 and 20 kg. Animals werehoused in individual cages and were permitted food andwater ad libitum.

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PATHOGENESISOF MENINGITIS, II

Microorganism. All experiments were performed withthe encapsulated strain of Diplococcus pneumoniae previ-ously used to produce infection by the intrathecal route(1). The steps for preparing the organism for infec-tion have been detailed previously (1).

Experimental infections. Animals were anesthetizedwith pentobarbital, the scalp was carefully shaved andprepared with soap, saline, and tincture of merthiolate.With the animal on its side, 4.0 ml of an 18-hour brothculture containing between 105 and 108 viable pneumococciwas injected into the saphenous vein. Exactly 2 minuteslater, cisternal puncture was performed and 2.0 ml ofCSF was removed under aseptic conditions. This fluidwas invariably sterile and contained no cells. All ani-mals with traumatic cisternal punctures were discarded.Initially, control animals were given 2 to 4 times theinoculum of the experimental group and cisternal punc-tures were not performed until 24 hours later. No ani-mal not subjected to cisternal puncture within 30 min-utes after injection of pneumococci developed infection.

For comparison, meningitis was produced in a groupof dogs by direct inoculation of organisms into the suba-rachnoid space through a small midline burr hole placedequidistant between the coronal and occipital sutures.This method has been detailed in a previous publication(1).

After administration of bacteria, animals were re-turned to their cages and cisternal punctures were per-formed at 24-hour intervals until death or recovery.Animals with three consecutive negative CSF cultureswere considered free of infection.

Pathology. The methods for embedding and sec-tioning the brains, and staining the sections have beendescribed (1).

Bacterial counts. The number of bacteria in the in-ocula, CSF, brain, and meninges was determined bycolony counts of serial tenfold dilutions. To determinethe number of bacteria in brain and meninges, autopsieswere performed on the animals under aseptic conditions,the brain and its covering removed, and the meningesstripped from the underlying cortex. Each tissue wasweighed on a quantitative balance, diluted to constantvolume in 0.85 per cent NaCl and ground in a TenBroeck grinder. Pour plates were made of serial ten-fold dilutions of ground tissues.

Blood cultures. Blood was obtained from the femoralvein under aseptic conditions and cultured in trypticasesoy and thioglycollate broth. Blood cultures were al-ways taken from the limb which had not been used forinjection of bacteria. For quantitative determination ofbacteria 1.0 ml of blood was added indirectly to 9.0 mlof trypticase soy broth and pour plates of serial tenfolddilutions were made. Leukocyte counts and CSF glu-cose were performed as described previously (1).

CSF pressures were determined with a direct-readingspinal manometer. The manometer was left in placefor 2 minutes to permit equilibration to take place. Allpressures were obtained in anesthetized animals.

A bacterial vaccine made from Salmonella typhosa

FIG. 1. COMPARISONOF RATE OF INFECTION BETWEENDOGS INFECTED BY THE INTRAVENOUS AND INTRATHECALROUTES. None of 9 animals given 103 and 102 bacteria i.v.developed infection.

(strain Ty-2, Felix) 1 was used in some experiments.Prior to inactivation by phenol and heat, this materialcontained 1010 viable bacteria. Sterile 6 per cent dextranand 50 per cent dextrose were purchased from com-mercial sources.

RESULTS

Incidence of infection during bacteremiia. Cis-ternal puncture was performed on 71 animalswithin 2 minutes after intravenous administrationof pneumococci; 42 of these animals developedmeningitis (Figure 1). With the exception ofthe 10 animals given 106 organisms, the incidenceof infection ranged between 50 and 75 per cent,and 104 bacteria appeared to be the minimum in-fecting dose. In experiments not shown in Fig-ure 1, five dogs were injected with 103 and fourwith 102 organisms and none of these nine dogsdeveloped infection. All infected animals died andno spontaneous recoveries occurred. Normal con-trol dogs were given 109 bacteria intravenouslyand not subjected to cisternal puncture until 24hours later; none developed meningitis.

1 Obtained from Dr. Maurice Landy, U. S. PublicHealth Service, Bethesda, Md.

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ROBERTG. PETERSDORF,DAVID R. SWARNERAND MANUELGARCIA

TABLE I

Relationship of number of bacteria in blood stream atthe time of cisternal puncture to development of

infection

Per cent of dogs infected

No. bacteria/ml blood 1 min* 5 min*

> 103 59 81< 103 33 17

* Time after cisternal puncture.

When pneumococci were administered intra-thecally, the rate of infection was almost twicethat after intravenous injection, and only 1 to 10per cent as many bacteria was required to pro-

duce meningitis. This is not surprising in viewof the dilution of the bacterial inoculum in theblood stream which would result in relatively feworganisms actually reaching the subarachnoidspace.

Relationship of number of microorganisms inblood stream to development of infection. Whilethere was some relationship between the magni-tude of the bacterial inoculum and the develop-ment of infection, it seemed probable that con-

siderable variation existed in the rate at whichbacteria were cleared from the blood stream inindividual animals. Therefore, the number oforganisms actually in the circulation at the time

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FIG. 2. RELATIONSHIP OF BACTERIAL INOCULUM TO

LENGTH OF SURVIVAL. There was a direct relationshipbetween the number of organisms injected and length ofsurvival. Arrow = mean, R= recovered.

of cisternal puncture seemed a more adequate in-dex of the number of bacteria necessary for thedevelopment of infection.

Femoral vein punctures were performed in 32dogs, 1 and 5 minutes after cisternal puncture (3and 8 minutes after intravenous injection of bac-teria) and the number of organisms per ml of wholeblood determined by quantitative plate counts.The results are summarized in Table I and clearlydemonstrate a direct relationship between thenumber of organisms in the blood stream and thedevelopment of meningeal infection. For ex-

ample, 59 per cent of animals with more than 103

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FIG. 3. ANIMALS DEVELOPING MENINGITIS AFTER IN-

TRAVENOUS INOCULATION OF PNEUMOCOCCI. Note thepersistent increase in bacteria and cells in CSF as in-fection progressed.

bacteria per ml of blood became infected within 1minute after cisternal puncture. The rate of in-fection among dogs with fewer than 103 organ-

isms was only 33 per cent. This difference was

much more striking 5 minutes after cisternalpuncture; 81 per cent of animals with more than103 bacteria in the blood stream at that time de-veloped infection, while only 17 per cent of thosewith fewer than 103 organisms contractedmeningitis.

Relationship of duration of illness to size ofbacterial inoculum. There was a direct relation-

322

PATHOGENESISOF MENINGITIS, II

ship between the number of organisms used toproduce infection and the number of hours theanimals survived. This is illustrated in Figure 2.For example, the mean survival time of dogs in-oculated with 108 bacteria was 48 hours and thatof animals given 107 pneumococci, 60 hours.Dogs injected with 105 bacteria lived for 85 hours.When the infection was produced by direct in-oculation of bacteria into the subarachnoid space,a much smaller number of organisms was re-quired to produce the same lethal effect. Ani-mals with a mean survival time of 48 hours hadbeen infected with only 105 organisms, approxi-mately 1 per cent of the dose required to producedeath by the intravenous route. Approximatelythe same relationship was true at other multiples.

Course of infection (Figure 3). Daily deter-minations of bacteria and cells in the CSF aretabulated in Figure 3. There was a progressiveincrease in bacteria from a mean of 5 x 103 pernml CSF on the day after infection to 4 x 106 perml CSF 3 days later. During the same period,leukocytes in the CSF increased from 1,800 toover 6,000 per mm3 CSF. The course of theintravenously induced infection is compared withthat produced by the intrathecal route in Figure 4.The former showed a steady increment in bacteriaand cells, while the infections produced by theintrathecal route were characterized by less con-sistent increases in the number of bacteria, anda heavy outpouring of leukocytes at the onset,with little further exudation as infection pro-gressed. CSF glucose was measured in most ani-mals and showed the expected fall.

Persistence of positive blood cultures (Figure5). Of the dogs with meningitis, 93 per cent hadpneumococci isolated from the blood at some timeduring the course of infection. Of the 32 animals,75 per cent had bacteremia on the first day afterinoculation of bacteria, 55 per cent on the secondday, 66 per cent on the third day, and 72 per centon the fourth day. In all instances the incidenceof bacteremia was higher after intravenous in-troduction of pneumococci than after intrathecalinfection. Also noteworthy is the finding that 4of 26 animals that did not develop meningitis hadpersistent bacteremia for 24 to 48 hours afteradministration of pneumococci. In contrast, noanimal given the organism intrathecally mani-fested bacteremia unless meningitis developed.

Ua.(n4000

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FIG. 4. COMPARISONOF CELLS AND BACTERIA IN CSFAFTER INTRAVENOUS AND INTRATHECAL INFECTION.

The higher incidence of blood stream invasionand sporadic persistence of bacteremia in theanimals infected intravenously are entirely con-sistent with the difference in route of administra-tion. Animals were carefully examined for evi-dence of bacterial endocarditis and none was found.

Spread of infection within the central nervoussystem. It seemed of interest to determinewhether the infection spread from the leptomen-inges to the brain, or whether these animals de-

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FIG. 5. INCIDENCE OF BACTEREMIADURING PNEUMOCOC-

CAL MENINGITIS. Note persistent bacteremia in someanimals given pneumococci i.v. that failed to developinfection.

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ROBERTG. PETERSDORF,DAVID R. SWARNERAND MANUELGARCIA

5105

30

FIG. 6. BACTERIAL COUNTS OF CSF, MENINGES, ANDBRAIN IN ANIMALS INFECTED INTRAVENOUSLYAND INTRA-THECALLY. In both instances bacterial counts in CSFexceeded those in the meninges, which in turn weregreater than those in the brain.

veloped a primary cerebritis with secondary in-volvement of the coverings of the central nervoussystem. Therefore, animals were sacrificed atintervals during the infection, the meninges andbrain removed aseptically, and simultaneous quan-titative bacterial counts of CSF, meninges, andbrain were performed. The results are sum-marized in Figure 6, which indicates that in everyanimal the number of organisms in the CSF ex-ceeded the number in the meninges, which inturn was always greater than that found in cere-bral tissue. This provided evidence that bacteriaentered the subarachnoid space directly from theblood and that cerebral infection occurred onlysecondarily. As might be expected, dogs infectedby the intrathecal route also had more bacteria inthe CSF and meninges than in the brain,

Pathological changes. Autopsies were per-formed on nine animals infected during bac-teremia. The morphological findings wereindistinguishable from those of animals infectedintrathecally and have been presented in detailelsewhere (1). The infection involved the entireneuraxis and the exudate was no greater in thecervical cord and the medulla, the areas closestto the needle puncture. Careful microscopic studyof the meninges did not reveal the site of entryof the bacteria.

Clinical picture. Except for the slightly moreindolent course in intravenously infected dogs, theclinical findings were identical with those ob-served in animals infected by direct instillation ofbacteria into the central nervous system.

Factors influencing development of meningitisduring bacteremia. In order to determine themechanism by which microorganisms entered thesubarachnoid space, experiments were performedin which dogs were subjected to maneuvers knownto alter the CSF pressure or to affect the perme-ability of the blood-CSF barrier. These may besummarized as follows.

1) Six dogs were given 250 ml of 6 per centdextran intravenously over the course of 1 hour.In control animals this had produced a fall in CSFpressure of approximately 50 per cent. Aftercompletion of the infusion, 109 bacteria were givenintravenously. Meningitis did not ensue.

2) Five animals were injected with 100 ml 5per cent dextrose intravenously during a 5-minuteperiod. This procedure resulted in a fall in CSFpressure of 40 to 70 per cent. Then 109 pneumo-cocci were administered. None of the animalsbecame infected.

3) A blood pressure cuff was placed aroundthe necks of anesthetized dogs and inflated to apressure of 30 mmHg. This regularly resultedin doubling the animals' CSF pressure. Theanimals were permitted to recover, and 3 dayslater were given 109 pneumococci intravenouslywith the cuff inflated. Meningitis did not result.

4) Six animals were given 2.0 ml of heat-killedtyphoid vaccine containing 1010 bacteria. Twohours later, when the animals were severely illwith fever, diarrhea, and lethargy, 109 pneumo-cocci were injected intravenously. The centralnervous system remained free of infection. Pre-vious experiments had demonstrated a markedincrease in the permeability of the blood-CSFbarrier as measured by penetration of sodiumfluorescein from blood to CSF in animals giventyphoid vaccine (9). Eckman, King and Brun-son have also demonstrated an increase in thepermeability of the blood-CSF barrier after ad-ministration of bacterial endotoxins (10).

5) Aseptic meningitis was produced in fourdogs by administration of 6.0 ml 0.85 per centNaCl into the cisterna magna (11). Four hourslater these animals had an average of 5,800 poly-morphonuclear leukocytes per mm3 CSF. Pre-

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PATHOGENESISOF MENINGITIS, II

vious studies had demonstrated that exudation ofthis magnitude was always associated with an in-crease in permeability of the blood-CSF barrier,as measured by transfer of sodium fluoresceinfrom blood to CSF (9). Five hours after induc-tion of aseptic meningitis (1 hour after the pre-ceding cisternal puncture), 7.6 x 107 pneumococciwere given intravenously. Cisternal punctures4 and 24 hours later did not reveal evidence ofmeningeal infection.

The preceding five experiments, in three ofwhich CSF pressure was drastically altered, andtwo of which were associated with marked incre-ments in the blood-CSF barrier, failed to facili-tate development of meningeal infection duringmassive pneumococcal bacteremia. In none ofthese was cisternal puncture performed within 30minutes of intravenous inoculation of bacteria.

To determine whether these alterations mightincrease the rate of infection in animals subjectedto lumbar puncture during bacteremia, nine ani-mals were given typhoid vaccine 2 hours beforecisternal puncture and bacteremia, eight were in-fused with dextran before cisternal puncture andinjection of bacteria, and two were given 100 ml50 per cent dextrose. Forty-three animals, sub-jected to cisternal puncture during bacteremia, butnot given any adjuvants, served as controls. Theresults, which are summarized in Table II, showthat these maneuvers did not alter the rate ofinfection.

Effect of initial, final, and change in CSF pres-sure on development of infection (Figure 7). Al-though approximately 2.0 ml of CSF was removedduring each cisternal puncture, there was markedindividual variation in the animals' CSF pressureat the beginning of cisternal puncture, after re-moval of fluid, and in the magnitude of the changein CSF pressure effected by release of CSF.There was no correlation between these indices

TABLE II

Effect on development of meningitis of procedures known toalter CSFpressure and permeability of blood-CSF barrier

plus cisternal puncture (C.P.) during pneumococcalbacteremia

No. No. Per centanimals infected infected

No adjuvants + C.P. 43 22 51Typhoid vaccine)6%dextran + C.P. 19 9 4750% dextroseI

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FIG. 7. INITIAL, FINAL, AND MAGNITUDE OF CHANGEIN CSF PRESSURESIN ANIMALS SUBJECTEDTO CISTERNALPUNCTUREDURING PNEUMOCOCCALBACTEREMIA. Therewas no difference between these parameters in infectedanimals and in those who did not develop meningitis.

in CSF pressure and development of infection(Figure 7).

If the fall in CSF pressure occasioned by therelease of CSF is a prerequisite for infection, thenreplacement of fluid immediately after its removalshould militate against development of meningealinfection during bacteremia. After administrationof 108 pneumococci intravenously, six dogs weresubjected to cisternal puncture, and 2.0 ml offluid removed. The mean decrease in CSF pres-sure in these animals was 50 mmCSF. Immedi-ately thereafter the CSF was replaced with re-turn of CSF pressure to within 10 per cent ofthe baseline level. Five of the six animals de-veloped meningitis despite replacement of fluid.

DISCUSSION

These studies demonstrate that microtraumato the meninges in the form of cisternal punctureduring pneumococcal bacteremia results in men-

ingitis provided sufficient numbers of microor-ganisms are in the blood stream at the time ofcisternal puncture. These results are in agree-

325

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ROBERTG. PETERSDORF,DAVID R. SWARNERAND MANUELGARCIA

ment with those obtained by Weed and associateswith A. aerogenes in cats (6, 8). However, thedata permit only one explanation for the mecha-nism of entry of microorganisms, namely, that thebacteria entered the subarachnoid space throughthe small opening made at the time of cisternalpuncture. The finding that development of in-fection was directly related to the number oforganisms in the blood stream at the time ofneedle puncture and the fact that infection onlyoccurred within 30 minutes of cisternal puncture-presumably because the hole is sealed off afterthat interval-favor this idea.

In contrast, Weed and his co-workers postu-lated that direct trauma was not the mechanism ofentry of bacteria, but that an acute alteration inthe volume of fluid in the subarachnoid space andin the choroid plexus consequent to release of CSFfacilitated infection. They marshalled the follow-ing evidence to support this hypothesis (6, 8):1) inability to demonstrate the site of entry, de-spite careful microscopic studies (12); 2) failureto localize cells and bacteria at the base of thebrain, close to the site of the needle track; 3)removal and replacement of CSF 30 minutesbefore intravenous administration of bacteria pre-vented development of meningitis, but the samemaneuver 30 minutes after bacteremia did notinterfere with the occurrence of the infection; and4) infusion of hypertonic saline solutions, jugularcompression, and cardiac standstill during bac-teremia resulted in meningitis without cisternalpuncture.

Our results confirm the failure to find the pointof entry, but this is not surprising since it seemslikely that the hole made by the needle was sealedoff rapidly, making it difficult, if not impossible,to find. The same explanation can be invokedto account for the differences observed when CSFwas replaced before and after bacteremia. Inthe former instance the defect in the meningeshad closed before bacteria were in the bloodstream, while replacement of fluid failed to preventinfection after microorganisms had been injectedintravenously. It is also not surprising that men-ingitis ensued when bacteria were injected afteradministration of hypertonic saline, since it hasbeen demonstrated that infusion of hyperosmolarsolutions of electrolytes into cats may cause dif-fuse hemorrhagic encephalopathy (13).

In our studies, no procedure other than direct

trauma to the meninges (i.e., cisternal puncture)was followed by infection. The divergence be-tween the observations of Weed and colleaguesand the present findings may be due to the factthat A. aerogenes is more virulent for the men-inges than D. pneumoniae. Although A. aero-genes undoubtedly elaborated a strong endotoxin,it is unlikely that meningeal virulence is dependentupon this toxin per se, because administrationof large doses of typhoid vaccine prior to pneu-mococcal bacteremia did not enhance passage ofbacteria from blood to CSF. It is also possiblethat the large encapsulated pneumococcus was un-able to penetrate the blood-CSF barrier throughthe submicroscopic defects resulting from in-fusions of hypertonic solutions, while these pro-duced sufficient trauma to permit entry of thesmaller gram-negative bacillus. Finally, the lep-tomeninges of the cat may be more delicate, andthus more permeable, than those of the dog.

These experimental results are not inconsistent,however, with the clinical axiom that pneumo-coccal meningitis usually occurs in a setting wherea small communication between the subarachnoidspace and the external environment may be pre-sumed to exist and where the meninges are notin their pristine state as in sinusitis, mastoiditis,otitis, head trauma, and so forth. It is certainlynot difficult to visualize that microtrauma doesoccur even in patients with no discernible portalof entry. It should be pointed out, however, thatthese studies are only applicable to one bacterialgenus, the pneumococcus, and to one animal spe-cies, the dog, and that they will have to be- ex-tended to other species and microorganisms.-

Failure to find a relationship between CSFpressure and development of infection in thepresent study may be due to failure of the methodsemployed for measuring CSF pressure to detectsubtle changes in CSF dynamics. Perhaps im-plantation of a catheter in the subarachnoid spacewith repeated measurements of pressure mayovercome this problem. However, the catheterwould act as a foreign body and would be com-parable to needle puncture in facilitating entry ofbacteria from the blood stream.

Also of clinical significance is the possibledanger of diagnostic lumbar puncture during bac-teremia. Wegeforth and Latham (14) performedlumbar punctures in 93 patients with suspectedmeningitis; in 55 of these cerebrospinal fluid was

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PATHOGENESISOF MENINGITIS, II

normal. Six patients had meningococcemia orpneumococcal bacteremia at the time of lumbarpuncture and 5 of the 6 subsequently developedmeningitis. On the basis of these findings theauthors condemn diagnostic lumbar puncture asa distinct hazard in patients with bacteremia.Remsen (15) shared, this viewpoint and added acase of streptococcal meningitis occurring undersimilar circumstances. It seems likely that thesefew cases are not representative of the over-allclinical experience, and that meningitis followinglumbar puncture is relatively rare. Pray (16)did not find an increased incidence of meningitisin children with pneumococcal sepsis who weresubjected to lumbar puncture. If the experimentalresults of the present studies are applied to man,the relative rarity of meningitis complicating bac-teremia becomes apparent. The large majority ofpatients with pneumococcal bacteremia harbor be-tween 2 and 100 organisms per ml of blood,an inoculum too small to produce infection inexperimental animals. The present data do notsupport the idea that suspected or documentedbacteremia constitutes a contraindication to lum-bar puncture. Compared with the risk of miss-ing the diagnosis of meningitis by omission oflumbar puncture, the chance of developing men-ingeal infection after the procedure is small.

SUMMARY

Type III pneumococcal meningitis was pro-duced in dogs by performance of cisternal punc-ture within 2 minutes after intravenous admin-istration of pneumococci. Development of in-fection was related to the size of the inoculumand, even more critically, to the number of or-ganisms in the blood stream at the time CSF wasreleased. The infection was characterized byprogressive increase in cells and bacteria in theCSF and was indistinguishable clinically andpathologically from meningitis produced by directinstillation of pneumococci into the subarachnoidspace. Procedures which altered CSF pressure,such as infusion of 6 per cent dextran, 50 percent dextrose, and jugular compression, and pro-cedures which enhanced the permeability of theblood-CSF barrier (i.e., administration of typhoidvaccine and induction of aseptic meningitis) didnot result in meningitis during bacteremia, anddirect trauma to the meninges in the form of cis-

ternal puncture was the only stimulus which per-mitted entry of bacteria into the subarachnoidspace.

REFERENCES

1. Petersdorf, R. G., and Luttrell, C. N. Studies onthe pathogenesis of meningitis. I. Intrathecal in-fection. J. clin. Invest. 1962, 41, 311.

2. Bull, C. G. Immunity factors in pneumococcus in-fection in the dog. J. exp. Med. 1916, 24, 7.

3. Amoss, H. L., and Eberson, F. Experiments on themode of infection in epidemic meningitis. J. exp.Med. 1919, 29, 605.

4. Austrian, C. R. Experimental meningococcus menin-gitis. Bull. Johns Hopk. Hosp. 1918, 29, 183.

5. Idzumi, G. Experimental pneumococcus meningitisin rabbits and dogs. J. infect. Dis. 1920, 26, 373.

6. Weed, L. H., Wegeforth, P., Ayer, J. B., and Felton,L. D. A study of experimental meningitis. IV.The influence of certain experimental proceduresupon the production of meningitis by intravenousinoculation. Monogr. Rockefeller Inst. med. Res.1920, 12, 57.

7. Wollstein, M. Influenzal meningitis and its experi-mental production. Amer. J. Dis. Child. 1911, 1,42.

8. Weed, L. H., Wegeforth, P., Ayer, J. B., and Felton,L. D. The production of meningitis by release ofcerebrospinal fluid during an experimental septi-cemia: Preliminary note. J. Amer. med. Ass.1919, 72, 190.

9. Swarner, D. R., and Petersdorf, R. G. Unpublishedobservations.

10. Eckman, P. L., King, W. M., and Brunson, J. G.Studies on the blood brain barrier. I. Effects pro-duced by a single injection of gram-negative endo-toxin on the permeability of the cerebral vessels.Amer. J. Path. 1958, 34, 631.

11. Petersdorf, R. G., and Harter, D. H. The fall incerebrospinal fluid sugar in meningitis. Some ex-perimental observations. Arch. Neurol. Psychiat.(Chicago) 1961, 4, 21.

12. Ayer, J. B. A study of experimental meningitis.V. Experimental acute hematogenous meningitis.A pathological study. Monogr. Rockefeller Inst.med. Res. 1920, 12, 113.

13. Luttrell, C. N., Finberg, L., and Drawdy, L. P.Hemorrhagic encephalopathy introduced by by-pernatremia. II. Experimental observations onhyperosmolarity in cats. A.M.A. Arch. Neurol.1959, 1, 153.

14. Wegeforth, P., and Latham, J. R. Lumbar punctureas a factor in the causation of meningitis. Amer.J. med. Sci. 1919, 158, 183.

15. Remsen, D. B. The r6le of lumbar puncture in thecausation of meningitis. J. Med. 1936, 17, 115.

16. Pray, L. G. Lumbar puncture as a factor in thepathogenesis of meningitis. A.M.A. J. Dis. Child.,1941, 62, 295.

327