EREBRO SP‘

NAL FEVER

Del iver ed befo re the R oyeu’

Co l lege of P hysicians of L ondon on

A pr il 3 , 8, and " 10 ,79 79

l

13mS IR

‘

) HUM P HR Y" R O L L E S TO N ,

M .D . ,

E M E R ITUS P HYSICIA N , S T. GEO RGE'

S H O SP ITA L ; P RESIDEN T O F TH E

R O YA L SO CIE TY O F M E DICIN E ; TEM P O RA RY SURGEO N-B EA R

A DM R A L , R .N .

.

TH E L A N CE T 79 79 , I 54 1-549,

ifumlriem itemize

CE R E B R O S P IN A L F E V E R .

L E C T U R E I .

IN TR ODUCTION .

MR . P R E SIDE N T, CE N S OR S , AND F E L L OW S O F THECOLLE GE ,

—For the honour o f entrusting me wit h thede l ive ry o f the L uml e ian lectures fo r 1919 I desi re toexpress my grateful thanks .In 1581 Dr . R ichard Caldwal l , sometime senior student o f

Christ Church and P resident o f this College in 157 0 , andJohn , Baron Lumley (1534—1 609) founded a surgical lecturewhich was subsequently altered in the terms o f the appointment and scope . It would appear probable that Caldwal lwas responsible for the original lines on which the lectureship was founded

,as his only extant work is a translation o f

the “ Tables of S urge rie ,

” by Horatius Morus , a Florentinephysician . Times have indeed changed since this lectureshipwas started ; 300 years ago William Harvey had recently

(1 615) begun his 41 years’ tenure o f office , and in 1 616 had

given a complete survey o f the circulation .

Cerebro-spinal fever has not , so far as I can make o ut ,previously been taken as the subj ect o f these lectures , andas it has become prominent during the war and has been thesubj ect o f numerous observations and much investigation itis , perhaps , appropriate to take a survey of our present knowledge o f the epidemiology , clinical picture , and treatment

'

of

the disease in these three lectures . I have been so fortunateas to have seen the notes and many of the cases in the R oyalNavy since the outbreak of war , and have freely utilised thismaterial .The official nomenclature o f “ meningococcal infection ,

varieties (a) cerebro-spinal meningit is , (b) posterior basalmeningi tis ,

” only dates from the last revision published in1918 ; before that the heading had always been CerebroSpinal fever, synonym epidemic cerebro-spinal meningitis ,

”

B

2

the only alteration ever made being the omission of theadditional synonym malignant purpuric fever ,

” whichmade it s sole appearance in the first edition of 1869. In theManual of the International List o f the Causes of Death

based on the second decennial revision by the International Commission at P aris in July , 1909,

ce rebro-spinalfever is the third subheading o f simple meningitis , and isseparated from posterior basal meningitis which , with anumber of other meningeal diseases

,is included in the fir st

division of simple meningitis . It was perhaps a propheticinstinct that led the framers o f our first nomenclature toplace cerebro-Spinal fever among the general rather thanamong the nervous diseases . For the title o f these lectures ,cerebro-spinal fever , though used in the same sense as , isperhaps preferable to , meningococcic infection , which mightrather suggest a more considerable discussion o f pathologicaland bacteriological problems than can properly find a placein these lectures which are now understood to be devoted toclinical medicine . By cerebro-Spinal fever is meant meningococcic infection both in it s general and local manifestations ,meningitis being the most frequent and clinically importanto f the local changes .

HISTOR ICA L .

The first undoubted account of the disease is of an outbreak in and around Geneva in the winter o f 1805 byV ieusse aux by the next year it had spread t o A merica andwas described at Medfie ld ,

Massachusetts,by Danielson and

Mann , who appear to have been ignorant of the epidemic atGeneva ; and in 1806—7 the P russian A rmy were attacke d .

In this country the first cases verified by necropsy were atS underland in 1830 , but , as Ormerod 1 suggests , a group of

cases , some with purpura , observed by Gervi s 2 at B lackat ono n Dartmoor in 1807 may have been o f this nature . In 1827 .

Al exander Monro , in the course o f an account of chronichydrocephalus , describe d what is now known as posteriorbasic meningitis , but was no t differentiated from tuberculousmeningitis until 1878 by Gee and Barlow

3 in their paperon cervical Opisthotonos in infants . In 1897 J . W . Carr 4

elaborated this distinction in his account o f non-tuberculousposterior basic meningitis of infants .A s the acute disease was known as the Spotted fever

and as the black death,

” confusion with other fevers of amalignant form , and especially typhus , has been inevitable ,and this must be taken into consid eration in connexion withany attempts to recognise descriptions of cerebro-spinalfever in the works of Hippocrates

,Celsus , P aul of E gina ,

and in other accounts written before 1805. Hamer 5 insist sthat S ydenham ’s description o f the new fever (influenza) in1685 po rtrays the clinical features o f cerebro-Spinal fe ve r

3

in 1915. Creighton-6 remarks that some symptoms o f theepidemic fever o f 1 7 7 1 in Ireland suggest cerebro-spinalfever and while admit t ing that the clinical accounts o f theo ld epidemics would apply equally to typhus , enteric , o r

cerebro-spinal fever, Councilman , Mallory and Wright "

point out that S ir John P ringle ’s account (in o f

j ail fever with suppuration about the brain is compatiblewith the interpretation that . t he cases were meningococcicmeningitis . Impressed with the frequency and endemicityof the disease in parts o f Central A frica , where few

Europeans have travelled , Chalmers and O’

F ar r e l l ” raisethe interesting question whether the real home o f thedisease may not be Central Africa , whence it may havepassed to Egypt , and so have been conveyed by carriersamong Napoleon ’s soldiers to France and to America ;but their search among o ld medical and other records o fthe S udan has not been rewarded by any positive evidencein favour of their suggestion .

In the absence o f bacteriological help , on which theaccurate recognition o f cerebro-spinal fever at the presentday so absolutely depends , the diagnosis is Open to so

many fallacies that past records afford little evidence o n

which to form reliable conclusions . Thus , as late as 1865such an authority as Murchison 1 ° stated that the groundsfor drawing a specific distinction between epidemic cerebroSpinal meningitis , o r the spotted fever o f A merica , andtyphus are most inconclusive ,

” and argued that the casesat Dant zic described by Burdon S anderson were reallytyphus . A lthough there can be little doubt that it wasnot a ne w disease in 1805, and that , as Hame r says , themeningococcus was not born in that year , it is difficult tosay more than this .

Incr ease of the Disease dur ing the War .

It i s unnecessary to detail the epidemics of the dise aseSince 1805, as Hirsch did this up to 1884, and Bruce L ow “

continued the task from 1886 to 1916 . Hirsch describedfour periods from 1805 to 1830 , from 1837 t o 1850 , from 1854to 187 4, and from 187 6 to 1882 ; some writers prolong thefourth period up to the present time , but it is probablybetter to start the fifth period from 1903, New York sufferingsever ely in 1904—5, S ilesia in 1905—7 , France in 1909—1 0 , andTexas in 1912 .

In Great Britain 1907 was marke d by outbreaks in Belfast

(623 cases with 135 deaths) and in Glasgow (998 cases with7 15 deaths) , and in Edinburgh (206 cases wi th 135 deaths) .No considerable outbreak occurred in England and Walesuntil the first year o f the war ; in 1912 , when compulsorynotification was permanently brought in , there were 272 caseswith 142 de aths , in 1913 there were 304 cases with 1 63

4

deaths (B . Low) , and in 1914 300 cases with 206 deaths .In 1915 there were 2343 cases with 1521 , or 64 9 per cent . ,deaths ; in 1916 , 127 8 cases with 838, or 656 per cent . ,deaths and in 1917 . 1385 cases with 906 , or 654 per cent . ,deaths (R eeceThere is t h e r e fe r e no question as to the incre ase of the

disease in this country after the outbreak of war . Thecause , as will be discussed later , appears to be mainly thecrowding together o f young recruits in camps and barracksin conditions which , on the one hand , led to an increase inthe carrier rate , and on the other , reduced the resistance o fthe individual . As the diseas e appeared on S alisbury P lainafter the arrival of the first Canadian contingent

,as four

cases occurred in their camp at V alcartier , in Canada , inS eptember , 1914 , three on the way across

,and some after

their arrival , it was popularly suggested that the disease mayhave thus been introduced into the country . This , of course ,is quite untenable

,for

,as has already been mentioned the

existence o f the disease in this country was well recogni sed .

But it might be argued that the advent of the Canadiancontingent aggravated the spread o f the disease . Thus , atP ortsmouth the disease began on Jan . 15th ,

1915, at EastneyBarracks , among men who came in contact with a Canadianfootball team visiting there o n Jan . 9th this , however , mayhave been a coincidence , for the disease broke out simult ane ousl y in other parts of the country , and none o f theCanadian visitors were known to have been carriers .

The Medical R esearch Committee ’s S pecial AdvisoryCommittee wrote that “ the reports from the S alisburyP lain area suggest , not indeed that the Canadians importeda new disease but that they did introduce a virulentstrain o f the meningococcus , and were in some degreeresponsible for its spread .

”A dami 13 vigorously controvert s

this , and points out that the strains obtained from theCanadian cases were identical with those isolated frompurely British cases .Epidemics vary much

' in their duration ; from days andweeks to months

,but usually last for six months . Dop t e r

quotes examples o f the persistence o f the disease in townsfo r years ; thus at Bayonne it lasted for seven years

(1837—1843) and at V ersailles for five years (1839

Cher/age of Typ e of the D isease

The question o f the change o f type o f the disease acquiresconsiderable interest from Dop t e r

’

s‘ 4 observation that in

France the type o f the infecting organism underwent achange during the European war and N etter correlated thegreater frequency o f se p t icae rnic cases and lesions , such asrashes , arthritis , iridocyclitis , with this alteration o f the infe ction from Type A (Gordon

’s Types I . and II I .) t o Type B

5

(Gordon’s II . and This question is referred to later under

the heading o f meningococcic purpura without meningitis .Kennedy and Worster-Drought 1 6 investigated the relationof the type o f meningococci to the clinical picture in 22cases and found that 8 cases infected with Gordon’s Type I .were all very gravely ill , with a fatal issue in 6 ; that o f

6 cases with Type I II . some were severe and some moderatelysevere ; and t hat the 8 cases o f Type II . all recovered ; o fType IV . there were no cases . These few observationssuggest that Types I . and II I . (Nicolle Type A ) are morevirulent as regards the meninges and Types I I . and IV .

(Nicolle Type B) specially prone to cause septicaemia andextra-meningeal metastases (vide also meningococcaemia) .But in a recent small outbreak o f 10 cases due to Type I Iwhich was under my observation

,the meningitic manifesta

tions were very severe . and the mortality was 60 per cent .A dsh e ad 1 6 analysed 49 cases in which Gordon ’s types o fmeningococci had been determined , with the obj ect o f

ascertaining if there were any conformity between the typeon the o ne hand , and the seasonal incidence , symptoms ,and mortality o n the other hand , but did not feel j ustifiedin drawing any definite conclusions . Observations on a largenumber o f cases are necessary before coming to any finalconclusion on the relation of bacterial strains and clinicalsymptoms .

E P IDE MIOL OGY.

Though it naturally attracts more attention when inepidemic form , cerebro-spinal fever is really endemic andsmoulders on for years , b reaking out under favourable condi tions into epidemics . These endemic o r sporadic casesbridge over the interepidemic periods and keep the diseasefrom dying out . It is by the suppression and isolation o f

such cases that the disease should be finally eradicated .

At and before the commencement o f epidemic outbreaks theSporadic cases become more frequent , and it may be difficultto draw the line between an increased number o f Sporadiccases and an epidemic . It may , indeed , be doubted if evenin 1915 there was a real pandemic o f cerebro-spinal feve r inthis country ; small outbreaks affecting a number o f

persons Simultaneously o r within a short interval o f time

(part o f Greenwood’s 1" definition o f an epidemic) certainly

occurred,but fo r the most part the cases continued t o crop

up at intervals o r in couples . The Special advisory com

mit t e e upon bacteriological studies o f cerebro-spinal feverduring the epidemic of adopting DO pt e r andA rkwrigh t

’

s‘ 9 view

,concluded that the epidemic is no t one

of cere bro-spinal fever as such , but what may be termed asaprophytic epidemic ” o f t he meningococcus in thethroats of th e population , cerebro-spinal fever being an

epiphenomenon of this epidemic , due to a secondar y

8

syst emic invasion from it s saprophytic focus in the nasopharynx , occurring in spare and isolated instance s which ,

as a rule , appear unconnected with each other .

S easonal Incidence .

In this country the vast maj ority o f the cases occur duringthe firs t six months o f the year, the numbers falling to alow level during the summer months , thus contrasting withacute poliomyelitis , and not rising again until the end o f

De cember .

Among 3621 cases occurring in England (includingLondonand Wales during 1915 and 1916 Co lonel R . J . R eece founthat there were in the fi rst quarter o f the year 1355, o r 37 4o r cent . in the second 1444 , or 39 6 per cent . in the th ird8, o r 124 per cent . ; and in the last quarter 374 , o r 10 percent . Thus , in the fi rst six month s o f the year 7 7 per cent .o f the cases arose . Among the 509 cases in the Navy duringthe fi rst four years o f the war 298, o r 58 5 per cent arose inthe fi rst quarter ; 120 , o r 236 p e r cent . , in the second quarter ;43, o r 84 per cent . , in the thi rd ; and 48, o r 9 4 per cent . , i nthe fourth quarter o f the year . Out o f the total 509 cases ,353, o r 69 per cent . , occurred during the fi rst four months1915 and during the first half of the year 418, o r2 per cent .

The disease , however , ne ver disappears entire ly in 1915 and191 6 cases occurred in every month of the year (R eece) . Th e

seasonal prevalence probably depends on a number o f accompanying factors ; thus , cold and wet may act indirectly bycausing overcrowding and close con tact , want o f fresh airand o f proper ventilation , sore throats , and other catarrhalconditions . These conditions favour increase of the carrierrate

,which , when it reaches a percentage o f 20 (Glover) ,

is followed by the appearance of cases o f cerebro-spinalfever . This much appears fairly clear , but the furtherquestion arises as t o the direct influence of meteorologicalconditions in favouring the systemic invasion by the meningococcus ; in other words , o f inducing a sudden outbreak ofcases in epidemic form this might depend on (a) diminishedresistance o f the individual o r (b) increased virulence o f themeningococcus .A s the winter (January to March) and spring are the

periods o f the year during which the disease is unusuallyprominent , me t e or ological condit ions might naturally beexpected to exert a definite influence on its incidence

,and

cerebro-Spinal fever might be regarded as a weather diseasethus

,east and north winds and a low temperature

,espe

cial ly sudden falls and oscillations of temperature , might byreducing the resistance of carriers and persons exposed tomeningococcic infection lead to systemic infection . S udden’

alte rations in th e atmospheric temperature have be en

7

emphasised by S ophian 2° and DO p t e r2’

as responsible forthe outbreak o f cases, and I got the same impression whenat

‘

the R oyal Naval Hospital, Haslar , A ugust , 1914—1 7 .

though , as will be seen below ,a comparison of the incidence

o f the cases and the temperature conditions in the earlymonths of 1915 did not j ustify this view . I investigated thepoints mentioned above in connexion with 93 cases occurringat large naval de pdt s during the first three months of

1915, but did not obtained results j ustifying a positiveconclusion .

“ 2

From comparison o f the monthly incidence of cerebroSpinal fever with the prevailing winds , it at first appearedthat there was some evidence to su pport the preconceivedview that northerly and easterly winds favour the occurrenceo f th e disease . At P ortsmouth , P lymouth , and Deal caseso f the disease followed in th e wake o f north and east winds ,but at Chatham no decided conclusion as to the influence o fwinds was forthcoming. The direction o f the w ind on

(a) the day o f onset o f the disease ; and (b) on the threerevious days was t hen plotted out fo r 93 cases occurring ato r t smout h , P lymouth , Chatham , and Deal . On the actual

day o f onset the wind was more o r less east o r north in50 cases , and south , west , or calm in 43. On the th ree daysbefore the onset o f the disease the wind was m ore o r lesseast o r north in 47 , south o r west in 35, and in 1 1 casesvaried during the th ree days . On the whole , there is no tsufficient evidence that east and north winds p lay animp ortant part in causing an outbreak o f the disease .

The question o f the atmospheric temperature was goneinto . In some , but not in all instances , the month s with th elowest average daily temperature Showed the largest numbero f cases o f the disease , but the difference in the average dai lytemperatures was so comparatively smal l that no conclusionas t o its influence is j ustified .

Th e influence o f a sudden fall o f temperature was nextinvestigated . The temperatures (day and night) for th reedays before the onset o f the disease in 93 cases fr omP ortsmouth , P lymouth , Chatham , and Deal were examinedin order to see if there was a sudden fall o f temperature o f10° F . o r more with in th is period. Out o f the 93 cases therewas such a fall in 37 only . Th ere is , therefore , no reasonto believe that a sudden fa ll of the atmospheric temperaturecauses an immediate outbreak o f the disease .

On the other hand , from investigation o f an epidemic atHong-Kong in the early month s of 1918 O l itsky 23 found thata sudden fall o f temperature was followed in about four daysb y a great increase in the number o f cases reported , and thatabsence o f sunsh ine had the same effect .Finally , an inquiry was made as to the relation betweenthe prevailing wind and the ave rage dai ly temperaturecombined and the incidence o f cerebro e spina l fever . Consideration o f the month ly incidences o f 82 cases o f cerebrospinal fever with the r e vail ing winds and the averagedaily temperature for anuary t o March at P ortsmouth ,

P lymouth , Chatham , and Deal shows that 40 cases occurredin Februar during wh ich the prevail ing wind was southwe st and t e average daily temperature whereas

8

in January 20 cases) the wind was west or south-west in thefirst half an north o r north-east in the second half , and theaverage dai ly temperature in March (22 cases) theprevailing wind was north-east and the average dailytemp erature There was not , therefore , any realevidence that north and east winds and a low atmospherictemperature played a causal part in the outbreaks o fcerebro-Spinal fever .

Va/rio ns Vi ews on Efi’

ect of Weat he r Condit ions.

A ccording to Comp t onfl‘4 the condit ions favouring invasion

o f the blood-stream by the meningococcus are a high degreeof sudden saturation o f the atmosphere with moisture andvery little variation in the daily temperature o f the air , themeningococcus being p resent ; and S ophian states thatduring the outbreak o f 2180 cases in New York in 1905 theweather was cold and wet . O l it sky , however, consideredthat humidity and rainfall did not exert any influence ont he number o f the cases . Closely connected with thehumidity are the atmospheric pressure , the rainfall , anddeficiency o f sunlight ; and 69 per cent . o f Compton

’s casesoccurred contemporaneously with a fall o f the barometer ,91 5 per cent . with rain , and 82 per .cent . with deficientsunshine . The high atmospheric humidity may conceivablyact in several ways (a) It may render the mucous membran eof the naso-pharynx more spongy and so more permeable tomeningococci (b) as the organism grows best in plenty ofmoisture at a temperature of S OO C . the inhalation of moistair , which slightly raises the bodily temperature , mayprovide the most favourable conditions for growth , i t beingwel l known that drying has a very depressing effect on thevitality o f the meningococcus ; (c) in addition , as a humidatmosphere diminishes evaporation and as a result o f

this the exudation of fluid from the nasal mucous membrane ,the meningococci are less readily removed . On the otherhand

,from observations at Camp McCl e l lan , R obey 25 came

to the conclusion tha t cold and wet weather increased thecarrier-rate and the incidence of cases on account o f thecloser contact o f the men in the tents and mes s-halls , andthat

,conversely , warm fresh air and sunlight had a powerful

effect in diminishing the carrier-rate .

S ophian ’s analysis shows that most o f the epidemics occurin exceptionally cold weather , but this relation is no t

constant , as some occur in quite mild conditions , and D rp t e r

considers that continued cold is less provocative than suddenoscillations o f temperature . In order to explain the simu ltane ous outbreak o f cases of the disease in distant fociNetter and Debre 23 suggest that certain cosmic influencesmay combine to raise the virulence of the meningococcus ,and that variations in its virulence comparable t o thosede scribed for the pne umococcus occur .

9

In 1894 He r r ingham27 Showed that th e me teorological

conditions which when me t with together caused an outbreako f pneumonia we re (1 ) a wide daily range o f temperature ,(2) a dry condition o f the air , and (3) an east wind . Asthese conditions do not , from what has been said , appear t obear a constant relation to the incidence o f cerebro-Spinalfever , it would be interesting to compare the curves o f

cerebro-spinal fever and pne umonia . This has been done byNewsholme , 28 who found that for three out of the four yearsof the war the curves closely corresponded

,but that in July ,

1918, there was an epidemic peak in the pneumonia curvebut no t in the cerebro-spinal curve . He concludes that thesame winter and spring conditions favour the incidence of

both . By plotting out the weekly mortality returns o f theR egistrar-General for the last few years I find that therewas a corresponding rise in the incidence o f cerebro-Spinalfever in the early part o f the year , but that the rise of pneumonia in the last two months o f the year was not accom

panie d by a rise in the cerebro-spinal fever curve .

Unless it can be convincingly proved that the outbreakso f cerebro-spinal fever can be closely and accuratelycorrelated with changes in the meteorological conditionsand that it is not so is clear from the confusing details j ustgiven— it becomes more probable that the conditions prevalent during the months of greatest incidence act byincreasing the carrier-rate or the power of carriers t o

Spread infection— namely,by coughing o r by both means

and so exposing a larger number o f possibly susceptiblepersons to the Opportunity o f systemic infection . Gloverhas shown that with a high carrier-rate the disease breaksout . The conditions favour ing a high carrier-rate are

(a) prevalence o f colds and coughs , which enable existingcarriers to infect others ; (b) close contact o f individualssuch as occurs in cold weather. Overcrowding has beenshown to be a factor o f almost constant occurrence in outbreaks o f the disease. Of course , neither catarrhal infe ctions nor overcrowding is effective without the presence o f

carriers,but a varying number , 2—5 per cent will always

be found in any considerable collection of persons .

Dust — The epidemic in 1 907 at Leith occurred duringcold

,dry

,dusty weather , and R obertson , 29 as Buchanan 3°

had previously done in India , suggested that meningococcicinfection may be due to air-borne dust . A S it is now knownthat drying rapidly destroys the meningococcus , it wouldappear that the part

,if any

,played by dust is to se t up

cough,and so render carriers more active in the Spread o f

the infection .

10

ZE TIO L OGY.

In this country our unpreparedness for war and thenecessity for rapidly raising large armies led to overcrowding of the inadequate available barracks and depots .

O ver cr owding.

Overcrowding is well recognised as an important factor inthe aetiology of cerebro-spinal fever and exerts its influencein several ways : it impairs the general health , favours theoccurrence of various infections

,especially influenza and

catarrhal infections o f the throat and upper respiratorypassages , which may dispose to meningococcic invasion , andgreatly increases the carrier-rate among the occupants o f thecrowded rooms .Overcrowding in military barracks has been defined by Dr .

J . A . Glover,

31 whose valuable deductions in relation tocerebro-spinal fever will be freely utilised , as the sl ightestexcess over the mobilisation standard ,

which,as a rule , is an

excess o f 50 per'

cent . of the number of men allowed b y thepeace standard . The peace standard ,

according to the R oyalCommission of 1861 , provided 600 cubic feet per man and aspace of one yard between the beds . The important pointso f overcrowding are the space between the beds and thee flicie ncy o f ventilation , the mere cubic space being an indexrather than a vital factor . With the peace standard o f oneyard between the beds the percentage o f meningococciccarriers is rarely more than 5, with the mob ilisat ionstandard of 1 ft . 4 in . between the beds the percentageo f carriers may be 1 0 , with a space less than 1 ft . 20 , andwhen the space is less than 9 i nches the carrier-rate is28—30 per cent . Overcrowding increases the carrier-rate ,the maximum being reached in three weeks ; a carrier-rateo f 20 per cent . is a danger-signal and is soon followedby the occurrence o f cases o f the disease and b y a wel lmarked increase in the proportion of meningococci that areagglutinable . In January , 1918, at a certain military de pOt ,Glover found the carrier-rate both among contacts and non

contacts as high as 7 0 per cent . In such overcrowding theremedy o f increasing the space between the beds to 25 feetis followed b y a reduction in the carrier-rate , but not sorapidly as the rise due to overcrowding .

The experience o f the American Expeditionary Force , forwhich I am indebted to the court esy of Lieutenant-ColonelHaven Emerson , shows that the conditions o f '

o ce an transport involving great concentration o f me n in close . illventilated quarters between decks and conditions contributingto a pronounced lowering of body resistance were responsiblefo r th e high incidence of the disease among the troops on

1 1

arriving at the disembarkation ports in France and Britain , .

for up to the stoppage o f tr0 0 p shipments in November ,not less than 50 per cent . at all times , and frequently 80 percent . , o f all the cases of cerebro-spinal feve r reported amongthe A merican troops in Europe were in men within two weeksof landing .

F at igue .

Fatigue is a factor of import ance in causing outbreaks o fthe disease

,and together with want o f sleep and exposure

reduces the bodily resistance and so Opens the way to infe ction . Dopt e r

32 quotes a remarkable incident from theV ersailles epidemic o f 1839, during which out o f a detachment o f 1 53recruits 7 9 developed the disease after a fatiguingmarch . He also refers to the increased frequency and

mortality of the disease among recruits after forced marchesduring the European war , and poin t s out that recruits suffermuch more on account of their lack

’

o f training than soldierso f two o r three years

’ service,though o f the same age .

Examination o f the notes of naval cases shows that in anumber o f cases the disease began shortly after going onleave o r returning to barracks ; the fatigue of the j ourneymay have playe d a causal part .

The R e lat ion t o Camp aigns.

This question naturally arises in connexion with the greatincrease o f the disease in this country since 1914 . In thepast it has no t , like dysentery and enteric , been considereda war disease . Osler 33 points out that there is noreference to it in the Napoleonic , Crimean , Italian , o r

Danish wars , there were but a few cases in the FrancoP russian , R usso-Japanese , and S outh African wars , thoughin the North and S outh A merican Civil War o f 1861—3 therewere outbreaks of moderate dimensions on bo th sides .A S there is little information as to the increased prevalence

o f the disease during previous wars , it may be interesting toquote the available details as to the present campaign .

According t o Galambos , “ though there have been sporadiccases in the various theatres of war there have no t been anyepidemics among the German soldiers . In the French troopsthe disease has not , generally speaking , been common ; in1915 there were 1 07 5 cases , or 48 per in 191 6 therewere 451 , or 1 8 per and in 191 7 . 406 , o r 1 5 per

Dopt e r35 explains the l ow incidence at the front

by the Open-air life and the comparative freedom from overcrowding

,and contrasts the conditions with those in camps

at the base .

By the kindness o f the Director-General of the ‘

A rmy

Me dical S e rvice I am e nabled to say that the incidence in

12

the Army in this country was as follows : From S ept . l gthto De c . 3l st , 1914, 50 cases . with a mortality o f 31 , o r

60 per cent . ; during 1915. 1 195 cases , with 586 deaths , or49 per cent . during 1916 , 967 cases , with 430 deaths , o r446 per cent . ; and during 191 7 , 1 337 cases , with 593

deaths . or 448 per cent . In the British ExpeditionaryForce in France the disease began to appear widely in ascattered fashion , so that two cases hardly ever came fromthe same unit , in January , 1915, or at the same time as

the troops in this country were attacked . He rr ingham3°

estimates that the outbreak in 1915,when

,as in this

country ,the available serums were useless

,was the worst ,

with a mortality o f about 50 per cent . , but that during thewar the mortality probably never fell below 35 per cent . Iam indebted to the courtesy o f the Director-General o f theArmy Medical S ervice for the information that the annualratio Of cases of cerebro-spinal fever per 1000 admissions was63 in 1915 and 31 in 1916 . I am much indebted to ColonelJ. G . A dami

’s lecture at the R oyal Institution for thefigures o f the Canadian Expeditionary Force out o f a totalo f officers and me n from 1914 to 1918 there were367 cases with a mortality of 198, o r 54 per cent . Lieutenant-Colonel B . Myers has very kindly provided me withfigures showing the monthly incidence among the NewZ ealand Expeditionary Force from July , 1917 , to S eptember,1918 ; there were 75 cases with 24 deaths , o r 32 per cent . ,among a strength varying from to ColonelR . J . Millard kindly informs me that among the A ustralianForce in the United Kingdom there were in 1916 65 caseswith 29 deaths , o r 446 per cent . ; in 1917 out o f an averagestrength o f oflice r s and men 104 cases with 36 , or 346per cent deaths and in 1918 out o f an average strength o f

23 cases wi t h 12 , o r 52 per cent . , deaths .

In a list 37 o f 42 diseases arranged in the order o f theirimportance in causing days of Sick wastage among theA merican Expeditionary Force during the year endingMay S l e t , 1918, meningitis and carriers were item No . 27 .

I am indebted to Lieutenant-Colonel Haven Emerson andCaptain T . J . Duflie ld fo r the accompanying table.During the war the disease first became prominent among

the military population in this country , and then the civilpopulation followed suit ; the increase in the incidence of

the civil case s during the war is striking : in 1915 thenumbe r o f civil cases was eight times that O f 1914, and in1916 and 191 7 four times that o f 1914 (R eece) .That the greater incidence since the outbreak o f war is

due t o some special conditions is obvious , and probably oneo f the most import ant is overcrowding in barracks ; it is adisease not of the Open campaign but of training camps ,mobilisation centres , and de pOts. This i s t o some extentborne out by t he incidence of the disease in the Naval de pOtsas contr asted with ships , whe re , howe ver, the life is by no

1 3

means the same as that in the field among 509 cases in theR oyal Navy during the first four years o f the war 59, o r

1 1 6 per cent . , occurred in se a-going ships , and 363, o r 7 1per cent . , at the large de pOts at P ortsmouth , P lymouth ,Chatham , and Crystal P alace . But the comparatively lowpercentage o f cases in ships may be due to other factors ,such as the longer service o f the men as compared with the

Incidence of Meningococcus Meningitis in U. S . F or ces in F rance

Ye ar. Mon th . A ve rage stre ngth . No . of Case s . R at e p e r

new entries in barracks who form such a large proportion o fthe cases . Other unusual conditions bearing hardly on

young soldiers are excessive fatigue , recurrent infections .

R ecruit s and N ew E n t r ie s.

The above are specially affected thus in 1914—15, out o f

15 cases at t he R oyal Naval Barracks,Devonport , 14 were

new entries with an average service o f 24 days (7 with lessthan 20 days ’ service) . In 1916—1 7 , out o f 143 cases in theNavy , 31 , o r 21 7 per ce nt . , occurred within three weeks o f

j oining the se rvice , and among 46 occurring in P ortsmouth

14

further anal ysed by Fildes and Baker 38 36 , o r 78 p e r cent . ,were new entries— namely , those who had been in the se rvicefo r a few days o r at most a few weeks . These authors , likeDo p t e r , concluded that recent e ntry was a more importantfactor than age .

O ccup ation— R ecruits and young childre n are specially

prone to be at tacked ; miners have also be en stated tosuffe r more severely than other worke rs .

Tr auma — Blows on the head causing fracture of the basehave been thought to play an important part by allowing adirect passage o f meningococci from the naso-pharynx orsphenoidal sinus t o the meninges . S hort o f fractur e , itmight reasonably be thought that any cranial

.

damage orinj ury w ould

,by diminishing resistance , favour the localisa

tion and multiplication o f meningococci present in theblood stream . There are comparatively few cases Showingthe sequence of cranial trauma and cerebro-spinal fever .

A nt ityp hoid inoculat ion and ordinary vaccinat ion have beenfollowed by the disease and may , by reducing the resistance ,favour infection . Antityphoid inoculation has been followedby a relapse , and it is possible that this may occur inabortive and latent cases o f meningococcic infection . Inthe Navy vaccination is usually carried out shortly afterentry , and ,

as mentioned elsewhere , the majority of thecases occur in new entries . Acting on the assumption thatvaccination may be one o f the factors favouring the incidenceo f the dise ase in new entries , vaccination has at times beenpostponed , but the disease has occurred in new entries whowere not recently vaccinated o r revaccinated .

R e lat io n of Influenza and othe r Infe ctions, e sp e cia l ly

Catar r ha l A fiections, t o Ce r e br o-sp ina l F eve r .

Influenza may be considered in relation to cerebro-spinalfever from three points o f V iew : as specially related to it ; as ,in common with other diseases , depressing the resistance o fthe body and so rendering it liable to infection ; o r as , i ncommon with other diseases o f the respiratory tract ,spreading the infection and increasing the carrier rate bycoughing and sneezing .

From historical and epidemiological considerations Hamer 39

argues that cerebro-spinal fever is a sequel o r complicationof influenza , it being assumed that in special circumstancessome individuals when attacked by influenza develop cerebrospinal fever ; he appears to believe that the meningococcusis not the cause of cerebro-spinal fever

,although it may

assume importance when activated by some “ unknowninfluence ” temporarily endowing it with virulence , and that

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fever , may b e mentioned ; in February , 1919, among anumber o f naval officers in the same ward for influenza , eightcases of cerebro-spinal fever occurred in a few days . Therewas no known case o f cerebro-spinal fever in the neighbourhood O f the hospital , and presumably a carrier in the wardhad become actively infective from the cough o f influenza .

During the height of the influenza epidemic in October ,1918, there was a notable increase in the incidence o f

cerebro-spinal fever among the heavily infected (influenzaand pneumonia) American troops arriving in France fromthe United S tates , as is shown in the figures already quoted .

The second wave of influenza , in October , 1918, was muchmore severe in its complications and secondary infections ,and it seems reasonable to explain the increased incidenceo f cerebro-Spinal fever as the result o f a lowering o f t h e

bodily resistance and an increase d susceptibility to infectionby the meningococcus .The part played by influenza would the n b e analogous to

that o f other diseases and depressing conditions that havepreceded and been thought to dispose t o me ningococcicinfection , such as measles , rubella , mumps , and alsomenstruation in women , and the status lymphaticus . Butas influenza may be overwhelmingly common it may becorrespondingly more often fol lowed by cerebro-spinal fever ,and it would appear that when cerebro-Spinal fever becomesmore frequent o r occurs in explosive outbursts after influenzathe two obvious factors are impaired resistance and thepresence o f a chronic carrier with an influe nzal cough whichthereby facilitates the spread o f meningococcic infection .

Co lds an d Catar r hal Afiections.

The relation o f colds and catarrhal affections to cerebroSpinal fever may be considered from two points of view

(a) The relation o f preceding colds and catarrhal affectionsto individual cases o f cer e bro-spinal fever ; and (b) therelation o f the prevalence of colds and catarrhal affections tooutbreaks o f cerebro-spinal fe ve r .

(a) Opinions differ wide ly as to an antecedent nasopharyngeal catarrh in cases o f cerebro-spinal fever , both asto it s occurrence and when it is present as to its nature .

S ophian believed that the meningococcus always causes anaso-pharyngitis , so that there is an initial catarrhal stageo f the disease , and has be en followed by Lundie , Thomas ,Fleming , and MacL agan ,

“a who recorded it as universal in1 7 0 cases . Horder regards it as a cardinal symptom , andHerr ick found it in a considerable proportion o f his cases .On the oth er hand , it " was present in very few o f S heffieldNeave ’s 7 3 cases , in 25, or 40 per cent o f Worster-Droughtand Kennedy ’s 62 cases , and is stated t o be rare by Foste r.

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and Gaskell . It is quite conceivable that naso-pharyngealcatarrh may dispose to infection by meningococci , and thereis some evidence that adenoids , which are so commonlyassociated w ith naso-pharyngeal catarrh , favour infection

(R osenthal C l e minson 4 5 found that carriers on anaverage had 50 per cent . more adenoid tissue than normalsubjects . 0 . S hearer 4° finds that nasal mucus favours thegrowth o f meningococci ; this may depend on the presenceo f bodies o f the type of accessory growth hormones

(vitamines) which are present in blood , serum ,and animal

fluids , and have been shown by Miss D . Jordan Lloyd 47 tobe necessary for the growth o f the meningococcus in vitro .

On the other hand,a profuse catarrhal discharge may

remove the meningococcus before it can settle down on th e

inflamed surfaces (Crowe ) .

(b) The Special A dvisory Committee of the MedicalR esearch Committee on the bacteriological studies o f theepidemic in 1915 considered that the relation with catarrhsand the disease was fortuitous . as both have a similarseasonal prevalence . the relation being the same as thatbetween catarrh and the prices o f coal . On the other hand ,the view that catarrhal throat affections b y inducing coughing and sneezing spread meningococcic infe ction and so

increase the carrier-rate and the chances of syst emic infe ction

,as urged by P ringle , “ seems highly probable . The

prevalence o f colds in the population would thus favour theoutbreak o f cerebro-spinal fever , but it is not necessary thatcerebro-spinal fever patients should have had colds o r nasopharyngitis .

R e cent A cut e Afiections.

The depressing effect o f recent acute infections , such asinfluenza

,mumps

,me asles , has been mentioned as a probable

factor in disposing persons to meningococcic infection this ,however

,is much less important than overcrowding . A mong

the naval cases previous acute disease , such as measles ,rubella

,and mumps

,occurred in a small percentage only .

The se quence o f events in the two following cases isp erhap s worthy o f mentioning. Two brothers from theFair Isle

, S hetland , had measles In S eptember , 1915, inB aslar . One developed cerebro-s inal fever 13 days afterthe onset Of measles and died . h e other , who had neverbeen well since the attack o f measles , died in B aslar th reemonth s later from t ubercu lous meningitis . In both cases anecropsy was made .

Herrick lays stress on the occurrence o f previous acutedisease among his 208 cases 26 had recently had measles ,1 5 mumps , and among another series in another A me rican

0

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camp the percentage was almost the same — 13 of measlesand 8 of mumps among 1 12 cases (Miller and MartinThe occurrence of meningococcic meningitis after mumps ,in which a lymphocytic reaction of the meninges is extremelycommon , suggests that this disease may render the meningesparticularly susceptible to infection . S ymmers 5° foundthat the subj ects o f status lymphaticus were especially proneto meningococcic infection , and this may be correlated withH . C . Cameron’s view that the status lymphaticus is theresult of a chronic infective condition . But in their accounto f the Australian outbreak Fairley and S tewart 51 state thatnearly all the patients were in good health before the attackand that the large . number o f fine young men struck downwas most remarkable .

Influence of A ge and S ex .

A ge i s an important aetiological factor ; the most sus

ce p t ib l e age is from birth to 5 years , and in some epidemics80 to 90 per cent . o f the patients have been under 15 yearso f age in the Dant zic epidemic o f 1865, for example , 93 percent . were under this age . It is generally estimated thathalf the total cases occur in the first five years o f life ;in England and Wales during 1914 51 4 per cent . o f thecases were in children under the age of 5 years and 7 24 percent . under 10 . But in 1 915 and 1 91 6 these percentages

(30 and 488 , and 387 and 548 respectively) were muchlower , although the military cases are not included (R eece) .Comp t on

f’2 connects the greater fragility and delicacy o f thenaso-pharyngeal mucosa in children with their susceptibilityto infection . In a chart of 7 50 cases among the Chinesepopulation at Hong-Kong the peaks of the curve of incidencewere : (a) from infancy to 5 years ; and (b) at the age ofl 7 ;v years (Gale

53) . Though common in infants cerebro

spinal fever is rare during the first three months o f lif e , andat this period meningitis is more often due to B . co li than toother micro-organisms among 19 cases o f meningitis in t henewly born

,collected by Barron , “ one only was meningo

coccic , and among 20 more under the age o f 3 months fourwere meningococcic . A ccording to Compton 55 the least suscep t ib l e age i s between 35 and 40 years . Children andrecent recruits are the members o f the community mostfrequently attacked , b ut in the case of the latter theirenvironment rather than their age is the determining factor .S ea: in itself is often stated not to exert any influence on

the incidence of the disease , but among the civil populationduring 1914 , 1915, and 191 6 Colonel R eece found thatthe total number o f males exceeded that o f females , the percentage o f males being 57 7 , 539 , and 544 . This predominance o f male incidence was Shown in practically allthe age-pe riods the exceptions we re the age-group 20—30 in

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1915 and 1916 , and the age-group 30 and over for 1916 . I tseems probable that the abstraction o f a large number ofmales from the civi l population would explain this ; at anyrate , the incidence o f attack on these age-groups would befar heavier on males than on females if the military andnaval cases were included . In the epidemic of 1918 amongthe Chinese population o f Hong-Kong males were attackedSl ightly more than twice as often as females . Why males ,especially males in early life , are more prone to attack is notcertainly known , but it is natural to explain it by theirenvironment and greater liability to overcrowding.

S PREAD O F INFECTION .

Granting that the meningococcus is the cause o f cerebrospinal fever and that so far man is the only recognisedcar rie r , it follows that the disease is always conveyed by ahealthy carrier o r b y a patient with the disease . P atientsare almost always confined to bed and their sphere ofinfectivity thus much restricted

,and the ra rity with which

on e case can be traced to another proves that infection isusually due t o contact with a heal thy and often unr e cognise d carrier . Of the carriers

,the chronic ones , who are

commonly So in virtue of an infected accessory sinus ,adenoids , o r other focus , are much more powerful for harmthan the ordinary carriers whose term o f activity is usuallynot more than three weeks . R obey ,

56 indeed,found that a

chronic carrier can usually be found among the contacts o f

a case of the disease .

The actual spread of infection is mainly due to dropletsexpelled from the naso-pharynx in coughing

,sneezing , and

violent expiratory efforts,so that the carrier

’

s power fo r harmdepends on the existence of cough , &c. , o n the number o fmeningococci , and also largely on their being of an epidemictype . Infection may also be conveyed directly from mouthto mouth , as in kissing . The question of the importance ofprostitutes as meningococcic carriers requires investigation .

Other methods o f spread o f infection are less important orvery doubtful . A dami 57 has recently advocated the Spreado f infection through the intermediation o f drinking vessels ,partially o r imp erfectly rinsed , in crowded canteens andrefreshment booths . For this indirect method of infectioncarriers are o f course necessary

,unless it be assumed that

the disease only passes from one case to another , and this isincompatible with the history of isolated cases . The spreado f infection by Sputum ,

through flies o r insect carriers , o r

by clothing is improbable from the l ow vitality o f theme ningococcus and its rapid destruction by drying .

When a carrier lives in close contact with healthy individual s the carrier state is prone , especially under conditionso f ove rcrowding , to be conveyed to others , and the se new

20

carriers act in like manner . A mong the individuals thu sexposed some may , from diminished resistance

,become

systemically infected , and , as Glover has shown , this shouldb e expected when the carrier-rate , which is normally under5 per cent . , rises to the danger-line of 20 per cent . Thatthe infectivity of the meningococcus is low or the generalresistance to it high is shown by the remarkable infrequencywith which doctors and those in attendance on patientscontract the disease and by the rarity of the spread o f thedisease when a patient is nursed in a general ward . It issaid in explanation o f the rarity with which nurses andattendants are infected that th e meningococcus usually disappears from the naso-pharynx about the fifth day of thedisease (F l iigge ).The low infectivity is also shown by the generally

acknowledged diflicul ty in tracing cases to contact withother cases and by the comparatively isolated incidence o f

the cases which occur sporadically more often than ingroups . Thus , among 3617 cases in 1915 and 1916 R eecefound that 3402 were Single cases and 100 instances o f

multiple cases in a house ; but occasionally several casesmay occur in the same family ; S cott

53 records four deathsin one day out of a family o f seven children from fulminating cerebro-Spinal fever . A number o f cases may occur atthe same time without any obvious connexion between them ,

as if due t o some meteorological influence , though thepresence o f a dangerous and chronic car rier may veryprobably be the real explanation . The carrier-rate is from10 to 20 time s highe r than the incidence of th e disease .

THE P ATH O F MENINGEAL INVASION .

Th e path by which th e meningococci reach the me ningeshas been thought to be (1 ) dire ct invasion o f the cerebralmeninges from the naso-pharynx and accessory sinuses viathe lymphatics (2) lymphogenous infe ction of th e meningesalong the spinal nerve-roots and (3) invasion of the bloodstream by meningococci from the portal o f entry in the nasopharynx and , subsequently, infection of t he meninges , fo rwhich the me ningococci have a Spe cial pre dile ction .

Dir ect Invasion fr om N aso-P haryncc and A ccessor y S inuses.

A s the meningococcus is relatively such a commoninhabitant of the naso-pharynx the analogy o f otiticmeningitis naturally suggested the once widely held viewthat the infection spreads directly to the base of the brain .

A s far back as 1883 this view was originated by Weigert andWe ichse lbaum

’s obse rvation that at ne cropsie s th e nasal

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mucosa was inflamed and covered with muco-pus . Thefollowing rou tes have since be en advocated

(a) Through the sphenoidal sinuses this was the earlyview o f We st e nho e ffe r ,

59 based on the observation that inone-third o f 29 necropsies these sinuses showed inflammationsubsequently , h e gave up this Opinion as a result of failure todiscover meningococci in the substance o f the sphenoid b one ,and in 1909 Elser and Huntoon 6 ° also failed to find meningococci ih the sections o f the walls of the sphenoidal sinus ando f the hypophyseal region of the skull . R ecently , however ,Embleton and P eters 6 1 described meningococci in the bonywalls of the sphenoidal sinus and in the contained pus andHolden 6 2 recorded a case with the sphenoidal sinus full ofmuco-pus containing meningococci , osteomyelitis o f theSphenoid , discharge of pus into the sella turcica , and perio st it l s over the area covered by the pons and pituitary . Butin 25 necropsies Worster-Drought and Kennedy 63 wereunable to find any evidence in support of the direct spreado f infection from the sphenoidal sinuses , and they point outthat when sphenoidal suppuration is associated with meningococcic meningitis it may be secondary .

(b) T ransethmoidal route . Communications through thecribriform plate of the ethmoid , between prolongations o fthe pia-arachnoid and the lymp hatics of the nose , allow thevirus of acute poliomyelitis to pass between the naso-pharynxand the cerebral meninges . Flexne r 6 4 found that when thisvirus is introduced into the naso-pharynx of experimentalanimals the disease results

,and in 191 7 considered that

meningococci probably passed along the lymphatic conn exions around the olfactory nerves , thus supporting thecontention put forward by Netter and De b ré 6 5 in 191 1 thatmeningococci pass from the nose through these communications direct to the base of the b rain . S o far experimentalproof is wanting A ustrian 6 6 found that the introduction ofmeningococci into the naso-pharynx of rabbits did not causemeningeal infection either in normal cond itions o r evenwhen the meninges had previously been irritated andrendered congested .

(0 ) Through the Eustachian tube to the middle ear and soto the brain . This route is rendered unlikely by the rarityo f otitis media in cerebro-spinal fever , and by its lateoccurrence when it does occur . I have seen a mixedmeningococcic infection in otitic meningitis , but this i squite exceptional .

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L ymphogeno us Infe ction a long the Sp inal N er ve R oots.

Lymphogenous infection o f the spinal cord by the passageof meningococci along the lymphatics o f the Spinal nerveroots in the cervical , thoracic , and abdominal regions ,resembling that described in some cases o f Heine-Medindisease , was suggested by S tuart McDonald ,

°7 who was ledto this conception b yGr e e nfie ld

’

s teaching that in tuberculousmeningitis the cord lesions may be older than the cerebral .McDonald postulated spread o f the meningococci to thecervical glands . to the lungs , o r b y swallowing to the intestines and mesenteric glands , and then extension along theperineural lymphatics to the meninges . Impressed with thefrequency o f enlarged and inflamed P eyer

’s patches inchildren dying o f the disease , R admann considered that theintestine was the portal o f entry .

Fowler 6 9 supported the view that cerebro-Spinal fever isdue to an acute abdominal infection on the grounds that

(a) the Spinal cord lesion is the Oldest ; (b) that theabdominal reflexes are abo lished— evidence that the lowerdorsal cord is aff ected ; (0) that there was only a slightdegr . e o f cerebral disturbance in some of his cases ; and

(d) that exclusively breast-fed infants are no t attacked .

These arguments are open to considerable criticism . Thefrequency o f intestinal catarrh , enlarged mesenteric glands ,and swelling o f the lymphatic tissue of the alimentary tractin necropsies on cases o f cerebro-spinal fever might appearto be in favour o f the view that the infection may enterthrough the gas t r O -intestinal tract . B ut the prevalence o fthese changes in animals experimentally infected throughthe meninges suggests that they are merely the result o fthe meningococcic infection , however produced (S t . ClairS ymmers

Infect ion fr om the B lood S tr e am.

Elser and Huntoon, A ustrian , and Herrick , 7 1 who on the

grounds of morbid anatomy , experimental research and clinicalobservations opposed the view that meningeal infection occursby direct extension from the naso-pharynx and accessorysinuses

,argue t hat the meningococci pass into the blood

stream,and thus reach the meninges

,especially the choroid

plexuses o f the lateral ventricles . In fact,that , as in tuber

culous meningitis , there is first a local focus , then a generalblood infection , and ,

lastly , a meningeal metastasis ; themain difference being that in cerebro-spinal fever the localreservoir of the meningococci is a saprophytic collection inthe naso-pharynx . The sequence o f events is exactlyparallel to that postulated by Draper and others in acutepo l iomyelitis— namely , naso-pharyngeal e ntry, general

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some extrane ous factor , or that after a time the meningococcic endotoxin is sufficiently concentrated to damage themeninges and render them permeable to meningococci .While the haemic infection of th e meninges appears to be

applicable to the maj ority Of the cases , the possibility that incertain instances in fection may pass by o ther routes , such asthrough the cribriform plate of t he ethmoid or the sphenoid ,

should no t be entirely excluded . In connexion with thepath o f infection Of the meninges the question arises wherethe meningitis begins , whether it starts in the choroidplexuses o f the lateral ventricles , as seems t o b e the generalview , in the Spinal meninges , or in both situations Simultane ously . That the meningococci firs t attack the choroidplexus is supported by the observation that lumbar puncture ,when repeated at short intervals , may eventually bring downmeningococci by drainage , and that in some fulminant casesthe cerebro-spinal fluid obtained during life is free frommeningococci . though after death meningococci are found inthe lateral ventricles (W . W . Herrick) . On the other hand

,

if the meningitis always Spread downwards from the brainto the cord it would be natural to expect that rigidity andre traction of the neck would constantly precede Kernig

’s Sign ,that is , if the view that this Sign is due to irritation of theposte r ior nerve roots and not to increased intraventricularpressure be correct . In many instances this sequence holdsgood . but by no means in all . Again , in some instanceslumbar puncture first yields turbid fluid and subsequentlyclear fluid

,o r the reverse o f that regarded as suggesting

that the choroid plexuses of the lateral ventricles are involvedbefore the Spinal meninges . In some necropsies the appearauces are compatible with the view that the cerebral andspinal meninges are attacked Simultaneously , and Ormerod 7 8

considers this more frequent than is ordinarily thought .P robably cerebral infection through the choroid plexuses isthe usual though no t exclusive site of initial invasion .

ME NINGOCOCCIC S E P TICIE MIA .

This condition may present several variations from theshort initial invasion o f the blood by meningococci

,which

probably precedes infection of the meninges in most,if no t

all , o f the cases o f meningococcic meningitis . P ossibly caseso f true meningococcic septicaemia are only more commonlyrecognised now than formerly

,but Netter 7 9 has suggested

that Dop t e r’

s observation that whereas before the war 96 percent . o f the cases o f meningococcic meningitis were infectedw ith the meningococcic Type A (Gordon

’s I . and II I . types) ,a change has taken place

, so that now the parame ningococcus , o r Type B (Gordon

’s II . and IV . ) is responsible for anequal , if not a larger , number o f the cases , may be correlatedwith an increased incide nce of me ningococcaemia and

25

me ningococcic manifestations in the Skin , j oints , and eyes .Brul e 80 also considers that parame ningoco ccaemia (due t o

Type B) is more frequent and more severe than meningococcsemia (due to Type A ) .Me ningo e o ccsemia appears to have been first established byGwyn 81 in 1899 in a case o f meningitis with arthritis .S alomon 82 in 1902 detected meningococci in the blood eightweeks before meningitis supervene d in the follow ing yearWarfie ld and Walker 83 described the first case o f meningococcic endocarditis with septicaemia ; a fulminating case ofmeningococcaemia also without meningitis was recorded byAndrewes “4 in 1906 , and in reviewing th e cases two yearslater Duval 8° summed up in favour o f the septicaemia beingsecondary to the meningitis , the reverse o f the presentOpinion . L iidke 86 described a case of meningococcicsepticaemia in which in addition streptococci were obtainedby b lood culture .

P o r t r e t 87 distinguished four kinds o f me ningo co ccmmia

(I. ) without meningitis , (I I . ) preceding meningitis , (I II . )with metastases , (IV . ) without metastases . The followingforms o f meningococcic septicaemia may be described

1 . In a certain number of cases a fulminat ing meningococcwmia proves fatal before any meningitis has had time tooccur

,and lumbar puncture , if performed ,

gives exit to clearfluid without any meningococci o r increased cell content . Atthe necropsymeningococci can perhaps be obtained from thefluid in the lateral ventricles o f the brain , but there is noexudation . The clinical features o f these cases are severetoxaemia often at the onset with a low temperature followedby feve r and perhaps hyperpyrexia , rapid pul se and respirations , and extensive haemorrhages into the skin , mucous andserous membranes , and adrenals . The clinical picture maysuggest the “ acute abdomen ” such as internal strangulation ,intussusception (P ybus

88) or Henoch

’s purpura,fulminating

purpura,haemorrhagic fevers .

2 . A bortive case s in which a blood infection is overcomeafter a short time b y natural immunity , though commonl yassumed t o be frequent , are diflicul t to prove . Cases offeb ril e meningococcic purpura w ithout meningeal sym

p t oms , o r presenting men ingeal irritation which ,as shown

by lumbar puncture , is no t due to meningitis and maytherefore be explained as meningism

,come under this

heading . S ainton and Maille ’s 6 9 case with a measly e ruption

,synovitis of two j oints containing meningococci , and a

positive blood culture but no meningitic symptoms , thewhole illness lasting about a week , belongs to this group o f

abortive cases . In order t o determine the incidence o f theseabortive cases during an epidemic 9° Maxcy selected 27 caseswith fever, he adache , and malaise , but without petechiae ,and made blood culture s which we re uniformly negative .

26

Doubt is thus thrown on the assumption o f their frequency ,

but further investigations of this character are desirable .

3. Intermittent meningococcic fever due to septicaemiamay (a) last for weeks without any meningitic symptomsever developing , o r (b) it may follow meningitis , o r (0 ) Showtransient meningitic symptoms , or (d) terminate in meningitis .

(a) S ome case s have se p t icse rnia fo r weeks o r months andmeningitis never occurs . In Liebermeister’s 91 case thedisease lasted four months and in Bray’s ”2 case , complicatedb y chronic pulmonary tuberculosis , there was fever for fivemonths and recognised meningococcsemia for three months .

Though striking , they have no t been very often recognisedNetter 93 had five exampl es among his 368 cases , and Brette 94

collected 22 cases in 1918. The attacks o f fever may bequotidian or tertian and in the intervals the patient may feelwe ll . The disease may resemble malaria

,quotidian o r

tertian , o r enteric fever— Netter ’s 95 pseudo-malarial and

pseudo-typhoid forms . The attacks o f fever may begin witha rigor and end with sweating , be accompanied by splenicenlargement ; j oint pains and orchitis may occur , and rashes ,such as polymorphic erythema o r erythema nodosum ,

herpesor papules , especially on the lower extremities o r around thej oints , o r petechiae may be present . But th e disease mayrun its course without any cutaneous manifestations (Z e issl e rand R eidel , 96 Worster-Drought and Kennedy In e xce pt ional instances malignant endocarditis is due to infectionwith the meningococcus (Warfie l d and Walker , Cecil andS O p e r ,

98 Worster-Drought and Kennedy . )

(6) In another group septicaemia follows th e subsidence o fmeningococcic meningitis . Brule 99 records a case withsepticaemia o f two mont hs’durat ion with purpura and positiveblood cultures on five occasions . L ance l in

’

s1 0 ° patient had

meningococcic meningitis,and after an afebril e period of

four days had fever imitating malaria fo r seven days andthen yielded to serum ; meningococci were no t obtainedfrom the bl ood , but the presence of purpura renderedsepticaemia highly probable . Among 126 cases Land ry andHamley 1 0 1 detected two cases o f post-meningitic septicaemia .

If blood cultures were more often done in chronic casessepticaemia would probably be shown to be comparativelycommon .

(0 ) During the course o f intermittent me ningococcic feverthere may be transient meningitic symptoms thus , Maxcydescribes a case with transie nt rigidity o f the neck. whichappear ed a week after the onset and rapidly passed o ff.

(d) In an allied group of cases the septicae mia is prolonged

,but is e ventually followed by meninge al infection ;

[ 6 l l l l‘

in A ine and Chéné’ seudo-masplenic e nlarg

two months ’

e intravenous inj ection o f

A correct diagnosis is seldom made in the absence O f

meningitic symptoms . Blood cultures should be taken duringthe febrile paroxysm .

In Can t ie r i’s 104 case the fi rst m eningitic symp tom sappeared on the eighty-fir st day o f the disease , and b y th istime the following diagnoses had been made : intermittentfever , Addison

’s disease , tuberculosis , Mediterranean fever ,septicae mia , and syph ili tic feve r .

R EF EREN CES To L ECTURE I .

l O rme rod , J . A . System of Me d icin e (A l lbut t and Rolle ston), 1905,i 939. 2. Ge rvis . H . : M e d . Chir. Tran s . , London , 1811 , i i . , 234.

3. Ge e , S . J . , and Barlow , T. : St . Bart ’s . Ho sp . R e p . , London , 1878,xiv . , 23. 4. Carr, J . W . : Me d . Ch ir . Tran s . , London , 1897 , lxxx . , 303.

5. Ham e r , W . H . Proc R oy . S o c . Me d . , 1915, viii . (E p id em io l . Se ct ),7 7 . 6 . Cre ighton , C . History of Ep idem ics in

'

B r it ain , 1894, vo l i i . , 247 .

7 . Councilman , Mal lory , and Wright : E p idem ic C e re b ro-sp inalMe n ingitis : a Re port to t h e State Board of He al th of Massachuse tts ,1898, 10 . 8. Pringle , J. : O b se rvation s on t h e Nature and Cure ofJay l Fe ve r , London , 27 . 1750 . 9 . Chalm e rs and O

’

F ar r e l l : Journ .

Trop . Me d . and Hyg . , London , 1915—16 , xix . , 101 . 10. Murch ison ,C

TH E LANCET , 1865, i . , 446 , 482. 1 1 . L ow , B . R e p . L o c . Gove rn . Board ,1916 Re port on Ce re b ro-sp inal Fe ve r , 1 15—183. 12 . Re e ce , R . J .

Ib id 1917—18, 46 ; and p rivate i nformation . l 3. Adam i J . G . : Th e

War Story of t h e C .A .M .O 7 2, 1918. 14. Do p t e r , C A nn . d’

hyg .

p ub l . e t d e med . l eg. . Paris , 1918, 4a S é r xxix ., 144. 15. Ke nn e dy and

Worste r-Drought : Brit . Med . Jour. , 1917 . i . , 261 . 16 . A d sh e ad , G . PTre atm e n t of Ce re b ro-sp inal Me n ingitis b y An time n ingoco ccic Se rumat t h e Royal Naval Ho sp ital , B aslar : Sp e cial Re port Se rie s , N O . 17 ,89, M e dical Re se arch Comm i t te e . 1 7 . Gre e nw ood , M . : S e ction ofHygie ne and Pre ve n tive Me dicin e , 49 ; Trans . " V I I . Inte rnat . Cong .

of Me d . ,London . 19I3. 18. Sp e cial Re port Se rie s , No. 2 , Me dical Re se arch

Comm itte e , 56 , 1916 . 19 . Arkw right, J . A . : Brit . Me d . Jour 1915, i . ,494. 20 . Sop h ian ,

A . : E p idem ic Ce re b ro-sp inal M e ningitis , 1913.

21 . Do p t e r , C . : B ul l . Acad . d e med Paris , 1918, lxxxix , 169.

22. Rol le ston , H . D . Journ . R o y . N av . M e d . S e rvice , 1915, i . , 381 .

23. R e p , r t on t h e Inve stigations of t h e Outb re ak O f E p idemicMe n ingitis in Hong-Kong, b y First Lie ute nan t P . K . O l it sky ,

US A . , of t h e Rocke fe l le r Institute for M e dical Re se arch , laid b e foret h e Le gislative Counci l by command of H is Exce lle ncy t h e O ffice rAdm in istrat ing t h e Gove rnme nt. O ct . 17 t h , 1918, Hong-Kong.

24. Comp ton , A . : THE LANCET , 1917 , i i . , 14 ; A nn . l’

Inst it . Paste ur,Paris , 1918, xxxi . , 1 11 . 25. Rob ey and othe rs : Journ . In fe ct . DisChicago, 1918. xxiii 318. 26 . N e tte r e t D e b r é : L a M én ingite Céré b rosp inale , 23, 1911 . 27 . He r r ingham , W . P . : Brit . Me d . Jour . , 1894, l . ,

1012. 28. N ewsholme , A . : Proc . R oy . S oc. Me d . , 1919, xii 729. Rob e rtson : Brit . Me d . Jour. , 1907 , i i . , 185. 30 . Buchanan , W . J .

Journ . HIg . , Camb ridge , 1901 . i . , 214. 31 . Glove r, J . A . : Brit . M e d

Journ ., 13

7

8, ii . , 509 ; also Military Ove rcrowd ing and t he Men ingo

28

coccus Carrie r Rat e , Medical Re search Committe e ’

s Pub l ications ,March 9t h , 1918 ; and Journ . R oy . Army Me d . Corp s , 1918. xxx . , 2332. Do p t e r , C . A nn . d

'

hyg. p ub l . e t méd leg. , Paris . 1918, 40 sér . , xxix . ,

163. 33. O sl e r , W . : Brit. Me d . Jour 1915, i . , 189. 34. Kr ie se pidemiologische Erfahrunge n , Wie n u . Le ip zig, HO ld e r , 191 200—21435. Dop t e r , C . : Bull . Acad . de med . , Paris. 1918. 30 ser . , lxxix ..

169 : and Comp t. re nd . 80 0 . de b iol . , Paris , 19l8, lxxxi . , 1021 .

36 . He r r ingham , W . P . : Brit . Me d . Jour . . 1919, i . . 20. 37 . Have nEme rson : War Me d icine , Paris , 1918. i i . , 178. 38. Filde s and Bake r :S cial Re port Se rie s , No. 17 , 29, Me dical Re se arch Comm itte e , 1918.

3 Hame r, W . H . Proc . R oy . S oc. M e d 1916—17 . x .« E p idemio l .

1 7-44 ; Re port of t h e County Me dical O ffice r of He alth and SchoolMe d ical O ffice r fo r 1917 . London Coun ty Counci l , 1918, 9. 40. Glove r,J . A . : TH E LANCET , 1918. i i . , 880 . 41 . Whitt ingham , H . E . : Ib id1918, i i . 865. 42 Fle tche r, W . : Ib id 1919, i . , 104. 43 Lundie , Thomas ,

Flem ing , and MacL agan : B r it . Med . Jour . , 1915, i . . 836 . 44. Rose nthalJour. d e s Prat . , Paris , 1917 , 723. 45. C lemin son ,

F. J. : Brit. Med .

Jour. . 1918, i i . , 51 . 46 . Quote d by Warren Crow e , THE LA NCET , 1915,i i . 47 . Jordan Lloyd , D . : Journ . Path . and Bacte riol . , 1916 , xxi . ,113. 48. Pringle , A . : Brit . Me d . Jour. . 1918, i 398. 49. Mille rand Martin : Un ite d S tate s N av . Me d . Bul l . , 1917 , ix 563.

50. Symme rs , D . : Ame r. Jour. Me d . S c Phila , 1918, clvi . . 57 .

51 . Fairle y and Stewart : Ce re b ro-sp inal Fe ve r, Commonw ealthof Austral ia, Quaran tine Se rvice , Se rvice Pub lication No. 9, 1916 .

52. Com p ton , A . : Journ . R oy . Army Me d . Corp s , 1918. xxxi . , 241 .

53. Gale , quote d b y O l it sky : Re port of Inve stigation s into t h e Cutb re ak of Ep idemic Me n ingitis at Hong-Kon 1918. 54. BarronAme r. Journ . Me d . Phila 1918, c lvi . . 58. 55. Comp ton , ATHE LANCET 1917 , i i . , 14. 56 . Rob e y , W . EL , and Othe rs : Journ .

In ie c . Dis Chicago, 1918, xxiii . . 317 . 57 . Adami , J . G. : Th e War

Story of t h e 7 1 , 283, 1918. 58. Scott, H . H . : In te rstateMed . Journ . , St . Lo uis . 1914, xxi . 59. We st e nh o e ffe r : Be rl . klin .

Wchnsch r . , 1905, lxii . , 737 . 60 . E lse r and Hun toon : Journ . Me d . R e s . ,

Boston . 1909. xx . , 517 . 61 . Emb le ton and Pe te rs : THE LANCET, 1915,i . . 1078. 62. Holde n , O . : Pub lic H eal th , 1914-15, xxviii 234.

63. Worste r-Drou h t and Ke nne dy : THE LA NCET , 1917 , i i 7 11 .

64. Fle xne r , S . : ode of In fection , Means of Pre ve n tion , and Spe cificTre atme nt of Ep idemic Me n ingit is , 3, 1917 , Th e Rocke fe lle r In stitute for Me dical Re se arch . 65. Ne tte r e t De b r é : L a méningi tecé réb r O-sp inale , 236 , 1911 . 66 . Austrian : B ul l . Johns Hopkin sHosp . , Balt imore , 1918, xxix . , 183. 67 . McDonald , S . : R e v . Ne urol .and P sychiat . . E d in b . , 1907 , v . , 702 . 68. Radmann : De utscheme d . Wchnse h r . , 1907 , xxxii . 69. Fow le r, J . S . : R e v . Ne uroland Psychis t . , E dinb , 1907 , v . , 257 . 70. S mme t e , St. C lai rTHE LANCET , 1908, i i . , 472. 7 1 . He rrick , W . : Arch . Int .

Med . , Chicago, 1918, xxi . , 541-563 ; and Journ . Ame r. Me d .

Assoc . , Chicago, 1918. lxxi . , 612-616 . 72. Horde r, T . J. : Ce re b roS p inal Fe ve r , 130 , 1915. Oxford Me dical Pub l ications . 73. C lin icalAphorisms from Dr. Ge e

’

s Wards , 1895-96 , colle cted and edite db y T . J . Horde r, N o . 59, St . Bart

’

s . Hosp . Re p s ., 1896 , xxxii37 . 74. B ae slack : Journ . Am e r. Me d . Assoc. , Chicago, 1918, lxx684. 75. Maxcy : Journ . In fe ct Dis . , Chicago , 1918, xxiii , 470 .

76 . N e t t e r , A . : R e v. d e méd Paris , 1917 . xxxv . , 133-150 . 77 . B lanchie r ,D . : These d e Par is , No . 40 , 1918. 78. O rme rod , J . A . , THE LANCET ,1905, i . , 1117 . 79 Ne tte r : Bull . e t mem . S oc méd . de s hOp . d e Paris ,1917 , 36 sér . , xli 883. 80. B r ulé : Ib id 1918, 30 sé r . , xiii 537 .

81 . Gwyn : Bul l . Johns Hopkins Hosp . , Baltimore , 1899, x . , 1 12.

82. Salomon : Be rl . klin . Wchnsch r . , 1902 , xxxix . , 1045. 83. Warfie ld

and Walke r : Bul l A y e r C l in . L ab . , Ph ila. , 1903, i . . 81 . 84. Andrewe s ,F . W . : THE LA NCET , 1906 , i . , 1 172. 85. Duval : Journ . M e d .

R e s. , 1908. xix 258. 86 . L iidke : De utsch e me d . Wchn sch r . . 1918xliv . , 1380 . 87 . P o r t r e t : These d e Paris , 1912. 88. PybusTHE LANCET. 1917 , i 803. 89 . Sain ton e t Mail le : Bul l . e t mem.

S oc. méd . de s h Op . de Paris , 1915. 39 sér . , xxxix . . 296 . 90 . MaxcyJourn . In fe ct . D is 19l 8, xxiii . , 470 . 91 . Lie b e rme iste r : Miinch e n .

m e d . Wchnsch r . , 1908, lv . , 1978. 92. Bray : Arch . In t . Me d . , Chicago ,1915, xvi . , 486 . 93. Ne tte r, A . Arch . de med . d e s e h f. , Paris, 1918, xxi . ,246 . 94. Bre tte : Th ese de Lyon , 1918. 95. Ne tte r , A . : Bull . e t

mém . S oc. méd . de s hOp . de P aris, 1917 , 30 sér . , xli . , 1018.

29

96 . Z e issl e r u. Re ide l : Deutsche med . Wchnsch r . , 1917 , xli ii 258.

97 . Wor ste r-Drought and Ke nne dy : THE LANCET . 1917 , i i . , 7 11 .

98. Ce ci l and Sop e r : Arch . In t . Me d . , Chicago , 1908, xix 258.

99. B r ul é : Bull . e t mem . S oc med . d e s h Op . d e Paris , 1918, 3a sé r . ,

xlii 537 . 100 . Lance lin : Ib id 1917 . 3e ser . , xli . , 1011 . 101 . Landryand Ham ley : A m . Journ . Med . S e . , Phi la . , 1919, civil 210. 102. A iné

e t Ch éné : Paris med . , 1918, viii . , 118. 103. Se rr e t Bratte : B ul l . e t

mem . S oc . méd . d e s h Op . d e Paris , 1917 , 3a sér . , xli 1328, and 1918,3e sér . , xlii 917 . 104. Can tie ri : Riv. crit. di cl in . me d . , Fire n ze ,1917 , xviii 448.

LECTUR E II .

CLINICAL P ICTUR E .

INCUB ATION .

MR . P RES IDENT , CENSORS , AND FELLO W S O F THE COLLEGE ,

The incubation period has been variously stated t o befrom one day up to as long an interval as 30 days , mostwriters inclining to a period o f four or five days

,and very few

regarding it as long as 1 0 days . These estimates have beenbased on the interval between known contact with a case o ra recognised carrier and the appearance of symptoms , butthe cases with an apparently long incubation period areOpen to the fallacy that they may have come in contactwith an unknown carrier in the interval . A more accuratebasis fo r deciding the incubation period would be providedby determining the average duration o f the period thatmeningococci are present in the naso-pharynx beforesymptoms o f systemic infection appear . There are notmany observations bearing on this point . It is generallyagreed that the disease very rarely attacks carriers ;and chronic carriers , as shown by Gates

,

” containimmune bodies in the blood and so may be regarded as

more or less protected . Among 485 carriers under theobserva t ion of Fildes and Baker 3° no case o f cer ebroSpinal fever occurred ; and these writers , having examinedwith a negative result 26 men who subsequently contracted the disease

,conclude that carriers seldom develop

the disease , and that the period o f time between theacquisition o f the meningococcus and the onset o f thedisease must usually be Short . Out o f these 26 casesfive were examined within a week of the onset , eight duringthe second week , and four in the third week before theonset . The general opinion , as voiced by von L inge l sh e im ,

Gordon , and Andrewes , is that meningococci are constantlypresent in the throat at the onset of the disease , and thatevery case arises in a carrier . Fildes and Baker’s ob se rvat ions , as far as they go , are certainly compatible with theV iew that the incubation period is very Short and need not bemore than a day or two , but their failure to find anymeningococci in the throats of persons who afterwardscontracte d the disease is exceptional , for other observers

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32

turbid fluid containing meningococci obtained . The association o f a haemorrhagic rash with an acute abdominal onsetmay present the clinical picture o f Henoch

'

s purpura .

The occurrence of cases with this abdominal onset might ,perhaps , suggest that infection entered through the al imentarycanal , but the frequency with which the medulla of theadrenals is disorganised with haemorrhage would satisfactorilyexplain the collapse , and by stimulation o f the adjacentsympathetic plexus the acute abdominal symptoms ; thisinterpretation gains support from the acute abdominalcrises occasionally see n in Addison ’s disease . It should beadded that alarming collapse may be induced by moving thepatient to hospital .

CLINICAL FORMS.

The manifestations are protean and as a result ofdifferences in the clinical features numerous forms havebeen described , mainly on the basis o f the rate at which thedisease runs its course . Cerebro-Spinal fever

,like acute

poliomyelitis , has two distinct phases : (a) the general orsystemic infection and (b) the localisation in the meninges .The evidence o f systemic infection is usually prominent inthe initial stages and the process is the n commonlyextremely acute , but it may continue for weeks , and inrather rare instances chronic septicaemia follows meningitis .

A most important factor influencing the course and typeo f the disease is the serum treatment . Absence of orinefiicie nt serum treatment is responsible for fatal resultse ither early in the disease o r after a chronic illness due toadhesions o r chronic septicaemia . The different types ofcerebro-spinal fever Show transitional forms , and descriptiono f the forms is apt t o be artificial and confusing , as a singlecase may appear to belong to two . Further , the clinicalpicture o f the disease is often abruptly changed by unexpectedalterations

,such as improvement o r the onset o f grave

symptoms . The following forms of cerebro-Spinal fever wil lbe briefly mentioned without a detailed description , andto avoid repetition the symptoms will be mainly dealtwith subsequently : (1 ) fulminating ; (2) ordinary acute ;(3) abortive ; (4) chronic : (a) septicaemic , (b) encysted o r

loculated meningitis , variety posterior basic meningitis ofinfants .

F u lminat ing F o rm.

Fulminating cases , fatal within 48 hours o r less from th e

onset,are extremely dramatic and from their rapid course

are often o f medico-legal interest and the subj ects o f

inquests . These cases are said to be more frequent early inthe course of epidemics . The onset is sudden with sym

33

p t oms o f int ense poisoning , collapse , vomiting , and severeheadache . A purpuric eruption is almost constant , thehaemorrhagic areas sometimes increasing so rapidly in Sizethat their progress can be watched with the e ye but labialherpes , which usually appears o n the fourth day o f thedisease , is hardly ever seen . Diarrhoea , acute abdominalpain , and coffee-ground vomi t from the gastric extravasations are occasionally present . 4 6 Headache may be absent ,and the temperature . though usual l y raised , may be low as

the result o f the collapse . A peculiar smell has beendescribed (Neave but I have not noticed it .Two groups o f fulminating cases with transitions between

t hem have been described , especial ly by MacL agan6 6

(1 ) the purely septicaemic cases without meningitischaracterised by rigors

,prostration

,cyanosis , cardiac

failure , and mental clearness to the end ; and (2) thecases with purulent meningitis in which unconsciousnessrapidly sets in and passes into coma . In a number o f

fulminating cases meningococci , though no t found inthe cerebro-spinal fluid drawn off during life , can be isolatedfrom the cerebral ventricles o r base o f the brain after death ,thus showing the transition from the general to the localinfection . The most rapidly fatal cases are those withgene ral infection only . P urpura occurs in both ,

and thesymptoms of collapse have been correlated with the h eemo rrhagic condition o f the adrenal medulla , for which , as forthe other nervous tissues , the meningococcus has a p r e dil e ction (MacL agan).The fulminating cases have been thought to be less often

seen in young children and infants than in older persons ,but possibly some at any rate of the rapidly fatal cases o f

adrenal haemorrhage in infants are of this nature . A ndrewes , 3

finding the adre nals sterile bacteriologically , suggested thepossibility of haemorrhagic small-pox , but some o f thoseless thoroughly examined may have been meningococcic .

In the fulminating cases meningococci may be found in theblood by smears o r blood cultures , and the proper treatmentis intravenous inj ection of serum in large quantities .

O r dinary A cut e F orm.

The ordinary acute cases pass by transitions into thosecalled by Netter and Debre

7 6 the hyperacute on the o ne

hand and into the mild cases on the other. The onset issudden , and after a short interval meningitic symptomsappear— stiffness and retraction o f the neck . very violentheadache , Kernig

’s sign— and a state o f cerebral irritationsupervenes , passing if unrelieved by treatment into coma .

Energetic treatment has a dramatic effect , but recrudescenceso f the symptoms from reinfection , either from the nasopharynx or from some localised focus in the meninges which

D

34

is no t reache d by the intrathecal inj ection of serum , mayoccur. S ome cases , because the treatment is begun late o ris no t efficient

,become chronic from the formation o f

adhesions , Obstruction of the cerebral ventricles , andhydr ocephalus .

A bor t ive F orms.

The word abortive has been employed in two differentways

(a) A S applied to case s in which the cerebro-spinal feverdoes no t go any further than the septicaemic stage , the bloodinfection subsiding under the influence o f natural immunitybefore meningeal invasion occurs , so that in 24 to 48 hoursthe illness may be quite over . These cases are analogous tothe frequent abortive cases o f acute poliomyelitis . This i sthe sense in which the term abortive ” has more recentlybeen employed . Clinically these cases may appear as febrilepurpura , a form described elsewhere . Herrick refers to acase with the clinical features of a subacute polyarthritis

,

and says that there may be meningism . A bortive meningococcaemia was discussed in the first lecture .

(b) A s describing abortive meningitis , the symptoms ,though appearing suddenly , rapidly subside after two t o

Six days . It is in this sense that “ abortive ” is used byNetter and Debre and by various British writers . The secases are prone to relapse . Abortive cases appear to be morefrequent towards the end of epidemics , possibly because theyar e then more easily detected . Culpin 22 described very mildcases characterised by slow pulse , and says that the cerebroSpinal fluid may be lymphocytic and Show an occasionalmeningococcus o r be negative .

Chr onic F orms.

The chronic forms of cerebro-spinal fever may be dividedinto (1 ) cases which are not treated , o r , if treated , do no t

receive the appropriate serum so that the meningococcicinfection continues unaffected (2) cases with meningococcicsepticaemia which may precede , follow , o r occur withoutmeningeal infection these conditions were described in thefirst lecture ; (3) cases with meningitic adhesions andobstruction to the free circulation o f cere b ro-spinal fluid , sothat parts of the cerebro-Spinal subarachnoid space o r thecerebral ventricles become cut o ff and form closed cavitiesinaccessible to serum inj ected intrathecally in the ordinaryway . This encysted or loculated form o f meningococcicmeningitis

,o f which posterior bas ic meningitis o f infants is

a varie ty , probably accounts for most o f the chronic cases ,

35

and as the adhesions are likely t o form if serum treatmentbe delayed o r ine flicie nt it may include many o f the chroniccases mentioned above in which the serum treatment has forone cause o r another not been successful .

E ncyst ed , loculat ed meningi t is ; closed vent r icular mening'

it is ; vent r icul it is ; e p endymit is ; p yocep ha ly ; hydr ocep halus— These various names are applied to loculation o r shut tingOff o f some part of the space containing the cerebro-spinalfluid . A s a result o f a large quantity o f fibrin the Spinalsubarachnoid space may b e d ivided into two parts ; thelower o ne can be drained by ordinary lumbar puncture andthe meningococcic infection brought under the influence ofantimeningococcic serum ,

whereas in the part above theob struction the meningitis continues and keeps up the sym

p t oms . This condition is characterised by a want o f corresp ond e nce between the character of the cerebro-spinal fluid ,

Wh iCh may be clear , free from meningococci , or o b tainablein a few drops only , and the symptoms which persist .Lumbar punct ure performed above the obstruction gives e xitto turbid cerebro-spinal fluid containing meningococci .More often meningitis seals the communications— the

foramina o f Magendie and Luschka between the ventriclesand the subarachnoid space

,and as a result the ventricles , if

infected (ependymitis) , become distended w ith turbid fluido r pus which may be extremely thick (pyoce phaly) , o r , i fno t infected o r the infection dies out , simply show chronichydrocephalus with clear sterile fluid . V ery rarely cerebralo r subdural abscesses containing meningococci may be foundHal l e z 42 mentions three examples . On account o f the smal lsize of the foramina and the frequency o f delay in diagnosisand treatment in the very young blocking o f the ventricu larexits is more likely to occur in infants and children than inadults . An interesting point arises as to the time that ittakes fo r the obs truction to the ventricu lar foramina to beestablished ; usually the symptoms do not appear until theprimary acute attack is subsiding o r is over , but they maybegin quite early

,and possibly in some instances the

meningococcic infection starts in , and is confined to , thechoroid plexuses o f the lateral ventricles , the spread o f

infection being prevented by rapid closure o f the foramina .

In rare instances one lateral ventricle only is dilated .

In cases with closed infected cerebral ventricles lumbarpuncture and intrathecal inj ection o f antimeningococcicserum may cure the spinal meningitis but cannot influencethe meningococcic infection o f the cerebral ventricles. Onlumbar punctu

’

re the cerebro-Spinal fluid may be small inamount

,at the most not more than 20 c . em . ,

o r ther e maybe none . The fluid may be clear with a predominance o f

lymphocytes and a normal power o f reducing Fehling’

ssolution

,and does no t corresp ond to the degree o f the

clinical symptoms,thus Showing that there is not an ordinary

36

re crudescence of the cere bro-spinal meningitis . In spite of

intensive intrathecal serum treatment the symptoms charact e r ist ic o f ventricular infection and distension persist theseare exce ssive wasting , although the patient may take foodwell , bedsores , incontinence o f urine and faeces , headache ,vomiting , mental torpor passing into semi-coma , hyperte sthe sia ,

Macewen’s Sign , rigidity and contractions ,paralyses , diminution o r loss o f vision and hearing ,nystagmus , dilated and sluggish pupils , and irregularitiesof respiration . The temperature varies ; it may be inte rmittent , with wide oscillations o r crises , or irregular , o r theremay be no fever at all . The symptoms may Show remarkableintermissions . P atients with encysted meningitis mayreact violently to inj ections o f serum given in the siteo f an ordinary lumbar puncture, with appalling headache ascribed to engorgement o f the choroid plexusesand increased intraventricular pressure . The outlookis bad unless the shut-off spaces be tapped , andwhen there is meningococcic : infection serum inj ected ;but sometimes , although the course is long with repeatedlumbar punctures , the Obstruction o f the foramina of theventricles Spontaneously passes off , causing relief o f thesymptoms .The preventive treatment is the early start of vigorous

and effective serum treatment . Measures to prevent blocking o f the subarachnoid Space and the formation o f adhesionsare washing out the intrathecal space with saline o r solutiono f sodium citrate before the inj ection o f serum . The treatment

,puncture of the ventricles , and inj ection o f serum in

case of ependymitis , and drainage alone in aseptic hydrocephalus is mentioned elsewhere .

P ost e r ior basic meningitis of infant s is chronic encystedmeningococcic meningitis in young infants

,and its Special

features appear to depend on the early age o f the patientsrather than on any peculiarity in the infecting organism .

More than 20 years ago S till1 03 showed that the disease was

due to a micro-organism almost identical with the meningococcus

,and of late years it has become recognised that there

is no constant bacteriological distinction between themeningococcus o f posterior basic meningitis and that o f

cerebro-spinal fever in later l ife . But A ndrewes 4 statesthat serologically the meningococci may be o f a differentstrain from those of the epidemic disease in adults , andLieutenant-Colonel M . H . Gordon kindly informs me thatthe meningococci in posterior basic meningitis do no t differserologically from those in adult cases

,except that some ,

which are more diflicul t to identify,are usually atypical

specimens of his Group IV .

With regard to the modifying influence o f age , it is, o f

course,the rule that infections run a more rapid course in

e arly that in late life , but it has se emed to me that both

87

meningococcic and tuberculous meningitis are exceptionalin the more rapid course in adults than in infants . Thismay to some extent depend on the expansile skull of theinfant which prevents the intracranial and intraventricularpressure from becoming excessive so rapidly as in the adulto r adolescent . Among the cases called posterior basicmeningitis half occur under sixmonths o f age , three-quarterswithin the first year , and practically all under the age o f

two years , but there is no essential difference between thecondition o f closed meningococcic infection o f t he cerebralventricles in infants and in adults .

The disease is sporadic and may arise at any time of theyear

,but , as in later life , most o f the cases occur in the first

half o f the year ; among F . E . Batten ’s 6 85 cases , 54, o r

635 per cent . , occurred during the first five months of the

year. Though a matter o f common knowledge,the disease

is not very common thus , writing in 1898, S till found thatat the Hospital for S ick Children , Great Ormond-street ,during the previous ten years , a period when the diseasemust have been exciting much attention , 49 cases only cameto necropsy .

It may be well to mention the main clinical featuresdifferentiating the clinical form called posterior basicmeningi t is from ordinary cerebro-spinal fever in adults1 . The chronicity o f the disease , for acute cases o f

meningococcic meningitis do not come under this heading .

2 . The rarity o f eruptions ; among Hilde sh e im’

s‘i 7 1 00

cases there was no example o f a purpuric rash,and herpes

was present in two cases only . In November , 1918,Dr .

Claude Ker showed me a case of posterior basic meningi tisof three months

’ duration with profuse infra-orbital herpesduring a recrudescence . An ill-de fine d erythema occursin a few cases . 3. A maurosis o r loss of vision withoutobj ective changes in the retina o r Optic nerve is common ;it was noted in 37 out of Hildesheim ’s 1 00 cases . 4 . Therarity o f deafness and the occasional presence o f auditoryhyperacuity . 5. The prominence o f Opisthotonos , due tothe greater flexibility o f the Spinal column . 6 . Jointinfection appears to h e usually peri-arthritic rather thanintra-arthritic

,and may be associated with pseudo-glioma

o r the opaci ty o f the_vitreous caused by meningococcic

invasion and imitating a glioma .

In the early stages the disease may be very diflicul t t orecognise

,as fever

,tremor o f the limbs , and some bulging

o f the anterior fontanelle may be the only symptoms . Insuch cases Z inghe r

1 13 urges that a dry o r sterile lumbarpuncture should be the indication for tapping the ventriclesand daily intr aventricular inj ection of serum until thefluid is sterile . According to Batten , 50 per cent . o f thepatients survive

,and of these 15 per cent . recover com

p l e t e ly ,while the remaining 35 per cent . are left with

blindne ss , hydroce phalus , and varying degre es of me ntalde ficiency.

38

CE R E B R o-SPINAL FLUID .

The characters o f the cerebro-spinal fluid vary at differentperiods of the disease , and changes in it s naked-eye appearance s may occur rapidly . During the first 24 hours thefluid may be perfectly clear according to Netter and De b réthis holds good in 7 5 per cent . of the cases . The clear fluidmay be free from meningococci , the p r e ome ningit ic or septiemmie stage , but it may , as shown b y films and e specially bycultu re , contain meningococci . Al though the fluid firstdrawn off may be free from meningococci , that coming offa little later from the cranial o r ventricular cavities mayShow meningococci . In other instances the fluid

,though at

first turbid , is subsequently clear , as if the meningitisstarted in the region of the cord rather than , as is probablyusually the case , in the choroid plexuses o f the lateralventricles . The pressure is increased , but this may alsooccur in meningism and it is reasonable to believe that inthe earliest stages o f cerebro-spinal fever there may bemeningism or toxic irritation of the meninges withoutmicrobic invasion .

The turbidity of the cerebro-Spinal fluid varies fromOpalescence t o very thick pus running with difiicul ty throughthe trocar . A dmixture w ith blood is nearly always due t otrauma during lumbar punctures

,and in such cases the

fluid at subsequent punctures is yellow from changes inthe haemoglobin (erythrochromia) . In some instances agolden yellow cerebro-spinal fluid con tains so much proteinthat it coagulates at once (Froin

’s syndrome) ; this is

explained by Hanes 43 as due t o stasis o f the cerebro-spinalfluid in a cul-de-sac o f the meninges w ith escape of bloodplasma from the damaged blood-vessels o f the pia-arachnoid ,

this xanthochromia being different from erythrochromia inwhich the remains o f red blood corpuscles can be seen . Ayellow colour is also seen in chronic cases with intrathecaladhesions preventing the passage o f serum t o the skull ;lumbar puncture a day or two later gives exit to the serumwhich has this yellow tinge (Chiray The outlook in caseswith adhesions is bad , and Forbes and Adam 35 found thatthe cases w ith Froin ’s syndrome were all fatal . Clottingafter withdrawal , apart from that due t o accidental admixturewith blood

,is evidence of some form of meningitis , and has

been minutely studied by Connal . 1 9 It appears with theslightest opacity , varies with the degree o f turbidity , andpersists after the fluid has become practically clear . Hedescribes several varieties o f clot in meningococcic meningitis ,which are always softer and more friable than in the tubercul ous form .

The intrathecal pressure is greatest in the early stages o fthe dise ase , and gradually falls with the amelioration of thesympt oms . But in the late stages of hydrocephalus , and

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40

Micr oscop ica l Char acte r s.

In the very early stage there is an increase in the smallnumbe r o f lymphocytes normally present . In some e xce pt ional cases there is a well-marked lymphocytosis at thestage , but , if the patient survive , this is succeeded b y theordinary polymorphonuc lear predominance (Dopt e r). Inchronic cases with hydrocephalus in adults and in theposterior basic meningitis o f infants , which is a chronicmeningococcic meningitis , the cells are mainly lymphocytes .With these exceptions the leucocytes are po lymo rpho

nucl e ars , which at first constitute 95 per cent . or more o f

the cells ; as improvement occurs the numb er diminishes ,and in favourable cases there may, on the fifth day o f treatment , be 50 per cent . of polymorphonuclears and 50 pe r cent .of lymphocytes , and later the eosinophils may increase atthe expense o f the other leucocytes until almost all thecells are eosinophils (Bloch and HebertIn addition to l e IJC 'JCYt e S the cerebro-spinal fluid contains

large mononuclear cells constituting , according to Netterand De b ré , 5 to 20 per cent . o f the cells ; they may beenormous , as large even as 20 to 40 leucocy tes , are phagocyt ic , and are derived from the connective tissue cells andlymph spaces of the pia arachnoid .

The meningococci may be extracellular or intracellular,and their number does not correspond to the clinicalsymptoms . Gordon ’s 3° remarks suggest that lysis of themeningococci and liberation o f endotoxin may account fo rthe difficulty in finding meningococci in severe cases .

MI" E D AND S ECONDARY INFECTIONS.

In addition to the meningococcus the cerebro spinal fluidmay show various micro-organisms , such as the tuberclebacillus , the pneumococcus , the influenza bacillus , streptococci , and staphylococci . Among 339 cases in the Navythere were 8 o f this kind , 4 with streptococci , 3 with pneumococci, and 1 with tubercle bacilli ; such cases are , o f

course , usually fatal , and recovery occurred in one case only ,with pneumococcic infection present at the first lumbarpuncture .

The commonest secondary infection appears to be pneumococcic ; Netter and S alanie r 8° met with 22 cases ofsecondary pneumococcic infection among patients w ithmeningococcic meningitis treated by intrathecal inj ectionsof serum during the first four months o f 191 7 , when fromthe increased incidence of p ‘ imary pneumococcic meningitissince December , 1916 the virulence o f the pneumococcuswas presumably int e nsrfied . These authors suggest that theinj ection of se rum into the subarachnoid space , especially

41

when large quantities o f se rum no t corresponding to the typeo f the meningococcus present are given

,may provide a

better culture medium and so favour pneumococcic infection .

B ut a mixed meningococcic and p neumococcic infection ofthe meninges may occur before lumbar puncture

,as was

found in a naval case and it would appear that secondarypneumococcic infection depends mainly on the virulence o f thepneumococcus , fo r in a previous series of 300 cases O f meningococcic meningitis Nette r and S alanie r 81 found four cases onlyo f secondary pneumococcic infection . On the other hand

,it

must be remembered that horse serum causes an asepticmeningitis and facilitates the passage o f micro-organismsfrom the blood through the meninges . In order to preventthis secondary infection these authors advise the additionto the antimeningococcic serum o f antipneumococcic serum .

But this would be likely to be effective only if the pneumococcus were Type I . and the corresponding serum

,which is

the effective one , employed .

Fitzgera ld ,31 who reports 12 cases o f meningococcicmeningitis , three o f which were also infected with pneumococci , suggests that this secondary infection is commonerthan is usually recognised

,and quotes Mervyn Gordon

’sopinion that it occurs in 5 per cent . o f the cases . He pointsout that unless the lumbar puncture fluid is bacter iologicallytested on each occasion cases may easily be missed , and thusthe real reason for ascribed failures of serum treatment heundetected . A l l the reported cases of combined meningococcic and , pneumococcic infection , with the exception of

three recorded by Netter and S alanie r , proved fatal .Combined tube r culous and meningococcic infection of the

meninges is very rare . Of the recorded cases B érie l andDurand 1 ° accept eight only . S ophian has never seen such acombination among 300 cerebro-spinal fluids examined fromcases o f tuberculous meningitis , and states that no suchcoincidence has been established in New York . Theinteresting question arises as to the relation in point o f timebetween these t wo infections . On general grounds it wouldappear probable that the more acute meningococcic isimplanted on the tuberculous infection (Lutaud but theopposite view— namely , that meningococcic infection facilitates tuberculosis o f the meninges has found supporters .Thus

, S ainton , “ in recording two cases o f this doublemeningitic infection with o ld tuberculous lesions in thelungs suggests two alternatives : (1 ) that the meningococcic infection led to transfer o f the tubercle bacilli t o themeninges ; and (2) that the active meningeal reaction dueto intrathecal inj ections o f serum awoke o ld tuberculouslesions there .

S tr ep t ococcic infection may spread from the lumbarpuncture wound

,be due to otitic infection , o r arise without

any obvious focus of infection . Mixed infections may

occur in case s of ear dise ase ; thus , Jafié5‘ re cords a case

42

o f a soldier with chronic otitis in whom after death suppuration of the right lateral sinus and pus at the base of thebrain containing meningococci , streptococci , and staphylococci were found . L iidke “2 mentions cases of bacteriologically proved meningococcic meningitis in which bloodcultures , though negative for meningococci

,showed

streptococci or staphylococci .

R ASHES .

The incidence o f rashes varies in different epidemics ;thus , in one o f the e arliest accounts o f the disease Northsays that haemorrhages , which in 1806— 07 marked almostevery case , w ere rarely observed in 1808—09. Writing in 191 1 ,Netter and De b ré stated that eruptions have been , generallyspeaking , commone r in Britain and America than inGermany , and especially in France ,In the years before the war rashes were very rare in

sporadic cases in adults and were hardly ever seen inchildren , but during the increased prevalence Since 1914rashes— and at present I am not including herpes— havebeen common ; thus , among 502 cases in the R oyal Navyduring the first four years o f war there were 296 , o r 59 percent . , with rashes . In F rance also purpura has becomemore frequent during the war and Netter 7 1 has suggestedthat this may be correlated wi th Dop t e r

’

s observation thatwhereas before the war the infecting strain of meningococcuswas in 96 per cent . of cases Type A (Gordon

’s I . andduring the war , Type B (Gordon

’s I I . and IV . ) has becomeequal ly if not more important , and that the increasedfrequency o f me ningoco cceemia is also thus explained . Inh e r thesis on the purpuric forms o f meningococcaemiaMlle . B lanchie r 1 1 has brought forward some evidence infavour o f this view ; out o f 1 0 cases sh e was able b y examination of fluid or blood from the haemorrhagic areas todetermine that in 5 cases the infecting meningococcusbelonged to Type B . (Gordon

’s Types I I . and IV . ) and in1 case to Type A (Gordon

’s I . andThis is

,perhaps

,the most convenie

’

nt place to refer to thecases of meningococcic purpura w ithout meningit is . A mong27 7 cases Netter had 19 of meningococcic purpura withoutmeningitis

,and states that it has become commoner and that

as b ul lse can be raised b y friction over the purpuric areasmore easily than in other forms , this may be utilised t o

determine the strain Of the infecting organisms and so

enable the corresponding serum to be selected . S urgeonLieutenant-Commander D . H . 0 . Given 38 described a serieso f febrile purpuric cases , many o f which I saw , arising inconnexion with cases o f cerebro-spinal fever in the P ower fulestablishment at Devonport ; in only 3 of these could

meningococci be cultivated and none of them could b e

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identifie d with Gordon’s types . Meningococcic purpura maybe associated with pain in the j oints and synovitis .

Var iet ie s of R ashe s.

The cutaneous rashes accompany o r closely follow theonset o f the disease . They appear on the first o r second dayo f the disease and are comparable to the rose spots o f entericfever . There i s almost always an interval o f two to threedays between the appearance of the initial rash and of labialherpes in cases which Show both .

The characteristic rash is haemorrhagic , and may be eithersmall and petechial , resembling that in malignant endocarditis , o r purpuric like that in the malignant forms o f theexanthemata and acute lymphocytic l eukaemia . S ir WilliamOsler has told me o f an Oxford undergraduate who diedwithin 24 hours o f fulminating septicaemic cerebro-spinalfever ; microscopically Dr . A . G . Gibson found the bloodvessels o f the Skin crowded with meningococci . Theprognostic significance o f the petechiae and the large purpuric areas differ the large purpuric areas are characteristicof the fulminating cases , whereas the petechiae are not o fgrave omen . The rash may be petechial or purpuric fromth e start , o r the petechial character may supervene on anerythematous , papular , rose-spot , macular , or blotchy e ruption . According to Herrick the large purpuric areas areindependent of , and do no t spread from , the p e t e chise . Thenon-haemorrhagic rash may not undergo any further change .

In one naval case the rash almost disappeared directly afterlumbar puncture . Among 339 naval cases during the second ,

third,and fourth years of the war there were haemorrhagic

rashes in 153 and non-haemorrhagic in 42 . The erythematousrash has been described as transient and is seldom recorded .

Occasionally the initial rash is described as urticaria".

The rose spots , papules , and p etechiae are presumablyembolic and evidence of the stage o f septicaemia o r bloodinvasion . They are more p rone to occur in parts exposedt o friction , espec ially the j oints ; in some instances thehaemorrhagic eruption may be partly vesicular , in othersbullae may form over purpuric areas , and in one such case inthe Navy a pure culture of meningococci was Obtained fromthe fluid . In rare instances ulceration may supervene inlarge haemorrhagic areas , and ye t recovery follow (Gordon ,

4 °

B o vaird ,

1 3 R obb , 89 Elliott and Kaye ,

2Gand a naval case) .

Trophic bullae may form on various parts o f the body ,such

as the finge r sn and , according to Fairley and S tewart ,28 are

sterile . These observers divide the rashes into 1 ) primarynamely

,the purpuric

,petechial

,and macular , due to septi

caemia ; and (2) the secondary , which do no t appear untilafter the third day of the disease and are regarded as toxic .

O f the lat t e r c lass they describe the“ elbow Sign ,

”which

44

consists of a flush on the extensor surface of that j oint andalso above the great trochanter o f the femur , generally comb ined with a condition of haemorrhagic goose Skin . Thisdescription applies to a condition commonly recognised

,but

regarded as the petechial rash on points o f pressure andaggravated by friction . The appearance is well shown inP lates I I . and I I I . o f Foster and Gaske l l ’s Monograph inpatients dying on the second and fourth days of the disease .

Fairley and S tewart contest its relation to pressure .

Herpes i s a well-recognised event in cerebro-spinal feverand may be considered under the two heads of (1 ) ordinaryfebrile herpes labialis and (2) herpes o f the zoster type .

He rp es labialis appears to occur with varying frequency indifferent epidemics , and the relative incidence o f herpeslabialis and of other cutaneous eruptions shows similarfluctuations ; from a review o f the literature up to 1898,Councilman , Mallory , and Wright 2 1 concluded that herpes isfar commoner than any other eruption . Netter 7 4 found thatherpes occurred in a third of his cases and was more frequentthan purpura , and S ainton 98 states that it was present intwo-thirds of h is cases . High estimates were also given byLeichtenstern (90 per Leyden (7 5 per Tourde s

(60 per and Friis (54 per On the other hand,

S tille ” 4 says that in the Massachusetts epidemic herpes wasinfrequent and much less often present than cutaneousrashes in 502 naval cases there were 1 17 , o r 23 per centwith herpes and 296 , o r 59 per cent with rashes . As herpeslabialis ordinarily is prone to occur again and again incertain persons

,it i s possible that it s incidence in cerebro

spinal fever is to some extent determined by personalidiosyncrasy . Out o f the 1 1 7 cases of herpes in the Navy ,96 , o r 82 per cent . , had in addition an initial rash aserum rash or bothLabial herpes appears later than the initial rash and

usually on the fourth day of the disease , but it may occurearlier , on the second day , o r be postponed until later ;in two naval cases it came out with the serum rash on theeighth and tenth days of the disease . and may then beregarded as part o f the serum disease rather than o f cerebrospinal fever . In rare instances it may recur during con

t inued fever, with a recrudescence of symptoms , o r with theappearance o f some compl ication . It is unusual in childrenand exceptional in infants ; among R obertson ’s 92 66 casesunder 1 6 year s o f age it did not occur , but it was noted infour out o f 33 children under 4 years o f age reported byMitchell and F al ke ne r , 6 9 and in 15 out of 48 chi ldren and intwo out o f 21 infants colle cted by Colle tte ;

1 8 among the

45

naval cases which range from 1 5 ye ars upwards age did notexert any obvious influence .

The causation o f ordinary herpes labialis is undecided ;it i s not generally thought to be associated with any lesiono f the central nervous system , though Howard , 48 from histological examination o f the Gasserian and other ganglia ,conside rs that the herpes o f pneumonia and cerebro-spinalfever has a similar anatomical basis to that o f herpes zoster .Though fre quently looked fo r , meningococci have veryseldom been isolated from the vesicles o f labial herpes

(Durand , von Drigalski) , but Durand24 argues that the

meningococci may be overgrown by secondary infections .

C linically the appearance of herpes on the fourth day ofthe disease , some days after the initial rash which is presumab ly due to emboli o f meningococci , m il itates against theview that these two eruptions are due to the same mechanism .

It has , however , been suggested that the vesicles are due tomeningococci . and their situation determined by inflammation o f the Gasserian ganglion . As herpes labialis hasbeen seen in persons reacting vigorous ly to prophylacticantimeningococcic vaccines (Gates

37) it appears t o me

reasonable to refer i t to the local action o f toxins ratherthan o f bacter ia in the skin . The vesicles commonly occuron both lips and may extend out on to th e cheeks and nose

(facial herpes) , so that sometimes it is difficult to determinewhere labial herpes and herpes due to implication of thefifth nerve begin and end .

H e rp e s of t he zost e r typ e occurs in cerebro-Spinal fever , butmuch less often than lab ial he rpes . The t wo forms may bepresent at the same time thus labial herpes and herpes o f

the external ear due to inflammation o f the geniculateganglion o f the facial nerve (R amsay Hunt o r labialherpes and herpes o f the neck may be combined . Herpeso f the face due to inflammation of the Gasserian ganglion ofthe trigeminal may be very profuse , o r single branches maybe picked out I have seen nasal herpes w ithout ulcerationo f the cornea Ballantyne 5 describe s herpes o f both eyel idso n one side . Herpes o f the limbs is rare R obb 9° refers tocases , Ne tter and De b ré 7 7 figure bilateral herpes on thebacks o f the thighs , and S ainton describes a case with supraand infra-orbital herpes and a fe w vesicles on the dorsum o f

the hand . It would be interesting to have figures to Showthe date o f the appearance of herpes zoster my impressionis that it occurs earlier than the labial form .

NE RV OUS S YMPTOMS .

Nervous symptoms are predominant at the onset ofmeningitis ; severe headache , vomiting , and mental stuporor delirium are usually present and there may be wild mania ,

46

symptoms suggesting delirium tremens , or epileptic seizures .The mental disturbances during the septicaemic stages , andbefore meningeal infection has occurred ,

are probably toxicand comparable to those a t the commencement of otheracute infections , such as pneumonia . Incontinence o f urineand faeces is common . S wallowing may be difificul t , eitherfrom (e sophageal spasm o r paresis

,and is probably more

frequent than the notes o f cases Show . Among the 502naval cases it was mentioned in 8 (5 fatal). In a caserecorded by McConne l l , Morris , and S eehorn 6 4 Oe sophagealspasm was so obstinate that gastrostomy was done , d e athfollowing 1 2 hours later . General hyperaesthesia is notuncommon .

The condition of the r efl exe s varies the deep reflexes areoften exaggerated and an extensor response may be presentamong 398 naval cases Babinski ’s Sign was noted in 35, o r8 8 per cent . ; it may be obtained on one Side only .

Herrick “ insists that where as in other acute infections thedeep reflexes may be equally exaggerated on the t wo sides ,in cerebro-spinal fever there is a notable inequality . It isstated that in the most severe cases both the superficial anddeep reflexes may b e abolished , but it is doubtful if anystres s can be laid on this ; among 21 naval cases in whichthe knee-j erks were noted to b e ab sent there were 8 deaths .

It may be mentioned that the knee-j erks are often absen t inpneumonia and may b e exaggerated o r ab sent in entericfever . Kernig

’

s Sign and rigidity o f the neck are practicallyconstant when meningitis has appeared ,

and are so wel lknown that they will no t be further discussed here .

Ifacia l p ar a lysis i s rare it appears early and is transient .Among 502 naval cases i t w as recorded in 7 , but amongR obb’s 230 cases there were 1 1 examples . A p hasia , probablydue to local pressure from exudation , may occur . Among502 naval cases it was recorded in 5 ,

in 2 of which it wastransient the other cases were fatal . Among R o bb’s casesthere were 3 of aphasia.

P ar ap legia .

P araplegia is rare among 502 naval cases it was noted in1 ; among more than 400 cases MacL agan found it in 3,

2 o f which recovered there was on e example among R obb’

s230 cases and none among 120 cases that recovered and wereanalysed by Worster-Dr ough t .

m It may be either organico r in very

.

rarely recognised instances functional .

O rganic p arap legia is described by S O phian1 02 as either

(1 ) spastic with ataxia , clonus , extensor plantar response ,no sensory changes ,

‘

and no vesical disorder ; o r (2) flaccidwith absence o f re flexes and sensory changes . Of the

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48

course o f the disease .

‘

These flaccid monoplegias must b edifferentiated from those due t o acute poliomyelitis , whichhave not the same tendency to recover .

N e r ve deafness is not nearly so common now as it appearst o have been formerly .

Thus , according to Hutt ,52 among 874 pupils in the LondonCounty Council schools for deaf ch ildren requiring tuitiononly l

'

was due to cereb ro-sp inal fever . Among 502 Navalcases deafness occurred in 26 ; it i s usually regarded as dueto extension o f inflammation from the meninges along thesheath of the auditory nerve and is permanent , but in2 cases t emp o rar y

'

de afne ss about the time o f the serumrash was regarded b y Temporar y S urgeon-Lieutenant A . C .

MacA l l ist e r as a toxic manifestation of serum disease .

Deafness may al so be due to otitis media , which is notregarded as a common complication of cerebro-spinal feveramong 502 naval cases it was noted in 10 . But some writersstate that a mild form o f otitis media is very common .

OCUL AR S IGNS AND S YMPTOMS .

The pup ils are usually dilated , due t o irritation o f thesympathetic , and when sluggish in addition point to increasedintracranial pressure . The pupils may diminish in size andregain their activity after lumbar puncture and relief ofpressure

,and dilate when an attempt is made to straighten

the head o r to obtain Kernig’s sign . In some acute casesthe pupils are much contracted . Inequality of the pupils i sfairly frequent , especially in bad cases ; hippus is commonbut without any special significance .

P hotopho bia , said to be rare and thus to contrast with itsfrequency in tuberculous meningitis , was reported in 52 , o r10 per cent .

, out o f 502 naval cases , and was almost alwaysan initial symptom . Among 73 cases Specially examinedBallantyne

5 never found true photophobia,though spasm of

t he eyelids , usually associated with general hyperaesthesia ,was very frequent

,and he considers that this has probably

been described as photophobia .

Conjunct ivit is is not very common ; it occurred in 5 6 percent . o f 502 naval cases . in 1 0 , or 9 per cent o f Councilman ,Mallory , and Wright

’s 21 1 1 1 cases , in 15, o r 20 per cent . , o fBallantyne’s 73 cases , and in 20 per cent . o f Fairley andS tewart

’s series . The pus may , but does not always , containmeningococci . A ccording to Councilman , Mallory , andWright suppurative conj unctivitis may be due to loss ofsensation depending on destruction of the Gasserian ganglion .

When occurring early in the course of the disease , as it

49

commonly does about th e second day , it is usually o f littleimportance , but when i t appears later it may be followed bypanophthalmitis . A certain degree o f conjunctival engorgement in association w ith vaso-dilata tion o f the face iscommon . Conjunctival haemorrhages are sometimes present

,

and are important diagnostically ,as they are practically

never se en in other forms o f meningitis . Among 339 navalcases conjunctival haemorrhages were noted six times .Corneal ulcer may occur and show the meningococcus . Theanal ogy o f gonococcic arthritis in the newly-born ,

whichmay be se condar v to conj unctival infection ,

i s possiblyparalleled b y Mil ler

’s 68 case o f an infant who when twoweeks o l d had conj unctivitis followed in two weeks ’ time bymeningitis .

P anop htha lmitis is rare and is commonly unilateral Levy31

(of Essen) had th e exceptional experience o f seeing 9 cases ,8 unilateral , among 1 65 cases o f the disease . Among the502 naval cases it occu rred in 7 , o r 1 4 per cent . , and wasbilateral in 2 and unilateral in 5, al l o n the right side ; inthis connexion attention may be drawn to Netter

’s suggestionthat the position o f the patient ’s head , on the right o r left ,determines the side on which unilateral panophthalmitisoccurs . A s long ago as 1867 Gordon

4° noticed the predominance of these infective conditions in the right e ye .

Councilman , Mallory ,and Wright insist that , contrary to the

firm belief o f most ophthalmologists , panophthalmitis is notmetastatic , but is due to direct extension of inflammationaround the optic nerve and arteria centralis r e t inas andgive a figure in support o f their contention . Herrickinsists that the infe ction travel s by the cil iary ve ssels andnot by the sheath of the Optic nerve . P anophthalmitis maybegin at different dates ; Netter and Debre mention thetwelfth to the fi fteenth day of the disease , but in two navalcases it began on the fourth and t he eighth .

S upp ur at ion in the or bit , a very rare complication , isregarded by Councilman

,Mallory

,and Wright as due to

extension from the meninges , whereas Netter and Debre consider that the inflammation spreads from the accessory nasalsinuses .

O pt ic N eur it is an d O t he r N e r ve L esions.

Op t ic neur it is is usually regarded as infrequent and thuscon trasting with its incidence in .tube rculous meningitis ;among 389 cases obtained b y adding together the seriesreported by Ballantyne

, R andolph , Travers Smith , Fosterand Cooke Uhthoff

,and Heine , 39, o r 10 per cent . , had

Optic neuritis . On the other hand , Fairley and S tewart"8

report the re sult o f a routine b i-weekly examination by Dr .

E

50

Gault o f 184 cases ; of these . 1 16 , o r 63 pe r cent . , had Opticneuritis , and o f these 7 8, o r 67 per cent . , had a rash , whereaso f 68 cases without Optic neuritis 32 , or 47 per ce nt . , hada r ash , the conclusion being drawn that Optic neuritis isspecially related to septicaemia . In cases with internalhydrocephalus optic neuritis was almost always absent , andthis is exp lained on the ground that when internal hydrocephalus is absolute there is no fluid in the subarachnoidspace to distend the vaginal sheath o f the optic nerve .

True nystagmus occurs in severe cases only , and byFairley and S tewart is regarded as pathognomonic o f

internal hydrocephalus,and therefore o f extremely grave

prognosis. It must be distinguished from pseudo-nystagmuso r j erky movements at the limit o f fixation , which , accordingt o Ballantyne , are without significance .

S t r ab ismus, usually due to implication of the sixth nerve ,is much less frequent than in tuberculous meningitis , and isusually transient . Ballantyne found that the squint wasnearly always (14 out o f 15 cases) Spasmodic , and thus cont rast e d with the squints in tuberculous meningitis , which aremuch more commonly paralytic . Among 502 naval case ssquints were noted in 59 cases

, o r 1 1 7 per cent . amongR obb’s 230 cases in 28 per cent . ; among Councilman ,Mallory , and Wright

’s 1 1 1 cases in 253 per cent . and inBallantyne ’s 73 cases in 255 per cent . Among the 59 navalcases with strabismus 31 , or 525 per cent . , proved fatal .S trabismus is an early symptom , usually within the firstweek o f the disease , whereas in tuberculous me ningitis ,strabismus i s a late event .

P t osis is much less frequent than strabismus ; out o f the502 naval cases it was noted in 18, or 3 6 per cent . , but 13,

o r 7 2 per cent of these 18 cases terminated fatally . Themortality was thus 20 per cent . higher than in the squintcases ; this may be correlated with the probable spasmod icnature o f many o f the squints and the paralytic origin o f

the ptoses .

R e t r action of the upp e r eye lids may occur among 73 casesBallantyne noted it in 15, one o f which also showedvon Grafe’s sign . A ccording to Batten 7 it is common as anearly manifestation in posterior basic meningitis beforehydrocephalus , o f which it is a recognised result , has

developed . It varies in degree and is exactly like that dueto stimulation o f the sympathetic but is no t necessarilyassociated with dilatation o f the pupi ls .

JUL“

9 l 9‘

CIRCULATORY AND CO MP L ICA T

P e r icar dit is isdeathin other conditions . Netter and Debre speak o f pericarditisas a phenomenon almost confined to the post-mortem table ,and some authors do no t refer to i t . R obb , "0 however , notedpericardial friction in 1 7 , o r 7 4 per cent . , out of 230 cases ,Herrick 4 5 refers to 1 1 cases amo ng 265, and it was heard in4 naval cases that recovered . Ex t ensive pericardial effusionis rare , and it appears that the pericarditi s is usually dryand fib r inous . In a case o f Herrick’s 44 1 10 c . em. of bloodstained purulent fluid , giving a pure culture o f meningococci ,we re removed

,and 30 c . em . o f serum inj ected into the peri

cardium with benefit . As subpericardial haemorrhage s arecomm on af ter death in fulminating cases pericarditis ofmeningococcic origin is easily explained , In 1908 Duval 25

collected 5 cases o f bacteriologically proved meningococcicpe ricarditis .

E ndocar di t is is probably no t so rare as it has been statedt o be , but the vegetations may be small and possibly aresometimes overlooked . A mong Ivy Mackenzie and Martin’s “5

20 cases 2 had malignant endocarditis , and Krumbhaar andCloud , 56 among 1 6 cases o f cerebro-spinal fever , found 3with acute vegetative endocarditis . Cases o f meningococcicendocarditis without meningitis are much rarer and arereferred to elsewhere . Cardiac murmurs , commonly at theapex and referable t o muscular incompetence , are no t infr e

quent . Among 339 naval cases this was noted in 16

(1 death). P ermanent valvular lesions , though they mightbe expected from the occurrence of me ningococcic e ndocarditis , must be very rare .

P hle bit is in the lower extremities has been reported inrare instances . Collette 1 8 describes the association witharthritis in a girl aged years .

The b lood shows a polymorphonuclear l eucocytosis o f fromto and , according to Koplik , 55 i s over

in more than half the cases in chronic cases the leucocytosismay fal l to normal .

P ulse and B lood P r essur e .

The p ulse is usually regular though it may , especially ingrave cases , be irregular . Like the temperature the pulserate may vary greatly within a short time . The outstandingfeature about the pulse is that it is so often slow in relationt o the tempe rature ; thus in a naval chaplain who was

52

maniacal in the early stage th e temperature was 105° F . and

the pulse 60 . The slow pulse depends on vagal inhibitiondue to increased intracranial pressure . S ainton 99 state sthat in the early stage of the disease pressure on the eyelidsdoes no t modify the pulse , but that later and at the heighto f the disease this oculo-cardiac reflex is always positive ,the pulse becoming slowed by 1 6 t o 50 beats per minute ,and that this shows that the usual slow pulse in cerebrospinal fever is due to vagotonia . In fulminating and septicaemic cases the pulse is rapid ,

as in most other acuteinfections . In fulminating cases the pulse may becomeimpalpable some time before death . In some cases thepulse is rapid during convalescence

,probably from toxic

changes involving either the myocardium o r the nervousmechanism of the heart . This rapid pulse is sometimes seenin patients who have go t up soon after the illness . Beforedeath the pulse may become extremely rapid .

The ar t er ia l blood p r essur e , which has be e n specially studiedby S ophian and more recently by F air l ey and S tewart , is lowin the septicaemic stage , and in the worst cases may b eimpossib le to record , rises with the increased intracranialpressure accompanying the onset o f meningitis , and maythen b e between 140 and 190 mm . Hg , and in internal hydrocephalus is almost always raised from pressure o f the cerebrospinal fluid on the floor o f the fourth ventricle . Duringconvalescence the blood pressure is , in the absence o f complications , normal o r subnormal . In the acute stage vasomotor disturbance is often extremely well marked , the faceis intensely and characteristically congested— more so thanin most fevers . This may

,perhaps , b e correlated with the

changes commonly found in the medulla of the adrenals .The tache cer e

’

br a le is usually well marked , but is no t of anydiagnostic value . Epistaxis is occasionally se e n .

TEMPERATURE .

The temperature is very irregular and does not conform to

any rule probably every case has fever at some time duringthe course o f the disease , but some charts show little o r noelevation o f the temperature . This may be because thetemperature varies rapidly and it so happens that when it istaken it is not up . In cases with a very severe onset thetemperature is often at first depressed from collapse and

then rises so that hyperpyrexia may occur . A low temperature is said to be characteristic o f the disease in elderlype ople . There may be extreme oscillations at very shortintervals— a feature o f some diagnostic value in the ear lystages according t o Netter . In chronic septicaemia thetempe rature chart may imitate that o f mal aria o r enteric ,and in chronic loculated meningitis the re may be irregular

53

bouts of fever which in posterior basic me ningitis have bee ndescribed as crises due to increased intracranial pressure .In some acute cases there is agonal hyperpyrexia

,in others a

low temperature .

P ULMONARY COMPLICATIONS .

P ulmonar y compl ications in this country since the warhave no t been very common ; bronchitis and bronchopneumonia have been the most frequent and import ant .Bronchitis as a complication is dangerous and cases in whichit appears after some days’ illness with meningitis usuallyprove fatal . A n initial bronchitis does not necessarily makethe prognosis so grave . P neumonia has been seen in somecases and it is known that pure meningococcic

,as well as

pneumococcic , pneumonia may complicate meningococcicmeningitis and even occur without meningeal infection

(Jacobitz53). P neumonia may be present at the onset o r

appear later in the course of th e disease .

P leur isymay , o f course , accompany pneumonia o r bronchopneumonia in the course of cerebro-spinal fever , but it mayoccur without any obvious lung lesion this was noted in3 out of 502 naval cases . Meningococcic pleurisy has beenrecorded by Herrick , but it may be due to other organismsthus , Krumb haar and Cloud mention a case with acutestaphylococcic pleurisy. Netter and De b r é re fer t o abilateral haemothorax in a child with a purpuric eruption .

In the past pulmonar y complications have from time totime been prominent features in individual outbreaks , andrecently Herrick found them not uncommon among 208

0 886 8.

COMPLICATIONS INV OLV ING THE ALIMENTARY CANAL .

P arotitis i s rare it may be due to an ascending infectionfrom the mouth , as in other fevers and conditions in whichthe mouth is dry . It may be unilateral and be associatedwith suppuration in the neck o r otitis , o r be non-suppurative .

In the pus of one o f Fairley and S tewart’s cases S tap hy

lococcus aur eus was found . But in a suppurative case R obbreported the presence of the meningococcus

,and as this

organism does no t flourish in the saliva the infection mayhave been haemic .

In the most severe case s there may be blood in the vomitand faeces , but rarely in considerable quantities . Diarrhoeais not uncommon as an initial symptom and , as mentionedelsewhere , abdominal symptoms may be so prominent as tosuggest an acute perforation of the alimentary tract ,appendicit is , o r Henoch’s purpura . Jaundice is quiteexce ptional , and one case of pe ritonitis is tabulated byHe rr ick .

54

LESIONS O F JOINTS.

A r thr a lgia , or pain in the j oints like that of influenza , iscommon at the onset and in the early stage of the disease ,but is often overshadowed by the more severe symptoms .It may

,however , be the precursor of synovitis and then is

presumably similar in nature . It may accompany a haemo rrhagic eruption on the skin , and is very probably due t omeningococcic emboli and haemorrhages in the synovialmembranes of the j oints .

A r thr itis , o r more often synovitis , is a recognised complication o f cerebro-spinal fever , and may occu r in meningococcic infection without meningitis ; fou r cases o f this naturehave been report ed by Cecil and S oper , 1 6 three b y S ainton ,

98

and two by P aroy and May ” ; it has been re corded inmeningococcic purpura (Given and in such cases hassometimes been regarded as “ peliosis rheumatica .

” I t isdue to meningococci carried to the j oints by the bloodstream , and may therefore be associate d with othermetastatic manifestations , such as irido-cyclitis , e pididymitis and orchitis . In cases of meningitis with synovi t is itis often found that there was an initial haemorrhagic rashthis was so in 15 out o f 1 6 naval cases in which the pointwas investigated . It usually occurs on the fourth

,fifth

, o r

sixth day of the disease , but it may precede other symptoms .The incidence was estimated at from 10 to 15 per cent .

by S ophian and from 5 to 20 per cent . by R oger , “ butamong 502 cases in the Navy it occurred in 24 , or 4 8 percent . , and among F air l e y and S tewart

’s 323 cases in 23, o r7 per cent . A mong 902 other cases (R obb

’s , Herrick’s

,

Netter and Durand ’s , 7 8 S aint o n’

s , L afo sse’

s ,53 and some others)

there were 59 cases o f synovitis , or 6 5 per cent . It is moreoften seen in adolescents and adults than in babies

,thus

recalling the incidence o f synovitis in acute rheumatism ;but when it does occur in babies the hands and feet ar especially picked out , whereas in older patients the larger ,j oints— the knees

,wrists

,and ankles— are usually attacked .

In posterior basic meningitis S till 1 03 found peri-articularinfection , the joint cavities being healthy , in 4 out o f 49

cases examined after death , and Osler, 82 in his Cavendishlecture said the lesions were general ly peri-articular .The j oint tissues are little affected , and though suppurative

synovitis with characteristic grass-green pus occurs , i t mustbe rare ; only one out of the 24 naval cases required aspiration , the affection being usually o f short duration

,as if a

serous synovitis,though two cases lasted for six weeks and

showed relapses . A ccording to Netter and Durand the pusin the early cases shows meningococci , which may die out i nthe chronic cases . Horder refers to a case with meningococci and S tap hylococcus war m in the pus .

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56

URINARY CHAN GES .

The urinary changes are no t charact eristic o r of clinicalimportance .

Ogst it is may occur , and the incidence of pyuria has variedin different outbreaks Fairley and S tewart ’s pe rcentage of40 is much the highest I have come across . P ye lit is was

reported in 5 per cent . o f the Texas epidemic by S ophian ,who described meningococci in the urine but general experie nce shows that meningococci are rare in the urine , andthat cystitis and pyuria during the disease may be due toother organisms ; in this connexion it may be mentionedthat the changes in the lymphatic tissue o f the alimentarycanal have been thought to favour haemic infection o f theurinary tract with B aci l lus co li . P o lyur ia is occasionallynoted it is stated t o be a critical phenomenon , but it maycertainly occur while the temp erature remains high .

A l buminur ia i s not very common , and when present isusual ly small in amount . Cazamian 1 5 is exceptional infinding it in all his 1 13 cases , but in many it was transiento r in traces only . It is commonest early in grave cases

,but

otherwise it has no prognostic significance , and permanentrenal change never follows . Albuminuria is rarely accom

panied by casts , and is regarded by Cazamian as not renal ,but due t o changes in the medulla oblongata . Occasionallytransient albuminuria occurs synchronously with oedema andurticaria serous haemorrhages — o f serum disease .

m atur ia is not common when it occurs it usually is ane arly complication , and is associated with a petechial o rhaemorrhagic rash ; it is presumably caused by haemo r

rhage s in the mucous membrane of the urinary tract , but isnot so often seen in the fulminating cases with muchpurpura as might naturally be expected . Among the 502naval cases it was noted in 4 only ; in 3 o f these it wasassociated with a petechial rash ; in the other it was due toan acute ascending pyelitis . Among Neave’s 7 3 cases twohad haematuria . If the patient be taking hexamine thismay be the explanation .

O h/cosur ia is rare and may be qui te transient . A mongCazamian

’

s 1 13 cases it occurred in 9, o r 7 9 per cent . , butacetone bodies were never p resent . There was one case onlyamong S ophian ’s series . It may occur at the onset , andwhen found in an unconscious patient has been thoughtto indicate diabetic coma . It may be associated w ithalbuminuria ; Flack

32 mentions a case of nephritis withblood and sugar in the urine

,which recovered rapidly . In a

naval case that re covered albuminuria , glycosuria , and

57

acetone in the breath we re noted on the second day of thedisease . It i s stated to be less frequent than in tuberculousmeningitis , in which it occurs late Garrod and Frew 36 foundit in 15 out o f 41 cases of tuberculous meningitis but neverin posterior basic meningitis . The glycosuria would appearto be nervous and central in origin

,but more than this it is

difficult to say. It is not due to increased intracranialpressure o r to hyperpituitarism which diminishes thesugar tolerance , for examination o f the gland does no t

reveal any changes different from those in pneumonia , andsome observations made b y Fairley and S tewart showedthat the behaviour o f the sugar tolerance and o f the bloodpressure in cerebro-spinal fever do not lend any support tothe view that peri-hypophyseal inflammation by causingincreased vascularity induces increased functional activityo f the gland .

Ur o bilinogenur ia was recorded by Cazamian in threequarters o f his 1 13 cases ; it was most intense at the onsetand was as frequent in the non-septicaemic as in the septicaemic cases . Indicanu/r ia i s stated to occur in grave cases

(Netter and De b ré ), but was detected by Cazamian in twoonly out o f his 25 fatal cases .

EPIDIDYMITIS AND ORCHITIS .

Epididymitis o r orchitis are complications o f cerebrospinal fever , and the meningococcus has been obtained bypuncture of the inflamed organ (F l o rand and Fiessingerbut the text-books rarely mention the lesion . Like othercomp lications , the incide nce varies ; it is said to have beenspecially frequent in the S ilesian epidemic ; among the 290cases at Camp Jackson in 1918 it occurred in 3 per cent . ,but in a Sporadic outbreak o f 36 cases at . the same camp inOctober , 1918, more than a third had epididymitis (LathamAmong 502 naval cases it was noted in 13, or 26 per cent .among Herrick ’s 4 5 208 cases at Camp Jackson in 9, o r

48 per cent among S aint on’s98 64 cases in 3. o r 47 per

cent . and among McConne l l , Morris , and S e e ho rn’

s“4

30 cases in 2 ,o r 6 7 per cent . In all these cases (36 , o r

39 per cent . , out of 922) the possibility o f gonococcic originwas

,o f course , excluded .

It appears that both meningococci (Gordon’s Types I . and

III . ) and para-meningococci (Gordon’s Types I I . and IV . )

may be associated with orchitis and epididymitis ; but it i sinteresting that Latham ’s cases were associated withType IV . ,

which seems particularly prone t o cause septicsemic and metastatic lesions , and is said to be the closestt o the gonococcus biological ly and culturally . Eschbach andL acaze

’

s“ 7 two cases o f simul tane ous synovitis and epididy

58

mitis recal l the morphological resemblance between themeningococcus and the gonococcus .

A curious sequence o f events i s recorded b y Beaussart 9 ina man who had cerebro spinal fever with double orch iepididymitis in 1917 , and in the following vear had influenzawith a recurrence starting In the testi s and spreading to theepididymis .

In some instances puncture o f the inflamed organ hasfailed to give meningococci , and Latham ,

whose cases allreceived massive intravenous inj ections o f serum , found thatepididymitis was not a sequel o f serum inj ection s inpneumonia in some o f the naval cases the onset coincidedwith a serum rash . These data raise but do not settle thequestion whether some o f the cases may be infective , otherstoxic o r anaphylactic . In Latham ’

s cases 7 0 per cent . hadgiven a positive blood culture , and though none of them hada relapse after the appearance of the epididymitis he inclinesto the view that the lesion is septicaemic .

The recorded descriptions refer both to epididymitis andorchitis , and some authors have recorded cases in which theepididymis and body o f the testis were affected successive ly (F lo rand and Fiessinger

, S ainton). In Latham’scases the epididymis alone was inflamed , in McConne l l ,Morris , and S e e ho rn

’

s 2 cases the testis exclusively . P robably the epididymis is more often attacke d . There does notappear to be any good reason to believe that orchitis andepididymitis are due t o different mechanisms ; i t might bethought that epididymitis is due to an ascending infectionfrom the bladder , late in the course o f the disease ; butevidence o f meningococci in the urine in such cases is veryscanty thus in three cases o f epididymitis on the 46 th , 23rd ,

and 15th days o f the disease , recorded by Lancelin , 59 themeningococcus was found in the urine in one only.

A s already mentioned , i t is generally considered that theepididymitis and orchiti s are septicaemic in origin , and itmight be thought that this applies particularly t o orchitis ,and that the incidence would usual ly b e early in the disease .

In six cases o f orchitis in t h e Navy the complication , whichwas bilateral in thre e cases , appeared on the sixth , eighth ,

tenth , eleventh . and twelfth days of the disease . In a caseo f F lo rand and Fiessinger the right testis became inflamedon the thirteenth day and the epididymis the next day. Itis possible that epididymitis o r orchitis may, like meningococcic arthritis , precede the onset o f meningitis . This issuggested by the history of a private in the Marines whohad pain in o ne epididymis without any evidence o f gono r

rhoe a fo r three days , and three days later had meningiticsymptoms and died four days later from the disease . I havenot any reference t o cases in boys under the age of puberty .

There may be orchiti s alone o r epididymitis only , or onemay pre cede the other ; in about 10 p e r cent . of th e cases

59

the le sion i s bilateral . Epididymitis begins in the globusmajor , and subsequently there may be some effusion into thetunica vaginalis . Orchitis o r epididymitis is almost alwaystransient , subsiding without suppuration and not beingfollowed by atrophy . P ick , 85 however , recorded suppuration in both vesiculae seminales due to the meningococcus .There is not any relation between the incidence o f e pididymitis and orchitis on the one hand

,and the clinical severity

o f the cases on the other hand .

R ELAPSES AND R ECRUDESCENCES .

There is some confusion between these two terms and .

therefore some uncertainty about the frequency o f truerelapses .R ecrudescences , sometimes called intermittent relapses ,

o r the r eturn o f symptoms before the patient has really .

recovered from the disease , are very common and a patientmay have several ; among the naval cases one patient had7 , and Ker quot es 13 recrudescences . They may be dueto reinfection from the throat o r from some focus untouchedby the intrathecal inj ections o f serum , but what often appearto be recrudescences are really manifestations o f encystedmeningitis o r infection o f the cerebral ventricles

,the

foramina o f which are obstructed .

True relapses are rare . Netter 7 3 app ears to draw the linebetween recrudescences and relapses at a month from thedisappearance of symptoms , and reported 4 , o r 1 6 percent . , among 255 cases . Herrick observed t wo relapses fourand thre e weeks respectively after convalescence among 208cases . S ophian , however , estimated that relapses aftercomplete recovery from the original attack occurred in 5 percent . o f his cases . R elapses are , l ike rec rudescences , due toreinfection ; in isolated instances they have followed antityphoid inoculation (S ainton ,

99 Massary and To ckmanno r an attack of enteric fever (L ab b é

57) o r measles (Netter) .

The introduction of serum treatment was at first fol lowed byan increased incidence o f relapses , but this is ascribed tofailures i n the application o f the serum treatment . In mostcases o f a true relapse t h e symptoms are similar to butmilder than in the original attack .

Late relapses at long intervals after the patient has beencured can hardly be distinguished from second attacks .These cases o f second attack are very rare it i s noteworthythat one attack o f meningococcic infection usually protectsagainst another

,and that

,as Adami 1 has pointed out , the

meningococcus thus differs from the maj ority o f pathogenicmicrococci . Councilman

,Mallory , and Wright , and more

recently Netter,have reviewed the literature on the subject ,

and refer to North ’s two cases at 25 and 21 months ’ interval ,Hermann and Kober

’s at a year’

s inte rval , and War schaune r

60

at five years interval . A naval rating had bacteriological lyproved meningococcic meningitis both in May , 1917 . and inFebruary , 1918, and on the occasion of the second attackafter 23 days’ normal temperature had a relapse withe ve ntual recovery .

DIAGNOSIS .

B acter io logica l E xamination .

For the certain diagnosis of meningococcic meningitisbacteriological examination o f the cerebro-spinal fluid formeningococci is necessary , and similarly in the p r eme ningit icstage o f ce rebro-spinal fever a blood culture is essential . Nodoubt genuine cases o f cerebro-spinal fever may be ruled outby failure o f bacteriological methods to give. positive results .But this error is probably much less than that which wouldresult from the inclusion o f cases diagnosed on clinicalgrounds , and in the latter event it would b e difl

‘icul t to know

where to draw the line .

Cases with meningitic symptoms and meningococci in thenaso-pharynx but no t in the cerebro-Spinal fluid

,though

often probably genuine cases , and . indeed , so regarded byFlack , 33 are Open to the criticism that they may be meningococcic carriers with meningitis o r meningism due to someother cause . Flack’s ground fo r his view was that t hemeningococcus isolated from the naso-pharynx in three casesin which it could not be grown from the cerebro-spinal fluidwas agglutinated by the patient’s blood , whereas the othertypes o f meningococci were not . But since then Gates 3"

has shown that the blood serum o f chronic carriers containsspecific agglutinins .No clinical manifestation is pathognomonic of meningo

coccic infection . In the presence of an e pidemic anacute onset with fe ver, vomiting , severe headache , andmalaise may we ll arouse suspicion , but a similar train o f

symptoms may occur in many toxaemic conditions , andtogether with cerebral symptoms (meningism) mayaccompany acute infections such as influenza , pneumonia .

ente ric fever , otitis , malaria. A haemorrhagic rash , thoughhighly suggestive of meningococcaemia , may be present inpneumococcic , streptococcic , and influe nzal infections , andin malignant forms of the exanthemata such as small-pox .

From other forms o f meningitis , such as tuberculous ,pneumococcic , otitic , influe nzal , an undoubted diagnosis canbe made only by lumbar puncture and examination of thece rebro-spinal fluid .

61'

JLJl. 9'

:l 9

p,P unctur e .

r l l

A s lumbar p unc ad‘

essen'

tial element in thediagnosis , it is well to insist that the risk o f

'

any harmfrom diagnostic puncture , provided the fluid is not withdrawn t o o rapidly o r in excessive quantities

,is almost

negligible ; some hamo r rhage may occur , but this seldomcauses serious damage . In one instance

,however

,in a

case o f tuberculous meningitis , lumbar puncture wasfollowed by a bullous eruption o n one foot , and after deatha clot o f blood was found inside the theca vertebralis andin contact with the posterior nerve roots .” The cauda equinamay be injured and severe pain in the lower limbs thuscaused , and I have heard of a case o f traumatic aneurysmo f a small artery on the posterior surface o f the cauda equinaas the re sult o f lumbar puncture . In a few instances painand wasting have followed in a lower limb

,suggesting

damage to the lumbo-sacral plexus , and it must be admittedthat signs of caudal myelitis and even widespread suppuration around the vertebra may supervene in cases in whichlumbar punctures have been frequently performed .

The risk of introducing infection and setting up meningitisby diagnostic puncture may be practically d ismissed , and isquite different from the danger o f infection from repeatedtappings . R ecent experiments by Weed , Wege fo r th , A ye r ,and Il

'

e l ton 1 08 show that after intravenous inj ection o f microorganisms withdrawal o f the cerebro-spinal fluid inducesmeningitis but lumbar puncture is so frequently performedin conditions in which micro-organisms are o r may bepresent in the blood stream , such as pneumococcic andinflue nza‘. infections , and clear fluid is drawn o ff without thesubsequent occurrence of meningitis that in practice thereis no risk that lumbar puncture alone will , by reducing thelocal resistance o f the meninges , le ad to their infection .

Lumbar puncture alone thus differs from lumbar puncturefol lowed by the intrathecal inj ection o f horse serum , a proce dur e which first sets up an aseptic polymorphonuclearmeningitis and then allows micro-organisms in the bloodstre am to invade the me ninges .

Case s in which Diagnosis R emains in Doubt .

A lthough it is simple enough to depend for the diagnosisof meningococcic meningitis on the examination o f thecerebro-spinal fluid for meningococci , there are a number ofcases in which a decision is still left in doubt . Cases certainly occur about which the purely clinical diagnosis appearsunquestionable

,but in which the cerebro-spinal fluid , though

turbid from the presence o f polymorphonuclear leucocytes ,does not contain any micro-organisms ; thus , among 121

62

cerebro-spinal fluids fr'om cases o f meningitis in the French

Army , S acquépé e , Burnet , and Weissenbach 97 found 6 withthe features of Widal’s puriform aseptic meningitis in whichno micro-organisms could be found by direct examination o rb y cultivation and A dshe ad ,

2 in an analysis of 7 1 cas e s ofcerebro-spinal fever , includes 4 with puru lent aseptic cereb roSpinal fluid .

No significance , o f course , can be attached to cases w ith aclear fluid at the first tapping and a s t erile turbid fluid aftera subsequent intrathecal inj ection o f serum . The occurrenceof cases with a sterile p o l vmo rph onucl e ar fluid at the firs tlumbar puncture recalls Hort’s 45 contention that the meningococcus is only one of the phases in the life-cycle of the virus ,and raises the unorthodox suggestion that in some o f thephases the organism may be a fil t e r-passer .These cases should be treated

,although they cannot be

tabulated , as meningococcic recovery is in favour of ameningococcic origin

,no t only from the point o f view o f

this therapeutic test , but also because other forms of polymo rphonucl e ar meningitis are usual ly fatal , recoveries inpneumococcic meningitis being most exceptional .

Difie r ent ia l Diagnosis.

As al ready mentione d , the cerebro-spinal fluid , thoughcharacteristically polymorphonuclear

,may , par ticula r ly in

chronic cases , show a predominance o f lymphocytes,and so

resembl e the cytology o f the meningitis o f tuberculosis,

syphilis,mumps

,malaria , acute lead poisoning , and of the

meningitic form o f acute poliomyel itis . Incidentally , someo f the clinical differences from tub " r cul ous meningitis havebeen referred to , and with regard to the others , though it isan interest ing academic study , lumbar puncture will alwaysbe necessary and more rapidly and surely decide t he

diagnosis and prognosis .

Meningism may be due to such a large number of acuteinfections that it would take too long to detail them .

P neumonia ,especially in children and in apical pneumonia

in adults,may be ushered in by signs

‘

o f meningeal irritation

,and the absence o f meningitis can only be certainly

and at once settled by examination o f the cerebro-spinalfluid

,for

, on the one hand , there may be pneumococcicmeningitis

, o r , on the other hand , even if a patient havephysical signs of pneumonia , there may al so be meningococcic meningitis , as was shown b y isolated cases in t h e

Navy and by Jacob it z’

s53 record of three cases o f meningo-r

coccic meningitis with meningococcic pneumonia . Muchthe same is true of o t it i s media , which may cause meningism ,

o r , as in five naval cases , may be followed by meningococcicmeningitis .

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64

may imitate me ningodoccic meningi ti s . In five case s o f

rapidly fatal anthrax recorded b y R eece 87 there werecerebral symptoms and anthrax bacilli in the cerebrospinal fluid , b ut the symptoms were characteristic ofcereb ro spinal fever in two only . During the same year ,1917 , there were two cases o f anthrax imitating cerebroSpinal fever in the Navy .

1 0 7 Meningeal hwmor r hage fromvarious cause may closely imitate the early stages o f

meningococcic meningitis , and for a correct diagnosisexamination o f the cerebrospinal fluid is then essential .

The meningit ic form of acut e p o liomye lit is .— Clinically the

resemblance to cerebro-spinal fever is very close ; thus in191 1 R eece 8“ found that a reputed outbreak o f cerebro-spinalfever was really one of acute poliomyelitis without anyadmixture o f meningococcic cases . S poradic cases ofmeningococcic infection occurring in the summer

,the

favourite period o f the year fo r poliomyelitis,and in the

presence o f the other disease are naturally liab le to be misinterpreted ; if recovery occur a residual paralysis suggeststhat the disease was really acute poliomyelitis . In July

,

1915, there was an outbreak o f 15 cases clinically resemblingcerebro-spinal fever among the youths at S hotley Barracks ,but only four were proved bacteriologically to b e of thisnature ; consideration of the notes j ustified the suspicionthat o ne might have been a case o f poliomyelitis . A s alreadymentioned the diagnosis depends on examination of thecerebro-spmal fluid

,which shows a lymphocytosis and

absence of meningococci .

E ncep ha lit is l e thargica ,when fi rst seen in P aris and else

where , was thought to b e meningococcic meningitis untillumbar puncture put this diagnosis out of court .” Thece rebro-spinal fluid is clear and the cell content usuallynormal ; if there be any cytological change it is in thedirection o f a lymphocytosis . A nother difference frommeningococcic infection is the absence of a hamic leucocytosis (P anton The striking features o f the diseaselethargy and ocular paralyses

,though the latter are not

constant— should arouse suspicion . On the other hand , thepatients may have erythematous o r petechial rashes , herpes ,swelling of the joints , and vomiting . When first seensome cases o f meningococcic meningitis may suggestordinary epi lep sy, t e tanus , o r even st rychnine p oisoning ; thisi s especially likely to occur in sporadic cases o r at thecomme ncement o f an outbreak .

Urwmia may be suggested by fulminating cases in an

unconscious condition,especially as there may be

albuminuria , o r from collapse , suppression of urine

(R obertson and a petechial rash which might be thoughtt o be uramic. In pre gnant wome n convulsions during

65

cerebro-spinal fever have been regarded as eclamptic

(Williamson In a case reported by R oberts and Ford ,91

pain and loss o f power in the legs , pufiine ss o f the face , andalbuminuria were thought to be due to acute nephritis andura mia . In fulminating cerebro-spinal fever t h e bloodpressure is low and the extensor plantar response

,obtained

In uram1a , 1 s rare .

The purpuric eruption of the fulminating and acute casesmay lead to confusion with fulminating and other forms of

purp ur a , such as acute lymphocytic l e ukamia ,streptococcic

se p t ica mia ,Henoch ’s purpura . and the diagnosis may be

cleared up onlyafter death (V e rb izie r ,1 0 6 P ape and Laroche

m or r hagic sma l l-p ox occurring in connexion w ith cerebro

spinal fever may be regarded as the meningococcic infection .

S ir William Osler tell s me that hamo r rhagic cerebro-Spinalfever was recognised in Montreal in 187 2, and that two yearslater a case o f hamo r rhagic small-pox was regarded ascerebro-spinal fever until the patient’s mother went sick withsmall-pox . In the past the disease app ears to have beenconfused with ma lignant measles, fo r in 1867 Gordon

4 0 statedthat hamo r rhagic measles always accompanied cerebrospinal fever . The mottled rash may suggest measles , and ina case o f me ningococcamia without meningitis , as in thatrecorded by S ainton and Maille , 1 00 a blood culture may benecessary to clinch the diagnosis . In typ hus the purpuricrash does not appear before the fourth day of the disease

,

whereas it is an initial Sign in cerebro-Spinal fever . Thefulminating cases may at first simulate severef ood p o isoning.

In acute ost e omye lit is of the sp ine lumbar puncture maygive exit t o pus from the extradural Space . This occurredin two cases in the R oyal Navy. In neither of these werethere definite symptoms o f cerebro-spinal fever, but Grisel ,

41

in a review o f this form of osteomyelitis , states that althoughin some cases the symptoms o f compression are quite definiteand disappear when the abscess is evacuated , there areothers in which the association with meningitic symptomsand se p t icamia re nders the diagnosis very difizicul t .

REF ER ENCES To LECTUR E II.

1 . Adami , J. G. : Journ . Iowa State Me d . S oc. , Cl inton , 1912, ii . , 375.

2. A dsh e ad : Th e Tre atme nt of Ce re b ro-sp inal Men ingitis b A ntime n ingococcus S e rum at t h e Royal Naval Hosp i t al , B aslar, 191 16—17 ;Sp e cial Re p ort Se rie s , No. 17 . 89, Me dical Re se arch Comm itte e .

3.Andrew e s , F . W . : Tran s . Path . S oc . , Lond . , 1898, xlix . , 259. 4.

Andrew e s , F . W . : THE LA NCET , 1917 , ii 847 . 5. Ballantyn e , A . JBrit

. M e d . Journ . , 1907 , ii . , 190 . 6 . Batt e n , F . E . D ise ase s of Childre n(Garrod ,

Batte n , and Thur sfie ld) , 746 , 1913. 7 . Batte n , F . E . : Systemof Me dicine (A l lbut t and Rolle ston ), 1910 , vi ii . , 174. 8. Be aussart :Bul l .

'

e t mem S oc. méd . de s hOp . de Paris , 1918, 36 se r . , xlii 294.

F

66

9. Be aussart : Ib id . , 10. Der l e l e t Durand : Lyon med . , 1913.cxxi . , 913. 1 1 B lanch ie r , D . : These de Paris , No . 40. 1918, V i o t Frere s12. B loch e t He b e rt : Arch . d e med . e t pharm . mil . , Paris , 191 lxix . , 70613. B ovaird : Arch . Int . Med Chicago, 1909, i ii 267 . 14. Bradford ,

Bashford , and Wilson . Quart . Journ . Med . O xford , 1918-19, xil . , 8815. Cazamian : A nn . de med . , Paris , 1917 , iv 165. 16 . Ce ci l and Sop e rArch . In t . Me d " Chicago , 1911 , viii . , 3. 17 . Chiray Pre sse med . ,

Paris ,1915, 481 . 18. Co l le t t e , H . : These d e Paris , No. 1917 . 19. Connal , A . :

Quart . Journ . M e d . Oxford , 1909—10 , ii i 152. 20 . Costa e t Troisie rBul l . e t mem . S oc . med . d e s h Op . d e Paris , 1918, 36 sér . , lxii . , 502.

21 . Councilman , Mal lory , and W right : Ep idemic Ce re b ro-sp inalMe n ingitis , a Re port to t h e State Board of He al th of Massachuse tts ,1898. 22. Culp in , M . : Brit . Me d . Jour. , 1916 , i . , 307 . 23. Dickson , 0 :

Ib id 1917 , i . , 454. 24. Durand , P . : Lyon med . , 1913, cxxi . , 920 .

25. Duval : Journ . Me d . R e s 1908, xix . , 258. 26 . E lliott and Kay eQuart. Journ . Me d . , Oxford . 1916-17 , x 363. 27 . Eschbach e t LacazeBull . e t . mém . S oc . med . d e s hdp . d e Paris , 1915, 36 sér . , xxxix . , 1024.

28. Fairley and Ste wart : Ce re b ro-sp inal Fe ve r, Commonw ea lth ofAustral ia , Se rvice Pub l ication . No . 29. Paroy e t May : Bull .e t mém. S oc . méd . d e s h Op .Id e P ar is , 1919, 36 ser . , xliii 44. 30 . Fi lde s, P . ,

and Bake r, S . : Me dical Re search Comm itte e , National Health Iueurance , Sp ecial Re port Se rie s , No . 1 7 , 1918. 31 . Fitzge rald , J . G . Journ .

Ame r . Me d . Assoc . , Chicago. 1918, lxxi . , 969. 32. Flack , M . : Bacte riological Studie s on t h e Pathology and Pre ve ntive Control of Ce re b rosp inal Fe ve r during 1915 and 1916 , Me dical Re search Commi tte e ,

Sp ecial Re port Se rie s , No. 3, 31 , 1917 . 33. Flack : I b id 41 .

34. F lo rand e t Fie ssinge r : Arch . d e méd . e t pharm . mi l . , Paris. 1917 .

lxvi ii . , 109 . 35. Forb e s and Adam : Pub l ic He alth , 1914—15. xxviii 225.

36 . Garrod and Fre w : THE L .

Journ . E xp or . Me d . , Baltimore . 1918, xxviii . , 449. 38. Give n , D . H . CJourn R oy . N av . Me d . Se rv. , 1918, iv . , 296 . 39. Gordon , M . H . Brit.Me d . 40 . Gordon , S . : Dub lin Quart. Journ . Me d .

S c . 1867 , xliii , 409. 41 . Grise l , P . : R e v . d'

.o r t hop Paris , 1911 ,36 145. 42. Hal l e z , G. L . These d e Paris , No . 27 , 1917 .

43. Han e s : Ame r. Journ . Me d . Phila. , 1916 . cli i . , 66—7 1 . 44. He rrick .W . W . Arch . In t . M e d . , Chicago , 1918, xxi . , 541 . 45. He rrick , W . W .

Journ . Ame r. Me d . Assoc. , Chicago, 1918, lxxi . 6 12. 46 . V ideHe r r ingham , McN e e , and Othe rs : Journ . R o . Army Me d . Cor s

1917 , xxix . , 463. 47 . H ilde she im , O . : THE48. Hort : Journ . R o . Army Me d . Corp s , 1916 , xxvii 312. 49. Howard ,W . Journ . ed . S c . , P h ila

Journ . Ne rv . and M e n t . Dis . , 1907 , xxxiv . ,73. 51 . Hurst Me dical Disease sof War , 79, 2ud e dit 1918. 52. Hutt : Pub l ic He alth , 1914—15, xxviii .53. Jacob it z : Z t sch r . f . R yg. 11 . l n fe ct . , L e i z . , 1907 , lvi 175. 54 . JafféMe d . Klin . , Be rl . und Wie n , 1918, xiv . , 3 5. 55. Kop lik , H . : Systemof Me dicin e (Osle r and McCrae ), 1913. i . , 605, zud e dit. 56 . Krum b haarand C loud : Journ . Ame r. Me d . Assoc. , Chicago. 1918, lxxi . , 2144.

57 . L ab b é : Bull . e t mém . S o c. med . de s h Op . de Paris , 1918, 36 sér . ,

xlii . , 535. 58. Lafosse : Ib id 1915, 36 sér . xxxix . , 299. 59. Lance linIb id . , 1917 , 36 sér . xli . 1052. 60 . Latham , J. A . Journ . Ame r . Med .

Assoc . Chica o, 1919, lxxi i . 175. 61 . Le vyy , E . : Quote d by Ne tte r ,Comp t . re nd . oc . d e b io l " Paris , 1915. lxxxviii " 90. 62. Ludke : De utschemed . Wchnsch r . , 1918, xliv . , 1380 . 63. Lutaud These d e Paris , 1909-10.

64. McConne l l , Morris , and Se ehorn : Ame r . Journ . Me d . S c. , Phila. ,

1918. clvi .. 105. 65. Macke nzie and Martin : Journ . Path . and Bacte riol . ,Camb ridge , 1908, xi i . , 539. 66 . MacL agan , P . W. : Edin . Me d Journ . ,

1918, N . S . xx . , 100 . 67 . Massary e t Tockmann : Bul l . e t mem . S oc.

med . d e s h 6p . d e Paris. 1918, 36 sé r . , xlii 481 . 68. Mille r : Ame r.Journ . Ob ste t. , 1917 , lxxvi . , 531 . 69. Mitche l l and F al ke ne r : N e w YorkMe d . Journ . , l 9 l8, cvii . , 102. 70 . N eave , S . THE LAN CET , 1917 , i . , 219.

7 1 . Ne tte r , A . : Bul l . e t mem . S oc . med . d e s hOp . d e Paris , 1917 , 36 sé r .

xli . , 883. 72. N e tte r , A . : Ib id 1915. 36 sé r . , xxxix . 73. N e tte r , A . :

Ib id . , 1918. 36 sé r . , xlii . , 527 . 74. N e tte r, A. R e v . d e med Par is , 1917 ,xxxv . , 133. 75. N e tte r , A . : Bull . Acad . d e med . , Paris , 1918, 36 sér . ,

lxxix . , 337 . 7 6 . Ne tt e r e t De b r é : L a mén ingi te cereb ro-sp inale , Paris ,1911 . 7 7 . Ne tte r e t Dob rcz Ib id 101 . 78. Ne tte r e t Durand : Bul l .Acad . d e med . , Paris , sé r lxii i . 441 . 79. N e tte r e t JosiasBul l . e t mém . S oc . méd . de s h ep . de Par is, sér . xvii . , 375.

80 . Ne tte r e t S alanie r : Ib id 1917 , 36 sér . , x li. , 789. 81 . 1b id . , 394.

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82. Osle r ; Brit . Med . Journ . , 1899, i. , 1521 . 83. Panton , P . N . : Proc.

R o S oc . Me d 1918—19 (Me d . xii . , 3. 84. Pap e e t LarocheB u 1. e t mem . S oc . med . d e s h Op . d e Paris , 1916 , 36 sér . , x1. 85. PickBe rl . klin Wchnsch r . , 1907 , xl iv. , 947 . 86 . Re e ce , R . J . Re po rt o f t h eMe dical O fiice r of t h e Local Gove rnme nt Board , 1911-13, App e ndix A ,

No. 4. 54. 1913. 87 . Re e ce , R . J . THE LANCET. 1917 , i . , 406 .

88. R e ve il l e t , Nové-Josse rand , e t Lange ron : Journ . d e physiol . e t

p ath . gén . . Par is , 1914-15, xvi . , 1080—86 . 89. Robb : Proc. R oy . S oc .

Me d Lo nd . . 1915 (The rap . ix . , 5. 90 . Rob b : Brit . Me d . Journ1907 , i i . , 1130. 91 . Rob e rts and Ford : 92. Rob e rtson ,

W . Ib id . , 1907 . ii 185. 93. Ro b e rtso n , W . : Ib id . 94. Roge rBul l . e t mem . S oc . m ed . d e s h Op . d e Paris , 1918, 36 sér . , xlii . , 225.

95. Ro ll e ston and Te b b s : Trans . C lin . S oc . , Lond . . 1904, xxxvi ii 46 .

96 . S ab razes : Gaz . h e b d . d e s . sc . med . d e Borde aux , 1917 , xxxiv 134.

97 . S acquép ée , Burn e t, e t We isse n b ach B ul l . A cad . d e med Paris , 1915,lxxiv . , 103 98. Sain ton : Arch . d e med . e t d e pharm . nav . , Paris . 1918,cv 1 13. 99. Sainton , P . Bull . e t mem . S oc . med . d e s h dp . d e Paris ,1918, 3e "

ser ., xlii 535. 100. S ain ton e t Mail l e Ib id . , 1915, 36

296 . 101 . Sain ton e t Bouque t : Ib id , 1916 , 3a ser . , xl .. 344. 102.

Sophian Ep ide m ic Ce re b ro-sp inal Me n ingitis , 1913. 103. Still . G . FJourn . Path . and Bacte r iol Edin . and Lond 1898, v . , 147 . 104. Sti lle ;O n Ep id em ic Me n ingi t is , Phila 1867 . 105. Symme rs , St . C lai r : Brit.M e d . Journ . , 1917 , i i . , 789. 106 V e r b izie r : Bul l . e t mem . S o c m ed . d e s

h Op . d e Paris , 1917 . 3a sér . , xli 616 . 107 . Warre n and WilliamsonJourn . R o y . N av . Me d . S e rv . , 1918, iv . , 212. 108. We e d , We ge fo r t h ,

Ave r, and Fe l ton Journ . Ame r. Me d . Assoc. , Chicago. 1919, lxxii . , 190.109 . We il , M . P . : Comp t . re nd . S o c . de b iol . , Paris , 1918 lxxxi . , 436.

1 10 . We isse nb ach e t Me st r e zat : Ib id . , Paris , 1918. lxxx1 . , 436 . 1 11 .

Worste r-Drought , C . : THE LA NCET , 1918, ii . , 39. 112. Williamson ,

J . D Brit . Me d . Journ . , 1907 , i i . , 1295. 1 13. Z ingh e r ; Journ . Ame r .Me d . Assoc , Chicago, 1919, clvi i . , 58.

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LECTUR E III .

MORTALITY AND P ROGNOSIS .

MR . P RESIDENT , CENSORS , AND FELLOWS O F THE COLLEGE ,— In considering the prognosis it is important to have someidea o f the natural history of the disease when unmodifiedby serum treatment . It s severity varies in different epidemicsand at different periods o f the same epidemic ; thus it isgenerally believed that fulminating cases are more frequentat the beginning and mild and abortive cases towards th eend of an epidemic .

From a review o f 41 epidemics Hirsch in 1866 found thatthe mortality varied from 20 to 75 per cent . , and accordingto R ollet the average mortality of epidemics in France up to1844 was 51 per cent. the extremes being 28 and 7 5 per cent .Flexner 2 6 gives statistics o f 18 epidemics be fore the serumera showing death-rates between 90 and 425 per cent . ; ofthese 18 epidemics one had a death-rate o f 90 per cent . , twoof 80 per cent . , nine o f 7 0 per cent . or more , three of morethan 60 per cent . , and one o f 425 per cent . Flexner alsocompares the death-rates o f cases in the same epidemictreated with and without serum showing a very great differe nce , 30 , 40 , o r even 50 per cent in favour of those treatedwith serum . Experience in the Navy also be ars witness tothe beneficial influence of serum

A mong 96 cases not treated b y serum 49, o r 51 or cent . ,proved fata l and out o f 105 cases treated in 1915 wit serumswh ich appeared to be inert 64 , or 61 per cent . , were fatal ;whereas out o f 295 cases treated with serum during th esecond , th ird , and fou rth years of the war the mortali ty was95, o r 32 7 per cent . ; 1 76 of these cases receiving Flexner

’sserum alone with a mortality o f 51 , o r 29 per cent . InBelfast the mortali ty fel l immediately from 72 to 30 per cent .on the introduction o f Flexner ’s serum (R o bb) .

In quite recen t years the mortality has been much higherin this country than would be expected on the assumptionthat serum treatment is available fo r all ; thus R eece foundthat among 5306 cases in England and Wales during theyears 1914 to 1917 inclusive there were 347 1 , or 65 4 percent . , deaths . This is more than double the percentage

(30 9 ) o f deaths among Flexner’s 1294 cases treated byserum , and probably many o f the British cases were untreated ,or if tr eated with serum at all no t e fficiently. By intensive

69

tre atme nt— namely , the intrathecal inj e ction o f 60 c . cm .

within the first 24 hours , o r in bad cases within 12 hoursWelsh and Brown 84 had two deaths only , o r 7 per cent . ,among 28 cases .

E ssent ia l F actor s in S e rum Tr eatment .

The effect of serum has bee n shown to depend to a veryconsiderable extent on its early use thus Flexner found thatamong 199 cases in which treatment began within threedays o f the onset the mortality was 18 per cent . among346 in which treatment began after the third and beforethe seventh day 27 per cent . , and among 666 cases in whichtreatment began after the seventh day 36 5 per cent . provedfatal . Netter , DO p t e r , Chr ist omano s , Levy , and Flack givesimilar evidence . When dealing with smaller numbers o fcases the mortality may no t fall regularly with the delay o ftreatment , because the fulminating cases swell the deathrate on the earlier days , and the mild cases that are atypicaland probably would recover under almost any conditionscome under treatment late . In a series of 25 cases whichwere not given serum before the 20th day o f the diseaseNetter 57 obtained cures in 1 6 , o r 64 per cent .It is particularly in the sep t icamic o r pre-meningitic stage

that e arly and vigorous intravenous administration of serummay cut short the disease . Herrick 41 has recently shownthat the free administration of serum intravenously reducedthe mortality to 185 per cent . from 625 per cent . obtainedin severe cases treated either by intrathecal inj ection aloneo r by intrathecal inj ection combined with small amounts o fserum intravenously .

A nother important factor in the serum treatment is thatthe serum should contain the antibodies Specific to the infe ct ing strain of the meningococci . This has been insistedon widely

,especially by DO p t e r , Netter , and Gordon .

Flexner’s serum from the R ockefeller Institute , which ismultivalent and made by the use o f 40 strains of meningococci

,has on the whole given better results than any other

serum ; but the use of a multivalent serum , or o f a pooledserum of the more probable infecting strains , until theactual type of the infecting organism is determined , whenthe univalent type serum is substituted , is the ideal plan .

Gordon and Hine 38 have recently published the results ofthe fi rst 90 cases treated with monotypical serums made b yS tanley Griffith at Cambridge in the University FieldLaboratories under the direction o f the Medical R esearchCommittee . Mono typ l cal serums have been fi

r e par e d forTypes I. ,

II . ,I II IV . , and are known as M . .C

.serum .

W hen a case i s first seen and until the type o f the 1n fe ct ingmeningococcus has been determined , Injections of pooled

Types and II . serums ar e give n ; the re asons for no t g1v1ng

70

pooled serum o f all four types are : (a) that if this we re done ,as migh t logically be suggested ,th e anti endotoxin againstthe existing type would be more dilute than in th e

pooled

serums o f Types I . and IL , and (b) that from 80 to 5 pe rcent . o f all cases o f cerebro-s

S

p i

I

nal fever are due to infe ct l onwith meningococci o f Ty

pes 1 . o r 11 . When the type is

determined the co r r e sp on ing serum is given .

Out o f the 90 cases 7 were fatal so lely o r largely fromcauses other than cerebro Spinal fever , and so may b e

eliminated . Out o f the 83 cases 34 were due to Type 1 . withone death , o r 3 per cent . ; 32 due to Type II . with 7 death s ,o r 21 9 per cent . ; 10 t o Type I II . with no death , and 7 tounknown t

yppe s with 2 death s , o r 28 6 p e r cent . Therefore ,

out of the 8 cases 10 only , o r 12 per cent . proved fatal .The reason why the univalent serum fo r Typ e I I . i s theleast successfu l of the monotypical serums is , as laboratoryexperiments Show , that it contains less anti endotoxin forthe homologou s meningococcus than the other serums do ;th is i s because the Type II . meningococcus , as shown b y theab sor tion test , i s more complex than the other typesP ossi ly a more successfu l serum will be obtained b yimmun i sing horses , each against a ch ief sub group o f

Type I I . meningococcus and then pooling their serums . Ihave recently observed a l imited outbreak o f 10 cases all dueto Type II . , wh ich , though vigorously treated with Type 1 1 .

serum , both intravenously and intrathecally b y CaptainE . H . S haw , did not react in a satisfactory manner .

E j ects of S e r um Tr eatment .

By comparison of the duration of the disease in var iousseries o f cases in the pre-serum era with 830 serum-treatedcases that re covered Flexne r finds that as the result of serumthe period of active symptoms is shortened and the cessationo f symptoms , which in th e natural history of the disease isalmost always by lysis , is by crisis in 30 per cent . o f thecases . The effect o f treatment on prognosis may alsobe e stimated by th e seque ls o f the disease in casestreated by the symptomatic and by specific (serum)methods . Complications appear to be less frequent Sincethe era of serum . In the pre-serum epoch the incidence ofinternal ear disease varied from 12 to 33 per cent whereasamong Flexner’s 1294 cases treated with serum it was35 per cent . ; and similarly the incidence of irido-cycliti sfel l from between 4 and 10 per cent . o f all cases to 1 per cent .Flexner also quotes Longo ’s small comparative series o f

cases in children showing the influence o f serum in preventing hydrocephalus , deafness , or mental defects .The factor In serum treatment that 18 o f essential import

ance in bringing about a rapid and permanent cure is theearly and sufiicie n t use of a serum containing the antibodiesspecific to the type of infecting meningococci so as toabo lish the infection ,

neutralise the t oxamia, and stop themeningitis be fore adhe sions and blocking of the ce re bral

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7 2

0

Individua l Symp t oms in R egar d t o P r ognosis .

The prognostic significance of individual symptoms maybe considered first as regards those due to the generalsystemic invasion . A very acu te onset with sudden losso f consciousness— the ap op le ct ifo rm onset— has a seriousoutlook , as death may rapidly follow , but if the acute stagedoes not prove fatal recovery may eventually occur .

Among 247 cases of cerebro-spinal fever in the Navyduring the second and third years of the war th is apoplecticonset occurr ed in 12, o r 5 per cent . , and 6 proved fatal .

A s the fulminat ing cases with large purpuric areas anda high mortality may also Show cyanosis and dyspnoea , theseSigns are very grave prognostics sweating is often associatingwith the cyanosis and dyspnoe a , but alone has no t the samesinister significance . The presence o f a r ash without furtherqualification does not affect the prognosis to any considerabledegree , but a distinction must be made in this respectbetween the hamo r rhagic rashes , and more especially largepurpuric extravasations on the one hand and the nonhamo rrhagic rashes on the other .

Among 502 naval cases 296 had rashes of some kind o r

another , with a mortality o f 1 29, or 435 per cent . , whereaso f the remaining 206 cases without recorded rashes 80 , o r39 per cent . , proved fatal . But out o f 153 cases with ha morr hagic rashes 65, o r 425 per cent . , proved fatal , whereas outo f 42 non-hamo r r hagic eruptions the mortality was 12, o r28 6 per cent . The 153 cases with ha mo r r hagic rashesinclude both the large purpuric rashes and the petechial ,and o f these the former have , o f course , much the graverprognostic importance .

A lthough it has been stated that , as in pneumonia , a lowl eucocyt e count i s a bad Sign , 56 it is generally agreed that noprognosis as to a fatal result can be made from the leucocytecount . S imilarly th e t emp e r atur e and the degree of headache have little , if any , ultimate prognostic significance .

As herpes labialis usually appears on the fourth day o f thedisease it is hardly ever seen in the fulminating cases thatprove fatal within 48 hours o f the onset . The goodprognosis formerly ascribe d t o he rp e s, and t o a se rum r ash ,

probably depends on the occurrence o f death in a conside rab l e number o f the severe cases before the time forappearance o f the rashes is due . Thus , out o f 86 fatal casesin the Navy during the third and fourth years of the war 27 ,or almost a third , occurred before the fourth day of thedisease . Cases with a serum rash usually do well , and Ker

4“

considers that sharp attacks o f serum disease exert afavourable action on the course o f the disease , possibly as are sult o f metabolic stimulation ; this view is confirme d by

73

L ongCOp e and R ackemann’

s49 demonstration that aft e r

serum disease antibodies to horse serum begin to appe ar inthe blood , at first slowly and later rapidly .

S ynovitis is a metastatic complication which , according toNetter , is seen in cases which eventually are cured . P ossiblythe local focus acts as a fixation abscess and raises theresistance to infection in the same manner as a vaccine .

A mong 24 cases o f synovitis in the Navy the mortality was6 , or 25 per cent considerably lower than the mortality fo rthe 502 cases . P e r icandit is is often latent

,and though

looked for during life may be found only at the necropsythis occurred in the 1904—05 epidemic in New York , andaccordingly Kop lik

47 speaks o f pericarditis as a fatal Sign ,but this view is unduly pessimistic . Among the navalcases it was found after death in three instances . andpericardial friction was heard in three cases that recovered .

The bearing o f the ar t e r ia l b lood p r e ssur e on prognosis hasbeen dealt with by Fairley and S tewart , who find that a lowblood pressure during the first three days is associated witha severe infection , and is therefore o f bad omen . Thedegree of the rise of blood pressure consequent on the onseto f meningitis and increased intracranial pressure is important among 1 16 cases with an average blood pressure above120 mm . Hg after the third day o f t he disease 7 0 per cent .proved fatal , whereas among 1 20 cases with an averageblood pressure below 120 mm . Hg the mortality was 21 percent . Cerebral hamo rrhage may occur as a result of theraised blood pressure .The occurrence of p t osis or hemip legia points to a definite

lesion and renders the prognosis grave .

A s pointed out above , the mortality among 18 naval caseswith ptosis was 13, o r 72 per cent . whereas that o f 59 caseswith strabismus (

gr obab ly mainly spasmodic and not para

lytic) was 31 , or 5'5 per cent . Among 12 naval cases with

hemiplegia 10 proved fatal .

On the other hand, facial par alysis o r p ar esis is an early

and transient event and does not cloud the outlook .

From routine examination o f 184 patie n ts , 1 16 of whomhad optic neuritis

,Fairley and S tewart found that the

presence o r absence. o f op t ic neur itis is of no va lue inprognosis

,for out o f the 1 1 6 cases 74, or 65 per cent. ,

recovered,and the intensity o f the changes did not bear any

relation t o the severity o f the disease . N ystagmus occurs ingrave cases and is re garded by Fairley and S tewart as

pathognomonic o f internal hydrocephalus . The nature ofthe cer e br o-sp inalfluid doe s no t fo rm a guide to the outcomeof the case

,except in so far as a large number o f extra

cellular meningococci make the outlook bad . A purulentfluid may rapidly clear after intrathecal inj ection of efficientserum o r a clear fluid may rapidly become purul ent .

The occurrence of br oncho-pneumonia naturally re nde rs the

7 4

outlook ve ry serious . Cheyne-S tokes breathing and Biot’sce r e nra l type of r esp ir ation , characterised by period s o f

apnoea at irre gular interval s , p oint to approaching death , as

does Slowing o f the respiration pulse ratio from the normal1 4 to 1 2 . The resp iration may fail entire ly whi le thepulse is we l l maintained . A ccording to Fairley and S tewartthere is no definite relation between the respiratory rate andthe intrathecal pressure as estimated by "uinoke

’s manometer.F inally , the prognosis is fallacious and diflicul t , as sudden

e xacerbations from reinfection may occur most une xpe cte dly .

R emote P r ognosis.

Ce rebro-spinal fever is a killing rather than a cripplingdisease . In the past it had a bad reputation fo r the numbe ro f disabilities— mental , nervous , and auditory , which inyoung children accounted fo r much deaf-mutism— leftbehind . But at the present time there is a general agreement that if the patient survive he is not likely

,apart

,

perhaps , from deafness , to be permanently crippled . A s

already mentioned , Flexner’s figures show that the incidence

o f complications and sequels is much diminished by serumtreatment . But it is not certain that the general rarity ofsevere after-results is entirely due t o the introduction of

serum treatment ; for eve n now a number o f cases do notreceive efiicie nt serum tre atment , and in 1915 the serumavailable in this country appeared t o be inert , and yetthe re was no noticeable cr0p of disabilities . Foster andGaskell.33 who relied mainly on lumbar puncture in thatyear

,noted very few sequels in their cases , and explained

t h e greater frequency o f disabilities in the past , whe nlumbar puncture was not in vogue , to the effects o f con

tinned increased intracranial pressure .

Mental changes do no t appear to be much more frequentthan after other severe d iseases . During convalescencethere may be some mental debility and occasionally impairedmemory , but no permanent mental defect is left behind .

Worster-Drought , “ 6 from analysis of 120 cases in 1915—1 7that recovered

,found that in none was there permanent

mental defect . In rare instances epilepsy has followedcerebro-Spinal fever ; N etter

58 has Seen five examples of

this,but among his 253 cases that recovered this sequel

occurred once only . S ainton 7 “ reported t wo cases ; in one

the epilepsy began a month after the dise ase , in th e otherafter an interval of six months ; he ascribes it to the persiste nce of some meningeal irritation , and Netter points outthat this may be anticipated in cases with hemiplegia o r

partial convulsions during the acute disease .

P aralyses of various forms , apart from the ocular manife stat ions dur ing the acute stage of the disease , are rare andar e very seldom pe rmanent . It is highly probable , as

7 5

pointed out by Netter and Deb ré ,61 that many of the

permanent paralyses formerly ascribed to cerebro-Spinal feverwere due to acute polioencephalitis

,the meningitic form o f

which may so closely imitate meningococcic meningitis .According to S ophian , most o f the paralyses in cerebrospinal fever are cerebral in origin , and this raises the question of the diagnosis from acute polioencephalitis in thoseinstances in which the diagnosis o f meningococcic infectionhas not been prove d bacteriologically .

Day of Death.

More than half the fatal cases occur during the first weeko f the disease .

Out o f 86 deaths among 225 naval cases during the thirdand fourth years of the war 1 7 occurred with in the first twodays o r were fulminating cases , eigh t on the th ird , and 12 onthe fourth day , so that 37 , o r 42 per cent . , of the deat h soccurred with in the fi rst four days . Th ree deaths occurredon the fi fth , 5 on the sixth , and 2 on the seventh day , sothat 47 , o r mo re than half the cases , were fatal within thefi rst week . During the second week there were 15 death s ,during the th ird week 12, during the fourth and fifth weeks3 each , 2 in the sixth week , 1 in the seventh week , andisolated cases on the 57 th , 67 th , and 9ot h days o f the disease .

P ROPHYLA" IS .

Hygienic Measur es.

Good general hygienic conditions are , of course , importantin maintaining the resistance o f the body to infection andso preventing the occurrence o f other diseases favouringmeningococcic invasion . Hence , fresh air , efficient ventilation

,proper clothing

,good food , the avoidance o f over

fatigue,and protection from depressing conditions are

desirable,particularly in the case o f recruits , new entries

into the N avy , and newcomers to institutions . Duringepidemics it is desirable , as far as possible , to temperthe wind to the raw recruits and to delay vaccination andan tityphoid inoculation until they have become accustomedto their new life . After vaccination and inoculation specialcare should be taken to avoid fatigue from drills and routemarches .A s catarrhal diseases , such as influenza , catarrh , tonsillitis ,

and sore throat,appear to play some part in favouring the

outbreak o f cere bro-spinal fever , and often precede itsappearance and may coincide with its prevalence , every

e ffort to limit their spread should b e made . S pecial care

7 6

should b e take n to pr e ve nt the common use of handkerchiefsand towels . Isolation when possible should be carried out ,and the cub ic space in the rooms may be increased . Thethroats and noses , both of the unaffected and o f the patients ,should b e spraye d with

'

dichloramine-T o r douched with amild antiseptic lotion , such as warm solution of permanganateof potassium , 1 in 1000 . When conval escent the men Shouldbe carefully protected from fatigue .

The avoidance of overcrowding is an essential factor inmaintaining the general he alth and , further, in preventing arise in the rate o f meningococcic carriers and the conse quentoccurrence o f cases of the disease . The importance o f a

sufficient cubic Space (600 cubic feet) per individual and of3 or at the least , as an emergency measure , 24 feet betwe enthe beds when more than one person occupies a room

,has

been shown by Glover . It was al so brought out by eventsat the naval barracks in the last quarter o f 1918 as aresult o f the severe influenza epidemic in S eptember andOctober an A dmiralty order came out in October to the effectthat the hammocks in the naval barracks Should be 25 feetdistant at their nearest points and that the men Should liealternately head and feet during October there were in theNavy 21 cases of cerebro-Spinal fever , all but one in bar rackso r similar establishments , in Novembe r there were 6 cases

(one in a ship) , and in De cembe r 2 .

S ear ch for Car r ie r s .

A S th e dise ase is spread by human carriers it should bee xterminated if al l the carrie rs were detected and isolateduntil they became permanently negative . A t present thegeneral public is no t educated up to this ideal , and even ifit were , the labour entailed by it s effective performancewould be almost , if no t entirely , prohibitive . Further , thefrequency o f intermittent carriers 3 and the failure of

bacteriological tests would pre vent such a drastic measurefrom being infallible .

The question of whole sale examination o f naval and

military forces for carriers has been much de bate d , and it iscle ar that unless th e naval and military units when thusclear ed from carriers are entirely isolated from the civilpopulation . infection will be continually re-introduce d . Bythe order o f S ir A rthur May , Director-Gene ral o f the MedicalDe partme nt o f the A dmiralty , swabs from the throats o f newentries into the Navy , and drafts . were examined bacteriologically from the early part o f 191 6 to the end o f December ,1918. A lthough t he number of cases in sea-going ships hasfortunately bee n l ow —48, o r 13 per cent . , out o f the 360cases— from the beginning of 1916 to December S l st , 1918,it was higher than in the first sevente en months o f the war .during which the routine search for carrie rs was no t carried

7 7

out and 1 7 case s , o r 87 pe r ce nt out o f 195 case s in the

Navy occurred in sea-going ships .It therefore appears that the relative fre e dom o f the se a

going ships from the disease depends on factors other thanthe se arch fo r carriers , and among them i s probably themore mature d condition o f the crews , for the disease occursmainly in new entries in barracks . Flexner ,

2 6 however,from

comparison of statistics from camps in which the search forcarrie rs had been carried out with those in which this coursewas no t adopted , considers that the incidence o f the diseasewas lower in the former and among the New Z ealand troopsisolation and disinfection o f carriers before embarkation fo rEurope was followed by good results On theother hand , Galambos 34 insists that the segregation anddisinfection o f healthy carriers are useless , as the incidenceo f the disease is not influenced thereby , and he quotes otherGerman writers , G . B . Gruber , Klinger , and F ourmann, t o

the same e ffect . Gruber considers that meningococciccar riers are on a par as regards their Significance withpneumococcic carriers ; but t his would appear to be on theassumption that isolation o f pneumococcic carriers is un

thinkab le , whereas recent observations on carriers of virulentpneumococci show their importance . Mink 55 from hisexperience at the Great Lakes Naval Training S tationconsidered the isolation of car riers quite worthless in theprevention o f the disease .

Two suggested methods , short o f complete search fo r andsegregation and disinfection o f al l carriers in naval andmilitary forces , may be quoted : (1) that search fo r carriersshould only be made when a case of the disease arises , andonly among the contacts , the carriers thus detected beingsegregated and disinfected ; (2) that ne w entries should bee xamined and the detected carriers treated in a selectivemanne r. Thus

,j ust as in pneumococcic carriers , so also in

the case of meningococcic carriers the saprophytic germsmay be o f the same or o f a different strain from that causingthe vast majority of the cases o f the disease . Thus 7 0 t o85 per cent . of all the epidemic cases of cerebro-spinal feve rare due to two strains of meningococci ; and fo r theexigencies o f the S ervice it has been suggested that allcarriers should b e treate d with sprays , but that only thosewith large numbers o f meningoco cci and me ningococci ‘

of

the epidemic strains should be isolated . These dangerouscarriers would be kept isolated until four successive weeklyswabs from the naso-pharynx have been shown t o be freefrom meningococci .

Tr eatment of Oar r ie r s.

Fresh air and sunshine are important the positivecarriers Should be kept separate from those who have becomenegative so as to obviate r e-infection , and carrie rs should b e

7 8

isola ted according to their types so as t o prevent crossinfection .

In local treatment of the naso-pharynx by gargles . douches ,s

’

wabbing , hand-sprays , and inhaling chambers,it is

important tha t mild antiseptics , such as dilute solutions ofch lo ramine-T, dichloramine-T, ac riflavine ,

carbolic acid ,carbolised solution o f iodine , boracic , permanganate

'

o f

potassium , sulphate of zinc , formalin , should b e employed ,

otherwise the naso-pharyngeal mucous membrane may be sodamaged that the carrier state is prolonged instead o f beingshortened . Gordon and Hine have supervised the construotion o f spraying chambers fitted up with Hine

’s special steamj et . The carriers should be three feet apart in the chamberand turned back to back , and in orde r to avoid cross infe ctions carriers o f the same type should be treated at thesame time . The men may with advantage sit down

,so as to

obviate fainting , and should be told to breathe in throughthe nose and out through the mouth .

B y the local application of dried antimeningococcic serumt o the naso-pharynx , by means of a special apparatus provide d by the P asteur Institute , Cayr e l

9 cured 23 out of 30meningococcic carriers in three to five days . A powdercomposed o f dried antimeningococcic serum

,arsenobenzol ,

benzoin , and bismuth carbonate has also been employed inFrance , the powder being blown into the nostrils four timesdaily (Derriey) .

21 V accines have be en occasionally used

(Chalmers and O’

F arr e l l but their failure is notunnatural , as th e carriers are probably vaccinating themselves as shown by the presence o f antibodies in their blood

(GatesA s transient carriers rapidly become negative spontaneously ,

whereas the cure o f chronic carriers is prolonged and difficult ,there is some difference of Opinion as to the value of antisep tic sprays and other methods in the treatment o f car riers .

Among 360 carriers at P ortsmouth Fildes and Baker "5found that 212 were mild car riers with an average durationo f 0 45 month , 126 being positive fo r one week only , and 148ch ronic carriers with an average duration o f 2 6 month s .The chronic car riers were nearly all o f the less pathogenicTypes II . and IV . , the latter being twice as numerous as thefo rmer . They also conclude that 33 per cent . of their carriersrecovered sp ontaneously and that about 50 per cent . o f thosetreated b y various antiseptic sprays recovered , and that noneo f the methods had any conspicuous merit , the differencebetween 50 and 33 per cent . being due not to the efficacy oftreatment but t o the fact that the figures were calcu latedfrom two series o f men .

At another naval do (it nine ch ronic carriers were rapidlycured b chloramine in an inhaling chamber . But atcamp cC l e l lan R obey 7 1 found that some carriers clearedup rapid ly and that others were unaffected b y various spraysfour times daily , and concludes that sunsh ine and warmfresh air were more effective than spraying in clearing th enaso-pharynx o f m e ningoco cci .

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meningococci and did not get above 1 00 million inGre e nwood ’s cases a first inj ection of 250 t o 300 millionswas followed a week later by 1 000 millions ; S ophian andB lack gave inj ections at weekly intervals o f 100 , 500 ,

and1000 millions , and Gates employed three inj ections , also atweekly intervals , of 2000 , 4000 , and 4000 or 8000 and foundthat these rarely caused more than the mildest localand general reactions . In exceptional cases with unusualsusceptibility to the vaccine severe symptoms o f meningism ,

sometimes suggesting the onset of meningitis , followed ;but these manifestations did not last more than a fe w hours .

A ccording to Whitmore , Fennel , and P etersen 85 a multivalen tmeningococcic lipovaccine— namely , with an oily suspension ,as in t h e T A B . lipo-vaccine o f Le Moignic— diminishes therisk of a local reaction .

S ERUM TREATMENT .

S e rum treatment , which , though first employed byJochmann , is chiefly due to Flexner

’s exertions, has greatly

diminished the severity and mortality o f the disease . Asthis was discussed in the section on prognosis no furtherfigures need be brought forward ; but the serum treatmentmust be efficient , and it is probably due to failures in thisrespect that the civil mortality (65 per cent . ) in thiscountry , as shown by R eece

’s figures for 1914—1 7 , is so muchhigher than statistics published from hospitals .

Imp or tance of Sp ecificity of the S er um.

Th e use of serum is no t so simple or so uniformlysuccessful as that o f antidiphtheritic serum , which isantitoxic

,whe reas antimeningococcic serum , possessing

bacteriolytic. bacteriotropic (opsonic) , and anti-endotoxicproperties , is more likely to fail in it s powers as a whole .

Gordon 37 found that the anti-endotoxin in deficient in a conside rab l e proportion of the samples o f antimeningococcicserum supplied fo r therapeutic use , although they containeda good supply o f opsonin , and that the clinical potency o f aserum depends on its anti-endotoxic capacity. The existenceo f different types o f meningococci with specific antibodiesrenders the success of the serum treatment less certain thanin the case o f antidiphtheritic serum . The widespreadfailure of the antimeningococcic serums available in 1915in this country appeared to depend on the absence o f

antibodies specific t o the infecting organisms , and stoodout in striking contrast t o the results obtained in 1916 , whenFlexner’s multivalent and other serums were available .

The establishment of different types o f meningococci andas a corollary the preparation of homologous serums so that

81

a multivalent or poole d serum i s given until the type of theinfecting organism is determine d when the specific univalenttype serum is substituted , has already , as Shown by Gordonand Hine’s analysis , greatly improved the results o f serumtreatment. The extreme importance of Specificity in theserum treatment o f the disease and the absence o f anybenefit from non-sp e cific treatment

, o r protein shocktherapy , o f which an extensive trial has unintentionallybeen made , are noteworthy .

The important question , indeed , may be raised whetherthe intrathecal inj ection o f inert serum may no t do positiveharm . As already mentioned . horse serum sets up an

aseptic meningitis and favours the passage o f meningococcithrough t h e meninges . It might , on the other hand

,be

argued that the increased number o f phagocytes thus provide d might do good . But it is Significant that in 1915 themortality among the naval cases treated with serum intrath e cal ly was higher (61 per cent . ) than among those treatedin other ways (41 per cent .) and .in this connexion anotherseries o f naval cases in that year may be quoted among 21cases treated with soamin alone there were seven deaths , o r33 per cent . , whereas among 18 . cases that received bothsoamin and antimeningococcic serum intrathecally the rewas a mortality of 1 1 , o r 61 per cent .

S ome Diflicul t ies in S e rum Tr eatment .

The nature of cerebro-spinal fever differs from that ofdiphtheria , and may be regarded in the first place as ageneral hamic infection o r invasion which later

,but not

necessarily , attacks the meninges , whereas diphtheria is ,like tetanus , a local infection which produces a t oxamia. Asa result o f the me ningococcamia ,

foci o f infection , unaffectedby intrathecal inj ection o f serum , may persist and causerecrudescences o f meningitis . Further

,inflammation o f the

meninges , like that o f other serous membranes , is prone tose t up adhesions and so produce isolated loculi where theinfective process , being out of the reach o f the intrathecalinj ections o f serum , continues to cause symptoms . A notherresult i s that the foramina o f exit of the cerebral ventriclesbecome obstructed and the ventricles become distended withturbid fluid containing meningococci

, o r eventually a ste rilehydrocephalus results . The persistence o f symptoms from ageneral me ningococca mia o r from an encysted infe ction ,especially of the cerebral ventricles

,may lead to a prolonged

course o f intrathecal inj ections which may cause gravesymptoms and from the nature of the case cannot do goodfor in these circumstances an intravenous o r intra-ve ntricularinj ection o f serum is required .

A s another explanation o f the failure of serum treatment ithas been suggested that the meningococci may become fast

G

'

82

to the se rum , but this hypothesis must no t b e allowed tominimise the importance of giving a serum strictly homologousto the type of the infecting meningococcus .A nother factor rendering the serum treatment difficult is

the occurrence of phenomena , variously called sero-toxicmeningism o r acquired intolerance of the meninges

,about

the time that the ordinary manifestations of serum diseaseare due The symptoms resemble a r e lapse ,

but the cerebrospinal fluid does not Show meningococci and does containsugar. If in these circumstances a fresh inj ection o f

serum be given , the patient may manifest severe pain ,become delirious , Show definite Signs of meningitis (videinfr a) , and often goes down hill .

Human S e r um.

In addition to the serum of immunised horses , the serumfrom convalescent patients has often been tried . In 1907Ivy Mackenzie and Martin 51 treated 1 6 acute and 4 chroniccases with serum from convalescent patients , the averageamount inj ected intrathecally being 15—20 c . cm . , andobtained 10 recoveries among the acute cases (2 receiving theirown blood serum) . Fairley and S tewart recently modifiedthis procedure by adding 5 c .cm . of blood serum from conval e sce nt patients , prove d to have a negative Wass

‘

ermann'

reaction to 20 c . cm . of a potent antimeningococcic serum .

The add1t ion o f human serum was made with the obj ect ofreinforcement of complement . The mortality o f the 1 0acute cases thus treated was 30 per cent . , whereas that ofacute cases treated by serum without complement reinforcement was 50 pe r cent . It is obvious that when blood serumfrom a convalescent patient is employed fo r treatmen t , thetype of the infecting meningococcus should be the same inthe donor as in the re cipient .

SERUM TREATMENT IN V ARIOUS FORMS O F THE DISEASE .

The serum treatment o f cerebro-spinal fever may be dividedinto (I. ) That of t h e general systemic infection before themeninges have been infected , o r of the pre-meningitic stagethis i s effected by the intravenous inj ection o f an t ime ningococcic serum . The hypodermic or intramuscular inj ection o fserum has also been advocated , but appears to be lesseffective for this purpose . (11 ) That o f meningococcicmeningitis by the intrathecal inj ections o f serum . (III .)

“ That o f closed meningococcic infections of the centralnervous system , fo r example , o f the cerebral ventricles or o ffoci i solated by adhesions from the intrathecal space , and so

out of reach o f serum introduced intrathecally after ordinarylumbar puncture . (IV . ) That of othe r foci of me ningococcic

83

infection , the j oints and the eye , by the local inj ection of

serum . This category is insignificant in importance to theothers .

(I. ) S e r um Tr eatme nt of the P r e-meningit ic S tage byInt r avenous Inj ection.

Comparatively recently it has been more generally realisedthat in the earl iest stage o f cerebro-spinal fever there is ablood invasion o r se p t icamia,

and that this is usually , bu tnot invariably followed by meningeal infection , and as acorol lary that in this pre-meningitic stage the proper courseis to introduce the antimeningococcic serum into the bloodstream .

In addition it appears that the intrathecal inj ection o f

serum b efore the meningococci have invaded the meningesis not a harmless procedure . Austrian 1 proved e xp e r i

mentally that meningococci inj ected into the blood streamdo no t pass through the meninges and se t up meningitis ;this is prevented by the barrier se t up by the meningealchoroidal complex , and recalls S herrington

’s 7 9 observationthat healthy secreting membranes are not pervious to thebacteria . B ut Flexner and Amoss , 29 as well as Austrian ,have shown that the defence o f the meningeal-choroidalcomplex is broken down by inj ury

,as can be done by the

intrathecal inj ection o f horse serum with resulting asepticme ningitis . The premature intrathecal inj ection of serumnamely , before the meninges have allowed meningococci topass through

,may thus determine meningitis .

The most efficacious method o f introducing the seruminto the blood stream is obviously by intravenous inj ection ,and from experience o f more than 1 00 patients thus treatedHerrick 42 finds that it is both satisfactory and safe . Histreatment aims at the sterilisation o f the blood before themeninges have become affected and is an advance on theusual methods which are concentrated upon the laterstage when meningitis is established . Large quantities

(200—600 c . cm . in all) o f serum are given intravenously and ,

when there is meningitis present,active spinal drainage and

comparatively small intrathecal inj ections of se rum arecar ried out . No bad effects followed the large intravenousinj ections and serious anaphylaxis was seen in only one

case . Go ldon 3“ found that intravenous inj ections o f

20 to 40 c . cm . were usually followed by more o r less shock ,with failure o f the pulse and respiration , lasting about15minutes , and followed by a rigor and a rise o f 2

° t o 4° of

temperature .

Of the four classes o f cases— the abortive , the ordinary ,

the severe,and the fulminating— Herrick’s most brilliant

results Were obtained in the severe cases , the patients oftencoming out of coma with ; rapid rece ssion o f the rash and

84

symptoms so that in 48 hours many are apparently out o fdanger ; large intrave nous inj ections reduced the mortalityof the severe cases from 64 to 19 per cent . S ubacute andchronic cases with cachexia , delirium , and other distressingsymptoms are seldom seen , the course of the disease i sshortened and the incidence o f comp lications diminished .

Out of Herrick’s 265 cases 64 , o r 25 per cent . , proved fatal ,but out o f 137 given ordinary intrathecal inj ections and lessthan 45 c . cm . intravenously 47 , o r 34 per cent . , proved fatal ,whereas out o f 128 treated intrathecally with small dosesand intravenously with large doses (50 to 800 c . cm . in all) ofserum 19. o r 15 per cent . , proved fatal . In mild cases goodresults followed either of these forms of treatment . Go ldon

usually found that one intravenous inj ection was sufficient ,and then , if meningitis was present , gave intensive intrathecal inj ections out o f 138 cases 29, or 21 per cent . ,proved fatal , but 1 6 o f these we re admitte d in an unconsciousstate with a purpuric rash .

S ome French physicians , such as Netter , 59 S ainton , 7 7 andB rul é ,

8 while fully recognising the principle that in the pr emeningitic stage serum Should be introduced into the circulation and that brilliant resul ts may thus be obtained , consider that intravenous inj ection is too dangerous

, and that inmost case s it i s wiser to employ hypodermic or intramuscularinj ections . In adopting this conservative attitude they ar e ,of course , fully aware of B e sre dka

’

s method of de

sensitisation .

(I I . ) S erum Tr eatme nt of Meningococcic Meningit is.

The treatment o f meningococcic meningitis by intrathecalinj ections of antime ningococcic serum , which exerts abacter iological action on the meningococci , favours theirphagocytosis

,and contains an anti-endotoxin , was intro

duce d by Flexner and Jobling 32 in 1907 on th e grounds thatt he antiserum is thus brought into direct contact with thefocus o f infection and inflammation , and that th e passage o f

colloids from the blood stream into the cerebro-Spinal fluidis a slow and imperfect process in health , and probably alsoin inflamed states of the membranes . In 1917 Flexner “7

restated the position and pointed out that , as very littleserum from the blood reaches the inflamed meninges , it isuseless t o inj ect it subcutaneously or intravenously in t h e

expectation that it will exert any influence on meningococciin the subarachnoid space . In the same year , however , inconj unction with Amoss ,3° he showed that in acute poliomyelitis the immune bodies , though they do no t pass throughhealthy choroid plexus from the blood to the cerebro-Spinalfluid

,are able t o traverse them when inflamed ; if this

hold good as regards meningococcic meningitis , his earlierargument is partially weakene d but this is only of academic

85

inte re st, for the succe ss of intrathe cal inj e ction of se rumin me ningococcic meningitis has bee n proved be yond allque stion , and this method has superseded the easier one ofhypodermic o r intramuscular inj ection .

Doubtful cases should be submitted to lumbar punctureat once if the fluid be turbid serum should be given ; butif it b e quite clear serum should be withheld unless meningococci b e subsequently found , as the aseptic meningitis setup by serum may facilitate the passage o f meningococcifrom the blood into the subarachnoid space . If the cerebrospinal fluid be sterile , and especially when a blood cultureshows meningococci , intravenous inj ections of serum shouldbe given without delay and , as the se p t icamic stage of

cerebro-spinal fever lasts on into th e meningitic stage ,th e intrave nous inj ections should be continue d for a time ,together with intrathecal inj e ctions .Lumbar punct ure and the inj ection of serum should b e

performed under a general ana sth e t ic or under the influe nceo f an inj ection o f scopolamine gr . , morphine gr . ,

and atropine gr . in 5 minims of water , as employedat Haslar by S urgeon Lieutenant-Commander A dsh ead . Th e

serum should be run in Slowly and in a quantity smaller thanthat o f the cerebro-spinal fluid removed 20 to 30 c . cm . of

serum should b e given twice daily fo r some three or four days ,for by this intensive treatment the best results are obtained .

The continuance or omission o f the inj ections is decided onthe state of t h e cerebro-Spinal fluid , the patient

’s general condition and the temperature . With the new Medical R esearchCommi ttee

’s serum the pooled serum corresponding to typeI . and II . is given until the type of the infecting meningococcus is established , and then the corresponding monotypeserum is substituted . The access of serum to the base of thebrain is facilitated by raising the foot o f the bed , andR amond 69 recommends that the patient should lie for atime on his face in order to direct the serum to th e region of

the optic chiasma .

When any recrudescence o r relapse appears serum treatme nt must be at once started again when an interval of 10days or more from the last inj ection o f serum has elapsedsteps must be taken to dese nsitise th e patient , otherwisesevere anaphylactic symptoms may appear a very small

—1 c . cm . ) hypodermic inj ection o f serum may be given4 hours before the curative dose of serum is given intrath e cal ly, o r B e sr e dka

’

s method o f rapidly repeated intravenousinj ections o f minute but progressively increasing amounts ofSerum may be employed , which though elaborate obviates thedelay necessitated by the simpler hypodermic method .

Before t h e curative dose is given , gr. of atropine shouldb e inj ected hypodermically . A smentioned elsewhere , an ana sthetic prevents the occurrence o f anaphylactic symptoms .In order to prevent the accumulation of pus and fibrin in

the subarachnoid space and the subsequent formation of

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adhesions , ir r igation with sa line so lution is ofte n practise d ,and an isotonic solution o f sodium citrate (38 per cent .) hasbeen recommended for this purpose by R osenthal . “ J . J .

O’Mal l e y

65 contrasts the results o f simple lumbar punctureand administration o f serum among 36 patients with amortality of 33 per cent . with those of the same procedurewith the addition of saline irrigation among 15 cases with amortality o f 13 per cent . S hefii e ld Neave has washed out theintrathecal space with saline solution containing 0 5 per cent

,

carbolic acid with beneficial results . In this connexionattention should be drawn t o Flexner and A mo ss’s 31 resultsshowing that lysol and protargol fail to benefit e xp e ri

mental meningococcic meningitis and exe rt an adverseinfluence by diminishing leucocytic emigration and phagocytosis .The number of int r athecal inj e ct ions o f serum Should be

carefully considered , for it is probable that harm may resultfrom a large number o f lumbar punctures . Thus thecerebro-spinal fluid continues t o collect , and as a result o frepeated withdrawals an excessive secretion o f cerebro-spinalfluid , perhaps comparable to cerebro-Spinal rhinorrhoea , maybe induced . S ome prolonged cases , probably those withadhesions , appear to become resistant to serum , and sometimes intrathecal inj ections are followed by aggravation o f

the symptoms , such as headache and Opisthotonos . Herrickwho considers that signs of chronic o r subacute caudalmyelitis are common in convalescents as a result o f inj uryfrom the needle , or the inj ury of serum , advises that if asatisfactory response does not occur after eight o r ten intrathecal inj ections the inj ection should be discontinued andsimple lumbar puncture performed only when signs of

increased pressure demand it .Gr ave symp t oms and even sudden death during intrathecal

inj ections have been ascribed to various factors , such asanaphylaxis , liberation o f toxins by rapid lysis o f meningococci

,the toxic action o f phenol often employed to preserve

th e serum ,and , most important o f all , increased intracranial

pressure and distension o f the closed cerebral ventricles . Toavoid this a smaller quantity of serum than that of thecerebro-spinal fluid removed is important , and the gravitymethod o f administering intrathecal inj ections has beenadvocated and practised

,especially in A merica .

The blood pressure was found by S ophian to be lowered bylumbar puncture

,and stil l further depressed by intrathecal

inj ection of serum ; h e therefore employed blood-pressureobservations as a guide to the amount o f serum inj ected .

Fairley and S tewart , however , found that the effect oflumbar puncture on blood pressure was variable , a rise beingalmost as common as a fall

,and an initial higher pressure

being followed by a fall and vice versa ; but they agreedwith S ophian in finding that a fall o f b lood pressure wascommone r than a rise afte r intrathe cal inj ection of serum.

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practise d fir st by Cushing and S laden , 1 8 can be comparative lyeasily done in the infant before the anterior fontanelle isclosed . Marcland collected 1 1 cases with 5 cures due toventr icular tapping , and contrasts these with 7 cases ofuntreated ventricular distension in infants found at thenecropsy . In adults trephining and subsequent inj ection o f

serum is a more formidable procedure . and , according toMarcland ,

54 there were 4 cures among 18 cases ; morerecently Landry and Hamley 48 had 1 recovery out of5 cases trephined and inj ected , and Fairley and S tewart

’s9 cases of trephining and drainage all proved fatal , thoughin some instances life was prolonged . It appears t o b e adesperate remedy fo r a desperate condition .

S tetten and R oberts 8‘ advocate the production of a wideopening in th e corpus callosum ,

thereby obtaining prolongeddrainage ; this method is preferable to puncture with atrocar, which gives temporary relief only and so must berepeated . They record a successful result in a soldieraged 19. If necessary serum can be inj ected into theventricles . In two desperate cases (one recovery) Cazamian

1 0

employed the orbito-sphenoidal route , practised by B érie l fo rthe inj e ction o f salvarsan in general paralysis o f the insane .In place o f trephining and drainage Herrick recommendsCobb’s method o f breaking down adhesions around theforame n magnum and fourt h ventricle by manipulations ofthe head under chloroform in order to relax the rigidityo f the neck muscles . This method , which might suggestdangerous traction on the roots of th e vagus , was oftensuccessful in causing a flow of cerebro-spinal fluid , and inone instance brought back respiratory movements afte r theyhad stopped .

A much less serious procedure advocated by Bloch andHebert 6 for cases in which the meningococci may be encystedin situations in contact , but not in communication , with themeninges— for example ; the fib ro-vascular tissue o f thechoroid plexus— is the intravenous inj ection o f serum . Intramuscular inj ection has also been employed fo r this purpose ,but it is less likely t o be successful . In this connexionChiray

’

s1 2 description o f the “ reflex Sign of pyoce phaly

”

may b e mentioned ; in a few cases minute intravenousinj ections o f serum , such as are used in B e sr e dka

’s method

of anti-anaphylaxis , are followed immediately by transientbut intense vasomotor , respiratory , and cardiac disturbances .

(IV .) S e rum Tr eatment of O the r F oci .

Inj ection o f antimeningococcic serum (5 to 10 c . cm . ) iscommonly advocate d fo r suppurative arthritis due tomeningococcic infection , but it is seldom necessary in thiscountry . S erum has also been introduced into thepe r icardium , and e ven into the vitreous humour of the eye

(Ne tte r

89

S ERUM DISEASE .

In the main the serum rash and other manifestations ar emuch the same after intrathecal as after hypodermic o r

intramuscular inj ection but some difl e r e nce wouldnaturally be expected on account o f th e inj ection into theclose neighbourhood o f the central nervous system . S erumdisease in man is generally regarded as anaphylactic , but itmust be borne in mind that there is a striking differencebetwe en the way in which man on the one hand and animalson the other hand react to a first inj ection of a foreign protein ;in animals

,and the problems o f anaphylaxis have naturally

been more elaborately studied in them than in man . theprimary sensitising inj ection is no t followe d by the train ofsymptoms so familiar in man .

F r equency of S e r um R eact ions aft e r Int r athecal Inject ions.

Flexner 2“ remarks that possibly the manifestations o f

serum disease are more frequent after the intrathecal thanafter the subcutaneous inj ection o f serum ; and from comparison of the naval cases o f cerebro-spinal fever with thereported incidence o f serum disease in diphthe ria I wasat first incl ined to this view , but further sifting of th e

evidence did not Show that there was any proof of this , andClaude Ke r , 4 6 who also investigated this question ,

came tothe same conclusion .

Flexner’s serum , which by the generosity o f theR ockefeller Institute has been mainly used in the Navy

,

appears to be particularly prone to cause a rash thus among121 naval case s that recovered o r survived more than tendays 81 , o r 67 per cent . , had a serum rash , and among Ker

’scases the percentage was even more— namely , 7 7 . But thisis not higher than th e incidence (67 to 81 per ce nt .) ofserum rashes in some series 7 2 o f cases of diphtheria speciallystudied from this point o f view . The variations in theincidence are therefore more probably due to peculiar itiesin the horses supplying the serum than to the method of

inj ection . From comparison o f series o f naval cases itappeared that a serum rash was commoner in cases receivingintrathecal inj ections alone than in cases having both intrathe cal and subcutaneous inj ections o f serum .

R e lation of Manife stat ions t o A mount of S e rum Infected .

Clinical experience Shows that the severity of the rashesand other manifestations o f serum disease varies directlywith the amount of serum inj ected .

S erum disease , according to L onc pe and R ackemann49

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de ends on a reaction between the injected serum . whichac s as the antigen , in the blood and antibodies formed inthe cells o f the tissues . During the incubation period of

serum disease there i s a constant amount o f the foreignserum in the blood but none o f the anti b odies ; when anexplosive union between the antigen and the antibodiesoccurs the manifestations o f serum disease follow , and theirin tensity depends on the amounts o f antigen and antibodiespresent . If the amount o f antigen be large and that ofthe antibodies small the manifestation s o f serum diseasewill be severe , prolonged and rela sing, and vice versa .

The antibodies only begin t o be extra ed into the blood afterthe serum disease begins , and are a protective mechanismagainst these manifestations .

It is therefore obvious that the smaller the bulk o f seruminj ected the less l ikely is serum disease to be severe , andthis appears to have been shown by the rarity (3 per cent . )of serum rashes after the prophylactic inj ection (2—3 c . cm . )o f the concentrated antitetanic serum (O

’

B rie n Butalthough , cae t e r is par ibus , i t is desirable to have a concent rat e d serum so as to avoid troublesome serum reactions , itis essential that the process o f concentration Should notdiminish its curative powers , and in this connexion it isimportant t o note that Miss A . Homer 44 has found that theimmune bodies in antimeningococcic serum are mainly associat e d with the pseudo-globulin , and therefore that attemptsto conce ntrate the serum by methods involving a heatdenaturation of the serum prote ins would considerablydiminish th e antibody conte nt of the se rum .

S e r um R ashes.

It was stated by Currie ” that an inj e ction o f antidiphtheritic serum just before a serum rash due to a previousinj ection might b e expected may determine the appearanceof a rash which otherwise would no t have developed .

Examination o f the notes of the naval cases did no t Showthat this seque nce is established in cerebro-spinal fever. Itis true that in a fe w cases lumbar puncture and the inj ectionof serum have been performed the day before the rashappeared

,there having been a pre vious interval o f some days

without the administration o f serum . But such cases are ,perhaps

,more satisfactorily explained by the view that the

symptoms which led to the lumbar puncture and the inje ction of serum we re premonitory o f the serum rash .

The serum rash is usually urticaria", erythematous , o r

morbilliform . and extremely irritating , but it may be soar lat inifo rm. In rare instances it is hamo r rhagic ; this mayoccur in association with a sore throat o r an infected woundo r boils cases of this kind have occurred in the Navy . Butall cases in which a serum rash becomes hamor rhagic ar e

no t explained by th e pre se nce of infe ction. L andry and

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Hamley 48 mention. a hamor rhagic'

se rum rash which was

thought to be evidence o f post-meningitic se p t icamia until ablood cultu re . proved negative . In another conditionnamely, true anaphylaxis , the rash may be hamorrhagic.

On the forty eighth day o f t h e disease , not h aving had anyserum fo r 27 days , a man had an intrathecal inj ection o f20 0 .cm . seven hours later he vomited , had a purpuric rash ,and was gravely il l . Next day the rash had faded but theright knee was full o f fl uid . He died seven days after theinj ection .

"uite commonly a serum rash appears , fades , and abouttwo days later again becomes prominent ; the first may beerythematous and the second urticarial

,and both extremely

irritating . These may be regarded as phases o f the samereaction . In rare instances two serum rashes appear at suchan interval as to j ustify the term double serum rash and tosuggest t wo separate reactions

,which might be supposed to

be the result o f inj ections on different days ; a number ofCar r ie

’

s cases bear this interpretation . This , however, i s notuniversally true , and the occurrence o f two or three distinctrashes after a single inj ection o f serum is now thought to bedue to the successive appearance

,at different time intervals

,

of sensitiveness to the different proteins— euglobulin , pseudoglobulin , and albumin— present in horse serum (Dale and

A r thr itic and O the r Manife stat ions of S e rum Disease .

A nother manife station o f serum disease is arthritic pain orle ss often effusion into the j oints . The recognised association o f erythematous Skin eruptions and j oint symptoms isexplained by the assumption that the synovial membranesShow changes similar to those in the skin . The arthriticmanifestations are less frequent than those o f the Skin , butthey occasionally occur without any recognisable cutaneousrash . The arthritic symptoms may accompany, precede , o r .

and this appears to be more usual , occur some three daysafter the appearance of the rash . P ain o r stiffness iscommoner than effusion . It does not appear that patientswho have had early effusion into the j oints from meningococcic infection are more liable than others to get sericarthralgia or effusion into the j oints . The arthritic manif e stat ions are toxic , and

,like those o f “ scarlatinal

rheumatism ,

” do no t react to salicylates .In a small number of cases the serum rash 1s accompanied

by oedema o f the eyelids,scrotum , hands and other parts ,

and at the same time there may be t ransre nt albuminuria .

A s the serum rash is so often urticarial it is no t surprisingtha t oedema— o r serous hamo r rhage into the skinshould sometime s occur . He re it may be mentioned that

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the administration of calcium lactate gr . xv. for six doses ,some days be fore the manifestations of serum disease areexpected , may be tried in order to obviat e them .

In some instance s transient deafness about the time o f

serum disease may possibly be a manifestation of that condition (A. C . MacA l l ist e r ) ; and I have been told byCaptain E . H . S haw , o f transient loss o f visionat the time o f the se rum disease A s an exceptional e ventde V e rb izie r ’s 3“ case of severe epileptic convulsions with thestatus epilepticus coinciding with a well-marked serum rashand arthralgia in an epileptic , who had not had any fitsduring the fever, may be mentioned .

S er io Meningism and Meningit is.

Th e fe ve r and constitutional disturbance prece ding oraccompanying the othe r manifestations o f serum diseasemay be associated with recrudescence of meningitic sym

p t oms, and a relapse is thus naturally suggested . This raremeningeal manifestation o f serum disease is peculiar tointrathecal inj ection o f serum , and though it occurs in asmall proportion o f cases Should be more widely recognisedin this country in view of the recent increase of cerebrospinal fever. It has not , however , passed unnotice d .

Netter and De b ré 62 in 191 1 gave a good account of it , andregarded it as a result o f se r o t oxic oedema o f the meninges .It may also be added that , as the mucous membranesoriginally attacked by diphtheria are liable to swell at thetime o f the serum reaction , an analogous seque nce may besuggested in the case o f meningococcic infection o f themeninges .If the meningism is part of the serum disease t o b e

exp ected after intrathecal inj ection , the question arises whyit is not noted more often . It does not appear to resultfrom large quantities o f serum given , for out o f the ninenaval cases showing these meningitic symptoms eight hadless than 100 c .cm . , and four of these eight less than50 c . cm . nor can it be explained as due to an intrathecalinj ection within a very few days of the appearance o f theserum rash . That it i s connected with some hype rsensitiveness of the meninge s is probable enough , but it isimpossibl e t o go beyond this vague statement .These symptoms can be distinguished from a true recru

de sce nce o f meningococcic meningitis , for which an inj ectiono f serum is urgently necessary , by examination o f the

cerebro-spinal fluid for meningococci and the presence o f

sugar . If the cerebro-spinal fluid is clear , contains sugar ,and is free from meningococci , there is no recrudescence of

infection,and fresh intrathecal inj ection of serum may b e

followed by very severe pain . delirium , and other signs o f

me ningitis . This is what DO pt e r”

calls ser ic meningitis,

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and he e xplains the symptoms as due to the formation of apre cipitate in the ce rebro-spinal fluid .

A naphylaxis.

True anaphylaxis may occur in a patient who has sometime previously had an inj ection o f serum , e .g fo r

diphtheria o r as a prophylactic against tetanus,Although

in the case o f ordinary subcutaneous inj ections o f serumanaphylaxis is , as a rule , more interesting than serious in it smanifestations , the effect of an intrathecal inj ection o f

serum in a sensitised person , though fortunately uncommon .

may be very grave . A l though anaphylactic shock does notalways occur when it might be expected , it is obviouslyadvisable before giving the first intrathecal inj ection o f

serum to inquire if the patient has ever had a previousinj ection . If he is unable to give any information and thereis reason to suspect that he has had an inj ection of serumfor example , evidence o f awo und in a soldie r from the front—the patient Should , before receiving a curative intrathecal inj ection be dese nsitised . Vide sup r a .)The anaphylactic symptoms are severe collapse , fall o f

blood pressure , rapid and feeble pulse , pallor , vomiting ,

feeling of thoracic constriction , failure o f respiration , rapideruption of urticaria or even o f a hamo r rhagic rash . In orderto counteract these symptoms the inj e ction o f adrenin andat r O pine has been recommended .

In several cases in the Navy intrathecal inj ections . o f

serum were given after an interval from the last inj ectionsufficiently long for anaphylaxis to have fully developed , butlumbar puncture was performed under a general ana sth e t icand symptoms o f anaphylactic shock did no t appear .B e sr edka pointed out that if the nerve cel ls are ana sth e t ise d anaphylactic shock is preve nted .

A man had cerebro-Spinal fever in May ,1917 , and

recovered after having 1 10 c .cm . o f Flexner ’8 serumfol lowed b y a serum rash . On Feb . 19th ,

1918, he againhad cerebro spinal fever , after one inj ection o f 20 c .cm . o f

F l exner ’s serum he remained well fo r 23 days , when arelapse occurred ; he then had two inj ections o f Flexner

’sserum (20 c . .cm on each occasion) and recovered. Theseth ree injection s were given under ch loroform and ether andwere not followed by any anaphylactic symptoms ; both theat

tac

lits were bacteriologically proved to b e meningococcic

ln cc Ion .

V ACCINES .

Curative vaccines have been mainly employed in subacuteo r chronic cases when serum appears to be losing it s effect ,and in a number of cases has been followed by improvementand re cove ry . Most writers spe ak of the treatment in a non

94

committal to ne , and Herrick argues that as relapses occurvaccine treatment is unlikely t o b e effective . A mong 21naval case s given a meningococcic vaccine , always inaddition to other treatment. 5 , o r 235 per cent . , provedfatal , the mortality o f the 509 cases in the first four years o fthe war being 213, or 41 8 per cent . The vaccine should b eautogenous , and may with advantage be sensitised . Thedose varies in the hands o f different workers

Chalmers and O ’F ar r e l l 1 1

ga

ge 200 million dead meningo

cocci fo r the fi r st dose and mi l lions two days later , andout o f t e n apparently hopeless case s had four recoveries .

B o idin 7gave ever three o r four da 9 200 , 350 , 500 , and

750 millions . Mac gan53 r e comme n s 50 to 100 mi l lions

fo r the fi rst dose , wh ich is repeated and increased everyth ree or five days . Fairley and S tewart "8 begin with 50millions and increase b y that amount until 600 millions aregiven ; out o f 52 subacu te and ch ronic cases 17 , o r 32

dpercent . , p roved fatal , and o f these 13 had internal hy r o

cephalus , the mortali ty o f the remainder being only 7 7 ercent . Warren Crowe 16 and Colebrook ,“ who r e comme n edvaccines much earlier in the disease , about the second o rthi rd day , gave much smaller doses , 1 million and 75 to20 m illions res

pectively . These two workers wrote o f the

epidemic o f 19 5 when the serum available in th is countrywa

sinert . Th e usual reaction is slight , with some headache

an ever .

In serious case s B o idin recommends the production o f a“ fixation ” abscess b y the inj ection o f 1 5 c . cm . ofturpentine into the subcutaneous tissues o f the thigh , inaddi t ion to the use o f an autogenous vaccine , and reportsthat as a result there is often definite improvement andsometimes cure when the abscess is Opened ; in some caseshe found it necessary to produce a second “ fixation ”

absce ss .

OTHER METHODS O F TREATMENT .

A part from meningococcic serum , and perhaps vaccines ,other forms o f treatment are o f very subordinate importanceand

,except when serum cannot be obtained or is inert , as it

appe ared to b e in th is country in 1915, are mainly of historicalinte rest .

S ur gical Measwr e s.

Lumbar puncture temporarily relieves pressure and headache

,but it is not an efiicie nt rad1ca l measure the drainage

is at be st intermittent , and from this point o f view the moredrastic method o f laminectomy and draining the spinalsubdural space is more logical . This was done in the prese rum days Osle r 9° refe rred to unsucce ssful case s Ope rate d

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In a few instance s antimony tartrate has be en givenintravenously .

Hexamine , which owes its antiseptic power to the liberation o f formaldehyde in an acid solution , has been extensivelytried in meningitis on the basis o f Crowe’s ” observationthat it deferred o r prevented experimental streptococcicmeningitis . P r e ssl ie and Lindsay

“3 speak well o f it , but ingeneral the clinical results have been most disappointing ,and it is obvious that formaldehyde was not likely t o beliberated in the cerebro-spinal fluid . Guest and Fairley

24

gave it in large doses by the mouth intravenously , and intrat he cal l y to 20 cases with 80 per cent . mortality , and foundthat when given by the mouth hexamine and not formaldehydeappeared in the cerebro-spinal fluid . In a similar thoughshort trial of h e lmit o l , which liberates formaldehyde in analkaline solution , they obtained more encouraging results .

REF ER EN CES To LECTUR E I I I .

1 . Austrian . Bul l . Johns Hop kins Hosp . Baltimore , 1918, xxix183. 2. Bal lance , C . A . Bri t . Me d . Journ

p, 1897 , i . , 1092. 3. Basse tt

Smi th and Lynch . Journ . Ro . N av. Med . Se rv . , 1917 . i i i 428.

4. Batte n , F . E . : THE LANC E T. 966 . 5. B lack : Journ . Ame r .Med . Assoc . , Ch icago, 1913, lx 1289 . 6 . Bloch e t He b e rt : Arch . d e

med . e t pharm . mil , Paris. 1918. lxix . , 697 . 7 . Boldin : Bull . e t mem .

S oc . méd . de s hdp . de Paris , 1918, 36 sé r . xlii 317 . 8. B rul é : I b id . ,

537 . 9. Cayre l . M . Bull . e t mem . S oc. med . d e s hOp . d e Paris. 191736 ser . , xli . 693—4. 10 . Cazam ian : Bul l . gén . de therap . , Paris , 1915—16.clxvi ii 293. 11 . Chalm e rs and O

’

F ar r e l l : Journ . Trop . Me d and

yg. , London , 1915—16 , x lx .. 101 . 12. Chiray : Pre sse mé l . Paris ,1915, 481 . 13. C lemin so n , F . J . : Brit . Me d . Journ . , 1918, i i 51. 14.

Cole b rook : THE LAN CET. 1915, i . , 1026 . 15. Crow e , S . J John s HopkinsHosp . Baltimore . 1909, xx . , 102. 16 Crow e , W . : THE LANC E T ,1915, i i . , 1 127 . 17 . Currie . J . R . Journ . v . , Camb ridge , 1907 . vii35. 18. Cushing and Slade n : Journ . E xp e r . Me d , 1908, x . , 548.

19. Dale and Hart le y . B iochem . Journ . Camb ridge , 1916 , x . 408.

20 . Dandy " A nn S urg . . 1918, lxviii 569. 21 . De r r 1e v, M. These d eP ar is , N o . Diagnostic e t Trait e rrie n t d e laMéningite céréb ro- ,sp inale 1918. 23. Fairle y and S te wart : Ce re b rosp inal F e ve r, Common w eal th o f Australia. S e rvice Pub lication s , No . 9,

Quote d b y Fairle y and Ste wart : Ib id 180 . 25. F 1 lde s , P . ,

and Bake r , 8 . L . : Me dical Re search Comm itte e , National Health Iueurance , Sp e cial Re port Se rie s , No. 26 . Fle xn e r , S . Mod e ofIn fe ction . Me ans of Pre ve ntion , and Sp e cific Tre atme n t of Ep idemicMe nin itis , N ew York , 1917 .Rocke fe lle r Institute for Me dical Re se archN .Y. 7 . Fle xne r, s Ib id . , 35, 28. Fle xne r. S . , Ib id , 42. 29. Fle xne rand Amoss : Journ . Exne r. Me d . , Baltimore , 1917 , xxv . , 525. 30 . Fle xn e rand Amoss : Ib id . , 499. 31 . Fle xne r and Amoss : I b id . , 1916 ,xxii i 683. 32. Fle xne r and Jo b l ing , Ib id 1908, x . , 200 . 3 . Foste r,M and Gaske l l , J. : Ce re b ro-sp inal F e ve r, 1916 , Camb r idge .

34. Galambos , A . : Krio se p idemio l ogisch e Erfahrunge n , 200 , Wie nund L e ip z . , HO ld e r , 19 7 . 35. Gate s, F. L . : Journ . E xp e r . Me d . ,

Baltimore , 1918, xxvii i . , 449. 36 . Go ldon , W . E . : U.S . N av.

Med . Bul l ., Washington . 1918, xii . , 474. 37 . Gordon , M . H . : Brit.Med . Jour. , 1918, i . , 110 . 38. Gordon and Hine : Th e Spe cific Treatmen t of Ce re b ro-sp inal Fe ve r, w ith an Analysis of t h e R eports on t h e

97

first 90 case s tre ate d w ith a monoty p ical se rum , Me dical Re se archComm itte e . Jan . 28t h , 1919. 39. Gre e nwood , M . : Proc. R oy . S oc .

Me d 1916-17 (E pid em . x . , 44 . 40 . He iman and Fe ldste inMe n ingococcus Me n ingitis , 298, 1913. 41 . He rrick , W . W . : Arch .

Int . M e d . , Chicago, 1918, xxi . , 541 . 42 . He rrick , W . W . : Ib id and

Journ . Ame r . Me d . Assoc . , Chicago. 1918, lxx i . , 6 12. 43. H ilde sh e im . O . : Practition e r, London , 1905. lxxv . 44. Home r, A . : Proc .

Phy sio". S oc . , p . xxxi . ; Journ . Physio" , Camb ridge , 1918, lii i .45. John sto n , T . A . : Bri t . M e d . Journ . 1915, i 376 . 46 . Ke r . C .

THE LANCET , 1917 . i i . , 822. 47 . Kop l ik. H . : System of Me dicine(Osle r and McCr ae ), 1907 , i i i . , 513. first e dition . 48. Landryand Ham l e y : Ame r. Journ . Me d . S c . , Phila. , 1919, clvi i . . 210.

49. L ongco p e and R ack emann : Journ . E xp e r . Me d ., B a ltimore ,

1918, xxvii . , 341 . 50 . L O W , G . C . : Brit . Me d . Journ . , 1915, i 376 .

51 . Mackenzie and Martin : Journ . Path . and Bacte riol . , Camb ridge1908 xii , 539. 52. MacL agan , P . W . : Edin Me d . Journ . , 1918. N . Sxx . . 236 . 53. MacL agan : l b id . , 375. 54. Marcland : Bul l . e t mem . S o c .

med . d e s h 6 p . d e Paris . 1918. 30 sé r xlii . . 1218. 55. Mink J . OJourn . Ame r. Me d Asso c .

, Chicago , 1918, lxx . , 563. 56 . M itche l l andF alke n e r : N ew York Med . Journ . , 1918, cvii 103. 57 . Ne tte r : Bul l .e t m ém . S o c. med d e s h 6p . de Paris 1915. S e sér . , xxxix . 305.

58. N e tte r , A . : Ib id 1918, 30 sér xlii 370 . 59 Ne tte r, A . : Ib id . ,

541 . 60 . N e tte r. A . : Comp t . re nd . S oc. de b iol Paris . lxxviii . ,90 . 6 1 . N e tte r e t De b r é : L a M én ingite cereb ro-sp inale , Paris , 1911 .

62. Ne tte r e t De b re : Ib id . , 264. 63. Ne tte r e t S alanie r : Bul l .e t m em . S oc. méd . d e s h 6 p . d e Paris. 1917 . 30 ser . , xl i 789.

64. O’

B r ie n : Proc . R o y . S o c . Me d . 1917—18 (Me d . xi . , 2.

65. O’

Mal l e v : Bul l . U . S . N av . Me d Washington . 1917 , ix 572.

66 . Osle r , W . : B rit . M e d . Journ i . , 1517 . 67 . Parke s , W . HIb id . , 1917 . i 262. 68. P r e ssl ie and Lindsay : Quart . Journ . Me d

Oxford , 1916 . ix . , 437 69. R amon d. F . : Bul l . e tmém . S oc . méd . de s h 6p .

d e Paris , 1916 , 36 se a , " L , 297 . 7 0. Rob b : Re p rin t of a Pap e r re adb e fore t h e Ulste r M e dical Socie ty .March . 1917 . 7 1 . Rob ey and O the rs :

Journ . In fe ct . Dis . , Chicago , 1918, xxii i . , 318. 72. Rol le ston . J . Fractit io n e r , 1905, lxxiv . , 660 . 73. Rolle ston and Al lingham : THE LANCET

,

1899, i . , 889 . 74. Rose nth al : Comp t . re nd . S oc . d e b iol Paris , 1918,lxxxi 183. 75. R o skam , J . : Arch . med . lxx . , 1019—1028.

76 . Sainton , P . : Bul l . e t mem . S o c. med . d e s hep . de Paris , 1918,3a sér . ,

xlii 370 . 77 . Sain ton , P . : Ib id 541 . 78. S h irco r e and RossTrans . S oc . Trop . Me d . and v . , 1913, vii . , 83. 79. She rringtonJourn . Path . and Bacte riol . , 1893, i 258. 80. Sophian and BlackJourn . Ame r. Me d . Assoc Chicago , 1912, l ix . , 527 . 81 . S t e t t e n and

Rob e rt s : Ib id 1919. lxx ii . , 244. 82. De V e rb izie r : Bul l . e t mem . S o c.

med . de s hfip . d e Paris 1918, 36 sér xlii . , 589. 83. We b e r. F . PBrain , I o ndon , 1902. xxv 140 . 84. We lsh and Brown : Me d . Journ .

Austral . , 1916 , i i . , 113. 85. Whitmore , Fe nne l , and Pe te rse n : Journ .

Ame r. M e d . Assoc . , Chicago, 1918, lxx .,427 . 86 . Worste r-Drought. C

THE LA NCET, 1918, ii . , 39.

Print e d at The Lance t O ffice ,423, S trand , London , W .C . 2 .