OBSERVATIONS ON TUBERCULOUS MENINGITIS *

BY

JAMES McMURRAY, M.D.

(From the Institute of Pathology, Queen's University, Belfast)

There are two aspects of tuberculous meningitiswhich are worthy of discussion. One is its mode ofdevelopment. Why, for instance, does it not arisein every case of tuberculous bacillaemia? The otheraspect is the frequency with which the bovine typeof tubercle bacillus occurs in tuberculous meningitis.Both these are well known to a few but not ap-preciated by many. In this paper investigationshave been made of both these aspects of tuberculousmeningitis.

PathogenesisFrom the pathological side attempts have been

made to determine the origin and development ofthe disease process in tuberculous meningitis.There are two schools of thought. Some think itarises as the result of a spread of tubercle bacillifrom a parent focus into the subarachnoid space.The initial lesion might either be in the meninges orjuxta-meningeal tissues of brain or cord. This ideawas first sponsored by Rich and McCordock (1933)and later supported by Macgregor and Green (1937).The previous contention was that the meningitis wasnearly always the direct result of a tuberculousbacillaemia and occurred therefore simultaneouslywith other haematogenous foci. In other wordsmiliary tuberculous lesions in other organs coincidedwith the meningitis and were the same age. Thisconception was maintained by some workers suchas Ragins (1936) and Radmann (1935) as beingthe way in which the majority of cases of tuberculousmeningitis developed.

Rich and others (1933) have experimentally in-vestigated the problem. They attempted to producethe meningitis in animals. The injection of tuberclebacilli into the carotid artery did not cause a rapiddevelopment of tuberculous meningitis. In a fewcases, however, the meningitis did develop, butalways after a lapse of some weeks. Post-mortemexamination revealed- the presence of miliarytubercles in the brain and elsewhere in the body andalso that the meningitic lesion was more recent thanthose tuberculous lesions elsewhere in the body.The injection of tubercle bacilli into the subarachnoidspace, however, promptly resulted in the develop-ment of tuberculous meningitis. These resultsstrongly support the opinion that tuberculousmeningitis does not arise directly from a bacillaemia

* Based on a thesis for which the Davis Scholarship of the BelfastHospital for Sick Children was awarded.

but indirectly as the result of the extension of ahaematogenous focus.

In this work a detailed examination of the brainsof eleven cases was made. In each case an attemptwas made to determine whether or not the followingwere true:

(1) A parent meningeal focus or juxta meningealfocus existed and was extending into the sub-arachnoid space to produce a meningitis.

(2) When miliary lesions did occur they were ofdifferent age from the meningeal lesions.

(3) The exudate spread from the parent focus andcollected around the base of the brain.

(4) The choroid was normal and the ventricularependyma was unaffected.

Technique. When possible a complete post-mortem examination was made in each case. Re-moval of spinal cord was not possible. The brainwas fixed and later serially sectioned in slices 1-2 mm.thick. Careful search was made for tuberculousnodules in the meninges or in the brain. Themeninges covering the brain and in the sulci werecarefully examined. The cut surface of the brainwas scrutinized for foci deep in the substance ornear the surface and encroaching on the meninges.Both the definite and the doubtful foci were examinedhistologically. Some of the standard criteria usedwere as follows.

A parent focus was recognized as such because ofits size or of its position relative to the meningitis.Large foci left no doubt. It was more difficult tobe sure of small foci in the superficial brain or in themeninges. In these the tissue reaction was the guide.A nearby gliosis in some cases and in others a sur-rounding zone of very extensive cellular exudatewith much necrosis and arteritis was regarded asevidence in favour of its being the exciting focus.Determination of the relative ages of the foci in thebrain and of the meningitis was based mainly onthe size and cellular character of the lesion. Incases in which the meningitis was thought to beolder than the miliary foci the meninges showed athick exudate, not much necrosis and arteritis andsome meningo-encephalitis. The cerebral lesionsshowed very little perifocal gliosis. If the meningitiswas regarded as the more recent, the haematogenousfoci were well formed and showed a more markedglial reaction around them. The meningeal exudatewas scanty but more necrotic and showed lesscompact cellular infiltration.

87

on February 2, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.19.98.87 on 1 June 1944. D

ownloaded from

ARCHIVES OF DISEASE IN CHILDHOOD

Results of investigationParent foci: meningeal or juxta meningeal.

Eleven brains were examined and two were foundto have localized foci in brain substance (table 1).One case had a localized lesion in the cerebellumwhich apparently had provoked a meningeal exudate.The other case had two foci, one in left parieto-frontal and the other in the cerebellum. The latterfocus had become walled off by adhesion to thedura mater. The parietal focus was surrounded bya thick plaque of meningeal exudate. Eight other

cases showed meningeal-foci, very often in a sulcusand frequently near a main cerebral artery. Thesewere distinguished from a basal condensation ofexudate by the fact that they did not occur sym-metrically. In one case a precipitating focus wasnot found inside the skull. In this case (No. 11)miliary lesions appeared older than the meningealexudate. Thus ten out of eleven cases showed aprecipitating focus inside the skull.

Miliary tuberculosis. Miliary tuberculosis oc-curred in five cases out ofthe eleven. In one of these

BLE 1

Parent focus

Meninges: rightrolandicMeninges: rightsylvianCerebellum

.Meningeal: nearleft middlecerebral arteryMeningeal: cere-bellar peduncleMeningeal: leftcrusMeningeal: rightmiddle cerebral

Meningeal: rightmiddle cerebral

Meningeal: ?

Left parieto-frontalMeningeal: leftmiddle cerebralartery

Miliary lesions

None

None

None

None

In spleen andlungsNone

Spleen, lymph .glands, lungs,liver and kidneysSpleen and liver

Spleen, liver andlungsSpleen, liver, lungs

None

Age ofmeningitis tomiliary lesions

Older

Older

Younger

Younger

Younger

Other foci

Hilar glands

None found

None found

In spleen

Intercostal andprostate

Cerevical lymphglands, right tonsiland mesenteric glandsOld lesion in spleen

Left cerebellum

Hilar and mesentericglands

FIG. 1.-Cerebral foci involving meninges, basal meningitic exudate, slight hydrocephalus, Case 12 (A2926).

No.

1

2

5

6

7

8

9

10

11

12

14

Sex

F.

M.

M.

M.

F.

M.

M.

M.

M.

M.

F.

Age,years

17

5

2

4

17I2

2

10

11

Primarycomplex

R.U.L.

Not found

Not found

R.U.L.

R.U.L.

L.U.L.

R.U.L.

R.U.L.

Mesenteric

Pulmonary

R.U.L.

l~~~~ I~~~~~~~~~~~~

1.. -I.-

88

11

on February 2, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.19.98.87 on 1 June 1944. D

ownloaded from

OBSERVATIONS ON TUBERCULOUS MENINGITIS

cases a precipitating focus was found in the leftparieto-frontal area. This focus was the same ageas the other miliary lesions in the brain, lungs, liverand spleen. The age of this focus was therefore olderthan the meningitis. Three of the other four casesof meningitis with miliary tubercles showed parent-foci in the meninges. In two of these cases themeningitis appeared to have occurred prior to themiliary spread. The other two cases had miliarylesions which appeared to have occurred after themeningitis. Thus in all five cases the age of themiliarv lesions was different from that ofthe meningitis. Six other cases showedno evidence of miliary tuberculosis.The meningeal exudate in all cases showed

a basal condensation of varied degree.However, in some cases the exudatethickened around the parent fcci. Thiswas well marked in those two with largecerebral juxtameningeal foci. In otherswith small precipitating foci in the men-inges this was not so apparent to the nakedeye, but nevertheless was obvious in thehistology (fig. 1 and 2).The chiaracter of the exudate varied

slightly in every case. In some, especiallyin the more recent, there was an exudateconsisting of about equal numbers ofmononuclear cells and polymorphs withsome areas of necrosis and periarteritis.In other, longer established cases the exu-date usually showed .more mononuclearsand also more necrosis and arteritis. Thisinvolvement of blood vessels in some caseswas very extensive. In one case (not in-cluded in this series) a small tuberculouslesion was seen in the wall of a vein. This FIGwould support the contention that miliarytuberculosis can be the result of vascular involve-ment in a meningeal exudate.

Choroid plexus. None of the brains showedevidence of tuberculosis in the choroid plexus.There was no evidence of tuberculous involvement ofthe ependyma of the lateral and third ventricles orof the aqueduct of sylvius. In one case theependyma showed involvement in the fourthventricle. This was maximum near the foraminaof Luschka and Magendie and diminished towardsthe Sylvian aqueduct. It was associated with avery thick exudate around the base and cerebellarpeduncles.

SUMMARY OF FINDINGSTuberculous meningitis, total sectionedMeningitis older than miliary lesions ..Meningitis younger than miliary lesionsMeningitis without miliary lesionsMeningitis with cerebral foci ..

Meningitis with meningeal foci..

I1 cases2 ,,3 ,

6 ,,2 ,,

8 ,,

DiscussionNow if tuberculous meningitis is the result of a

tuberculous bacillaemia miliary tuberculosis should

occur in every case. In this series only five out ofeleven cases also had miliary tuberculosis. Further-more, the miliary tuberculous lesions should presentthe same age characteristtcs as the meningitis lesion.But in none of the cases did such happen. In twocases the meningitic exudate appeared more longstanding than the miliary foci and in three it seemedmore recent in origin. Therefore miliary tubercu-losis was not always coexistent with tuberculousmeningitis and when it was the lesions of each werefound to be of different ages.

2.-Meningeal focus involving brain producing localmeningo-encephalitis.

The character of the exudate in all cases was thesame. There was in all cases an apparent collectionof exudate at the base of the brain around the basalvessels of the circle of Willis and the optic chiasma.In those cases with fairly large foci it was evident tothe naked eye that the exudate was more markedaround the foci than at the base. No cases showedany diffuse spread of exudate over the vertex asmight be expected in a bacillaemic type of meningitis.Histologically too, if such were the usual mode oforigin the vessels themselves would show evidenceof multiple tuberculous thrombi as they would beinvolved in the inflammatory process and show acellular infiltration of decreasing intensity fromwithin out. This is not the usual finding in thesecases examined. Instead, the common finding wasthat the maximum involvement of the wall of thesmall arteries was in the adventitia to a less extentin the media and usually slight in the intima(fig. 3).Another suggested possibility as to the patho-

genesis is that bacilli passed through vascular endo-thelium in the choroid plexus into the cerebrospinalfluid. In those cases no evidence was found tosupport this.

89 on F

ebruary 2, 2020 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.19.98.87 on 1 June 1944. Dow

nloaded from

ARCHIVES OF DISEASE IN CHILDHOOD

FIG. 3.-Meningeal exudate, necrosis and arteritis.Note: necrosis and infiltrations diminish fromwithout inwards.

It may therefore be assumed that meningitis dueto the tubercle bacillus arose in the followingmanner: blood-borne tubercle bacilli were localizedin the meninges or in the juxta meningeal tissues toinvolve the surrounding meninges and produce alocal meningitis. Further extension of this provokeda more marked meningeal exudate and so tubercu-lous meningitis resulted.

BacteriologyThe main thing about the bacteriology of tubercu-

lous meningitis is the frequency of the occurrenceof the bovine type of bacillus. It is agreed that thebovine bacillus infection in most of these cases hasbeen milk borne. It can thereby be determined howmany of such cases might have been prevented fromcontracting the fatal illness. In this series of twenty-six cases of tuberculous meningitis strains of tuberclebacilli were isolated during life from twenty-four.All strains were isolated by culture and subsequentlyexamined as to cultural characteristics and virulencein rabbits. Detail of the results is found in tables 2and 3.

Technique. Cerebrospinal fluid was centrifu-galized. A smear was made and examined micro-scopically. The deposit was then planted on solidmedia. Nearly all strains were isolated on Lowen-stein's medium; a few were isolated on Dorset'segg medium. After reasonable amount of growthhad occurred the strains were subcultured onDorset's egg media, some containing glycerin. Thecultural characteristics were thus obtained. Typedifferentiation by culture was based on the follow-ing findings. The human type gave a more rapidgrowth on ordinary media; the growth on media con-

taining glycerin was even more rapid. In mostcases the culture was dry and nodular often re-sembling breadcrumbs. It was frequently pig-mented. The bovine strains grew more slowlyon all media and in some cases were inhibitedon media containing glycerin. The appearanceof the culture was different. It tended to bemoist, confluent and did not become pigmented.As soon as the strains had been differentiatedby culture small amounts were inoculated in-travenously into rabbits. In the case of humanstrains it was found that they normally survived0 I mgm. of culture and only developed a fewlocalized lesions. However, bovine strains weremore virulent and usually 0 01 mgm. killed therabbit inside six weeks time. This technique issimilar to that used by Blacklock (1932).

Results. The cerebrospinal fluids of twenty-six cases have been examined microscopicallyand culturally for the presence of tubercle

TABLE 2

POSITIVE RESULTS

SourceNo. Sex Age Lesions of Direct Type

infection

C3 F. 10 Pulmonary Family Pos. Humanmiliary historyT.M. denied

C4 M. 14 Pulmonary Parental Neg. HumanT.M.

C5 M. 10 Pulmonary Parental Neg. HumanT.M.

C6 M. 7 pulmonary Parental Neg. Humanhip joint

C8 M. 14 ?Abdominal Unknown Pos. BovineT.M.

C9 M. 19 Pulmonary ?Family Pos. HumanT.M.

CIO M. 10 ?ulmonary ?Family Pos. HumanT.M.

Cli F. -2 Pulmonary Family Pos. HumanT.M.

C12 F. 51 ?ulmonary ? Pos. HumanT.M.

C13 F. 14 Abdominal ?Milk Pos. BovinemiliaryT.M.

C14 M. 19 Pulmonary ? Pos. HumanT.M.

C 15 M. 11i Mesenteric Milk Pos. BovineT.M.

C16 F. 10 (Primary) ? Pos. BovineAbdominalT.M.

C17 F. 10 Mesenteric Milk Pos. BovineT.M.

C18 F. 19 Mesenteric ? Pos. HumanT.M.

C19 M. 13 ?Primary ? Pos. BovineT.M.

C20 M. 7 Pulmonary Family Pos. HumanT.M. negative

C21 F. 9 T.M. ? Pos. Bovine

T.M.= tuberculous meningitis.

90 on F

ebruary 2, 2020 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.19.98.87 on 1 June 1944. Dow

nloaded from

OBSERVATIONS ON TUBERCULOUS MENINGITISTABLE 2-continued

Age

7

6

3

12

2

19

Lesions

PulmonarysecondarymesentericT.M.?PulmonaryT.M.PulmonaryT.M.PulmonaryT.M.PulmonaryT.M.PulmonaryT.M.

Sourceof

infection

Familyhistory

Family

Family

Family

Family

Direct Tvne

Pos.

Pos.

Neg.

Pos.

Pos.

Pos.

T.M.=tuberculous meningitis.

Human

Human

Human

Human

Human

relationship between the age and sex of the patientand the type of the bacillus.THE PRIMARY COMPLEX. Only seventeen were

sufficiently fully investigated clinically or patho-logically to determine the entry route of the tuberclebacilli. Of these primary pulmonary complex oc-curred in twelve. All the twelve pulmonary caseswere associated with bacilli of the human type.Four mesenteric cases were due to bovine type andone to the human bacillus. Entry by the naso-pharynx was not proven in any of those casesmentioned above.THE SOURCE OF INFECTION. Out of ten cases

under fifteen years of age and due to the human typea source of infection was found in the family in eight.The source of infection of those bovine cases couldnot be established on a satisfactory basis because ofthe interval from the time of the actual infection tothe time when the strain was isolated.

TABLE 3

NEGATIVE RESULTS

Case Sex Age Lesions *Direct Culture Remarks

C7 M. 8 Tubercu- Neg. Neg. Removedlous frommeningitis hospital

C31 F. - T.M. and Pos. Neg.primaryunknown

bacilli. Analysis of the findings has been madebelow under the following lines:-

1. The results of the direct microscopical examina-tion of the cerebrospinal fluid.

2. The types of the bacilli isolated and the rela-tion to the ages of the patients and the sex of thepatients.

3. The primary complex and the source ofinfection.

MICROSCOPICALLY. Of the fluids which gavepositive cultures tubercle bacilli were seen in twenty.Of the two cases which were negative on culture onewas positive on direct examination. The mor-phology of the organism was not a guide to the typeof the bacillus. All the seven fluids which containedbovine bacilli were positive on smear examination.THE TYPES OF BACILLI. Twenty-four strains were

isolated. Of these seven were of the bovine typeand the other seventeen the human type. Thismeans a bovine incidence of twenty-nine per cent.When only those under fifteen were included, that istwenty, the incidence was thirty-five per cent. Theages of the patients ranged from two months tonineteen years. All the bovine strains occurred inchildren of fourteen years old and under. Bovinebacilli were isolated from three males out of thirteenand from four females out of eleven. Of thoseunder fifteen, twenty in all, three bovine strainswere obtained from eleven boys and four from ninegirls. The total numbers of cases is too smallhowever to justify any significant conclusion on the

I

SUMMARY OF FINDINGSCerebrospinal fluids 26.Tubercle bacilli i24 strains 17 human 13 smear positiveand types X t 7 bovine 7 smear positive

Two fluids culture negative, 1 smear positive.Bovine incidence, 0-19 years 29 per cent.; 0-15 years

35 per cent.Thirteen males-3 bovine.Eleven females-4 bovine.Primary thoracic complex, 12 out of 17-all human.Primary abdominal complex, 5 out of 17-4 bovineand 1 human.

DiscussionIn comparison 29 per cent. in all ages and 35 per

cent. in under fifteens roughly correspond with thefindings of other workers. As regards the incidenceof types of bacilli, Griffith in 1920 identified twobovine out of twelve strains in a mixed group oflesions (16 per cent.). Later, in 1929, Griffithfound 21 8 per cent. bovine bacilli in all ages andof 34 per cent. in those under fourteen. In 1932Griffith and Munro found it to be 13X3 per cent.Later, in 1934, Griffith in a series of 151 Englishcases found the percentage of bovine to be 218 andfrom thirty-seven Scottish cases the figure was 40 5.Thus in the later series the incidence in Scotland wasmuch higher than in England. This fact is partly ex-

plained by the fact that the majority of them weredrawn from the rural districts of Scotland whereasthe English cases came from industrial areas. In1935 MacGregor, Kirkpatrick and Craig found thebovine type in 28 per cent. of cases in Edinburghand district. These latter findings correspond to the29 per cent. recorded here for Belfast. Regardingthe prevalence in this country of bovine bacilli inbetween 20 and 40 per cent. of cases findings in othercountries are interesting. In Greece (before 1939)and other countries where milk was boiled beforeuse to prevent it going sour only an occasional caseof tuberculosis was found to be due to the bovinebacillus. In Toronto since 1916 when pasteuriza-tion was made compulsory, Price (1932) was unableto find any bovine tubercle bacilli in 500 cases of

No.

C221

C23

C24

C27

C29

C30

Sex

M.

F.

M.

M.

F.

F.

-

91

I I rF%

on February 2, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.19.98.87 on 1 June 1944. D

ownloaded from

92 ARCHIVES OF DISEASE IN CHILDHOOD

tuberculous children. This is in direct contrastwith the present findings of 29 per cent. in all agesor of 35 per cent. in those under fifteen years ofage.

Eleven cases of tuberculous meningitis have beenexamined to determine the pathogenesis of thecondition.From the findings it is concluded that tuberculous

meningitis commonly arises as the result of theextension into the subarachnoid space of a focus inthe meninges or in the juxta meningeal tissues. Thisfocus is blood borne and may or may not be one ofthe foci of a miliary tuberculosis.

Cerebrospinal fluids from twenty-six cases oftuberculous meningitis have been examined.Tubercle bacilli have been found microscopicallyin twenty and strains have been isolated in twenty-

four. The incidence of the bovine type of bacilliwas 29 per cent. in all ages (26 cases) and 35 percent. in those under fifteen years of age (20 cases).

REFERENCES

Blacklock, J. W. S. (1932). Medical Research Council,Special Report, No. 172., and Griffin, M. A. (1935). J. Path. Bact., 40, 489.

Buzzard, F. (1929). Brit. med. J., 1, 839.Griffith, A. S. (1920). J. Path. Bact., 23, 129.

(1929). Ibid., 32, 813.(1934). Lancet, 1, 1382.and Munro, W. T. (1932). J. Path. Bact., 35, 271.

Macgregor, A. R., Kirkpatrick, H. J. R., and Craig,W. S. (1934). Lancet, 2, 18.

(1935). Edinb. med. J.,42, 101.s and Alexander, W. A. (1937). Ibid., 44, 561., and Green, C. A. (1937). J. Path. Bact., 45, 613.

Price, R. M. (1932). Amer. Rev. Tuberc., 25, 383.Radmann, C. (1935). Virchows Arch., 295, 563.Ragins, A. B. (1936). J. Lab. clin. Med., 21, 1217.Rich, A. R., and McCordock, H. A. (1933). Johns

Hopk. Hosp. Bull., 52, 5.

on February 2, 2020 by guest. P

rotected by copyright.http://adc.bm

j.com/

Arch D

is Child: first published as 10.1136/adc.19.98.87 on 1 June 1944. D

ownloaded from