A Contribution to Our Knowledge of 
Epidemic Cerebro-Spinal Meningitis. 
» 
BY 
SIMON FLEXNER, M.D., 
ASSOCIATE IN PATHOLOGY, 
AND 
LEWELLYS F. BARKER, M.8., 
FELLOW IN PATHOLOGY, JOHNS HOPKINS UNIVERSITY, BALTIMORE. 
( From the Pathological Laboratory of Johns Hopkins University and Hospital, 
Baltimore.) * 
ProM 
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 
February and March, 1894. Extracted from The American Journal of the Medical Sciences, February 
and Mai’ch, 1894. 
A CONTRIBUTION TO OUR KNOWLEDGE OF EPIDEMIC 
CEREBRO-SPINAL MENINGITIS.1 
By Simon Flexner, M.D., 
ASSOCIATE IN PATHOLOGY, 
Lewellys F. Barker, M.8., 
AND 
FELLOW IN PATHOLOGY, JOHNS HOPKINS UNIVERSITY, BALTIMORE. 
(,From the Pathological Laboratory of the Johns Hopkins University and Hospital.) 
Epidemiology, Etiology, and Pathology, 
The epidemic of cerebro-spinal meningitis to be reported here was one 
of the most extensive which has prevailed either in this country or 
abroad for many years. The outbreak, which began in January, had 
by the first of February become so alarming as to lead the State Board 
of Health to decide on making an official investigation for the purpose 
of determining the cause, and, if possible, of adopting some means to 
prevent the further spread of the disease. 
The fact that one of us (Dr. Flexner) was officially delegated to make 
this investigation made it easy for us to gain access to a large number 
of cases, and we wish to acknowledge gratefully the many kindnesses, 
direct and indirect, received at the hands of Dr. C. W. Chancellor, 
Secretary of the State Board ; Drs. J. D. and W. Q,. Skilling, Drs. 
M. G. and A. S. Porter, Dr. J. O. Bullock, of Lonaconing, and Dr. A. 
W. Smith, of Ocean. Without the co-operation of these gentlemen these 
researches would have been impossible; as it was, every opportunity 
was given us for a full and complete study of all individuals affected 
during our visit to the diseased region. 
The town of Lonaconing is a mining centre in the Alleghany moun- 
tains and contains some 5000 inhabitants. The location is peculiar and 
is more or less of interest from an epidemiological standpoint. The 
town is situated in a narrow valley and extends well up the sides of the 
steep hills which enclose it. Through the bottom of the gulch runs a 
muddy stream known as George’s Creek. The mountains rise more or 
less abruptly from the edges of the creek, and the town may, for our 
purpose, be divided into two parts: first, that lying in the valley in 
1 A report on the epidemic disease which prevailed during the winter and spring of 1893 
at Lonaconing, Maryland, and at other places in the George’s Creek valley. 2 
FLEXNER, BARKER: CEREBRO—SPINAL MENINGITIS. 
which are situated the business portion and for the most part the dwell- 
ings of the professional and business men of the place, and second, that 
built on the mountain sides, consisting almost entirely of miners’ 
dwellings. The stream and valley are somewhat tortuous at this spot, 
and give the place the appearance of being surrounded on all sides by 
mountains. 
One is struck almost at once by the arrangement of the houses on 
the incline. They are placed in long rows, tier above tier, facing 
the valley; behind, and therefore above the houses, are situated the 
privies, placed flat upon the ground; and not infrequently the cow- 
stable is located quite close to the dwelling. Before our arrival at 
Lonaconing there had been a heavy snowfall, but the weather soon 
afterward became mild, the snow melted, and exposed to view and made 
doubly striking by contrast the dreadful conditions which existed. 
The water streamed down the mountain sides, carrying with it the 
general refuse from the yards, the material from the cow-stables, and 
the excreta from the outhouses of the upper tiers, through the yards, 
past the dwellings situated below, and finally entered the creek, which 
acts as a huge sewer winding through the centre of the town. On 
their way these polluted surface-washings found no system of drains 
for their reception, and in places crossed the common roadway in little 
rivulets, through which the inhabitants of the town had to drive and 
walk. 
The water supply of Lonaconing is derived partly from surface 
wells and partly from cisterns, and we actually observed during a 
thaw the entrance of surface water and the accompanying filth directly 
into wells which were in daily use for drinking and culinary purposes. 
Significant, too, is the fact that in the valley the wells are situated 
often only a few feet from the creek, and it is certainly not hard to 
believe that the contaminated water from the creek could penetrate 
through the soil and become mixed with the water of the wells. The 
slaughter-houses are in the heart of the town upon the banks of the 
creek, and the blood and waste material from these find their way into 
its waters. 
These unsanitary conditions are not confined to Lonaconing alone, 
but in its course George’s Creek passes through a number of small 
towns, each of which adds its quota to the general filth, and only a short 
time ago an investigating party inspecting the river between Western- 
port and the Phoenix mines found among other things carcasses of horses 
in the stream or lying along the banks. 
The population of Lonaconing is chiefly made up of coal-miners 
and their families. In many instances there was distinct evidence of 
overcrowding, as many as eight and ten individuals living, eating and 
sleeping in a house of four small rooms. In one house in which a fatal FLEXNER, BARKER: CEREBRO-SPINAL MENINGITIS. 
3 
case occurred eleven persons slept in three bed-rooms. The individual 
houses in the long rows on the hillside are built so close to one another 
that often there is scarcely room for a footpath between them. There 
were, however, among them many well-built and commodious houses, 
though, as we shall show later, the occupants of these were by no means 
immune from the disease. 
From what we have said it will be obvious that, whether or not 
cerebro spinal meningitis is a filth disease, Lonaconing and the other 
towns situated along the banks of George’s Creek are, and have been 
for years, in about as unsanitary a condition as could be well imagined, 
and it would be little wonder if typhoid fever, diphtheria, dysentery, 
and the whole group of filth diseases should find in them an endemic 
home. And during the past spring, besides meningitis, the medical 
men of Lonaconing have had under their care many cases of scarlet 
fever, measles, parotitis (an epidemic of over 100 cases), influenza, 
pneumonia, diphtheria, and acute articular rheumatism. 
By far the greater number of the cases of meningitis occurred in the 
higher portions of the town, and they were usually found confined to 
little foci or groups of houses, points which have been noted by different 
observers also in other epidemics. To this rule, however, there were 
numerous exceptions. A few of the patients lived close upon the margin 
of the creek, and isolated cases were by no means rare. One boy, who 
died on the ninth day of the disease, lived on Jackson Hill, fully a 
quarter of a mile from any other habitation, and of the patients at 
Ocean none lived more than thirty feet above the level of the stream. 
The earliest cases of which we have notes occurred during the first 
week in January, 1893. During the course of a dance two young men 
who had overheated themselves imprudently rushed into the open air to 
get cool. The weather outside was extremely cold, and it is said that 
their hair, wet with perspiration, was frozen upon their heads. The 
drive to their homes afterward was long and very cold, and these two 
men, aged twenty and twenty-two respectively, developed symptoms of 
cerebro spinal meningitis next day. Immediately afterward the disease 
became epidemic, appearing in many different places in Ocean, Mid- 
land and Lonaconing about the same time. After every marked fall 
of temperature there were fresh cases to record, and the disease pre- 
vailed there in varying intensity up to the middle of May. Up to March 
Ist there had been sixty-eight well-marked cases, besides some forty 
which were classed as abortive cases, making a total of over one hun- 
dred cases. Since our return there have been many more cases in 
Lonaconing, as well as an alarming outbreak in Frostburg, making the 
total number of cases about 200. 
Of the sixty-eight patients in whom the symptoms were clearly defined 
thirty-seven were males and thirty-one females. In other epidemics the 4 
FLEXNER, BARKER: CERE B R O-SP IN A L MENINGITIS. 
number of females attacked had, as a rule, slightly exceeded that of the 
males, and it would seem probable, therefore, that sex bears little or 
no relation to the etiology of the disease. Undoubtedly, children and 
young adults were most susceptible, although the occurrence of the 
disease among older people cannot be denied, one of our cases being 
a man of thirty-eight years, another a woman of forty. The youngest 
patient observed was a child of five months. 
The study of different epidemics of cerebro-spinal meningitis has not 
as yet led to the detection of a common factor or set of conditions in the 
localities attacked. The disease shows no special predilection, so far as one 
can judge, for particular regions, or for any season of the year, and no one 
class of people is affected, the apparently robust and the weak suffering 
alike. It has, indeed, been established that, cceteris paribus, young indi- 
viduals are more susceptible than adults, and although there is no sharp 
line to be drawn in the occurrence of the disease under different circum- 
stances, yet its greater frequency under unfavorable hygienic surround- 
ings, such for example as in barracks and in country districts, is to be 
borne in mind. Epidemics have occurred in the same district, affecting 
areas slightly removed from one another. Such an epidemic, studied 
by Low, appeared in 1890 in certain of the eastern counties of England. 
The parishes affected all lay within short distances of one another in 
agricultural communities, in all of which it was the custom to use the 
house-refuse for fertilizing purposes. The drinking-water was obtained 
from wells and from open pits, though the water from the latter is said 
to have been boiled before being used. In other epidemics, after a con- 
siderable period of quiescence, the disease has reappeared in the same 
locality, examples of which are given by Wolff, who studied the Hamburg 
epidemic. 
Osier states that epidemics have occurred more frequently in winter 
and spring, and that villages and country places have in certain of 
these suffered relatively more than cities. The Leipzig epidemic which 
Striimpell studied appeared there in 1879, continued into 1880 and 1881, 
beginning in the winter and becoming more severe in April and June, 
almost ceasing in February and March of 1881, only to appear again 
in a sporadic form later. Claverie described an epidemic at Rochefort 
which prevailed during the winter of 1885-86 in which there were 
marked oscillations of temperature, although at no time did the ther- 
mometer fall below zero. Lemoine observed in the epidemic at Orleans 
during the winter of 1886 that a sudden lowering of the temperature 
was followed in one or two days by a marked increase in the number of 
cases. 
The epidemic at Lonaconing appeared in the winter and reached 
its maximum during the coldest weather. The winter was, more- 
over, one remarkable for its severity, and there were heavy falls of FLEXNER, BARKER; CEREBRO-SPINAL MENINGITIS. 
5 
snow, with very cold weather alternating with thaws of short duration. 
During the month of February, however, when the cases were perhaps 
most numerous, the weather, as shown by the observations reported 
from Cumberland, Md., to the U. S. Weather Bureau, was exceptional 
only for the rainfall, for while the average rainfall for the month of 
February during the past twenty-two years has been 2.51 inches, this 
year the rain and melted snow amounted to 3.58 inches, the snowfall 
itself measuring twenty inches. During the month there were eight 
clear days, two cloudy, ten fair, and eight of rain and snow. The highest 
temperature during February, 1893, was 58° F.,the lowest 3° F.; mean 
33° F. The averages for the last twenty-two years are: Highest tem- 
peratures 58°, lowest 2°; mean temperatures, 33°. It may be men- 
tioned that this epidemic agrees with that described by Low in that the 
disease occurred in several of the neighboring places in the same valley. 
The epidemic and sporadic cases of cerebro-spinal meningitis which 
have occurred since 1886 are of especial interest inasmuch as they have 
been studied bacteriologically. This method of study has been rewarded 
by the isolation of a particular micro-organism from the exudate in the 
meninges, namely, the micrococcus lanceolatus, which there is now reason 
to believe bears an etiological relation to the disease. 
Weichselbaura found this organism in the exudate in the meninges in 
1886, and Netter obtained it from cases in the epidemic studied by 
Lemoine in the same year. Goldschmidt isolated it from a case in 1887, 
Ortmann in 1888, and Foa and Bordoni-Uffreduzzi in cases in an epidemic 
occurring in Turin in 1888. Banti found it in 1889, and Bonome obtained 
it at autopsies during a small epidemic in Padua, which occurred in 
1890. Mirto obtained the micrococcus lanceolatus in 1891 from the 
exudate in a case of epidemic cerebro-spinal meningitis—a man twenty- 
two years of age. The cocci were in every way typical, and when inocu- 
lated into rabbits gave rise to fatal septicaemia. Klippel found it in 
sporadic cases in 1891 and Ribbert in 1892. Ribbert’s cases were those 
of two brothers who were affected almost simultaneously, one of them 
dying in forty-three, the other in forty-seven hours. 
The first to isolate the micrococcus lanceolatus from the exudate in 
meningitis was Eberth, in 1880. The meningitis in this case was sec- 
ondary to pneumonia. Since this time many others have studied this 
form of meningitis and have obtained the same organism. Thus Boz- 
zolo and Leyden in 1883, Weichselbaum and Fraenkel in 1886, and 
Meyer and Netter in 1887; Hansen and Bonome in 1888, Monti in 
1889, and Gabbi and Puritz in 1890. In Professor Welch’s laboratory 
in Baltimore, in three cases recently the same organism was isolated. 
There is another class of cases in which a meningitis develops in the 
course of diseases other than pneumonia, or follows upon injuries. In 
some of these the micrococcus lanceolatus has been found, in others dif- 6 
FLEXNBR, BARKER: CEREBRO-SFINAL MENINGITIS. 
ferent bacteria. For example, Netter found in 1889 the Friedlander 
bacillus in a case of meningitis following otitis media. Mills claims to 
have isolated the Friedlander bacillus also from a case of pneumonia 
associated with meningitis, but it is not improbable that his organism 
was the Fraenkel-Weichselbaum diplococcus. Monti, in the same year, 
found the micrococcus lanceolatus in a case of combined arthritis and 
pleuritis. Kainen, in 1890, separated a bacillus which he regarded as 
identical with the typhoid bacillus; and in the previous year Adenot 
had likewise isolated an organism which he thought to be the typhoid 
bacillus, Debove about this time described a case of combined perito- 
nitis and meningitis due to the pneumococcus. Hanot and Luzet, in 
1890, isolated streptococci from the exudate in the meninges in a puer- 
peral woman who had died of meningitis and general infection. Le 
Gendre and Beaussenat, in 1892, obtained from a case of meniugitis 
associated with otitis media, arthritis, and broncho-pneumonia, the staphy- 
lococcus pyogenes aureus. Klippel, in 1892, found, in a demented indi- 
vidual who died of acute meningitis, the micrococcus lanceolatus. There 
was an old area of softening present, and over this the exudate was 
most marked. Boulay and Courtois-Suffit, in 1890, isolated the micro- 
coccus lanceolatus from a case of combined peritonitis and meniugitis 
without pneumonia, and Bonome has observed a case of combined pleu- 
ritis, pericarditis and meningitis due to the pneumococcus. Zorkendorfer, 
writing from Chiari’s laboratory, reports a very interesting case observed 
during this year in which at autopsy, besides a purulent meningitis, 
there was a well-marked inflammation in the ethmoid cavity and suppu- 
ration in the sphenoidal sinuses. Besides, the mucous membrane of the 
pharynx was reddened and covered with a thin layer of pus. From the 
pus in the meninges, as well as that in the sphenoidal sinuses, he found 
diplococci in cover-slips. He succeeded in isolating them also in pure 
culture, and found, by injection into the peritoneal cavity of rabbits, 
that they set up a fatal septicaemia, the organisms in the blood at autopsy 
corresponding in every respect to the micrococcus lanceolatus. In three 
cases of purulent meningitis examined by Neumann and Schaeffer, once 
the pneumococcus, once the staphylococcus pyogenes aureus, and in the 
remaining instance a fine bacillus was found. In a fourth case the results 
of the examination were negative. Netter has also in one case found the 
staphylococcus pyogenes aureus. Roux states that he isolated from a 
case the staphylococcus aureus and albus and a bacillus resembling that 
of typhoid fever. Mircoli claims to have obtained from one case a 
staphylococcus resembling the aureus and a bacillus which he identified 
as the bacillus pyogenes foetidus, the latter being obtained in cultures 
from the motor cortex and medulla. 
Friis describes an epidemic at Copenhagen in which 185 persons (111 
under fifteen years of age) were affected. From the pus of nine cases FLEXNEE, BARKER: CE R E BRO-S PI NA L MENINGITIS. 
7 
examined by Roosing a thick, short bacillus was obtained which is de- 
scribed as approaching a coccus in form, and is stated to grow charac- 
teristically on gelatin. We recently made an autopsy on a young man 
who died of meningitis, following an injury to the head. There was 
contusion of the scalp but no loss of continuity in the bones of the skull. 
In the exudate of the meninges the micrococcus lanceolatus was found ; 
no other focus of suppuration was present in the body. Prudden, in a 
case of traumatic meningitis occurring in a child of thirteen months 
(a patient of Holt’s) has isolated the micrococcus lanceolatus from the 
exudate. White mice inoculated with the organism died in thirty-six 
hours from septicaemia. 
The number of bacteriological examinations of uncomplicated cases of 
meningitis, occurring either sporadically or in epidemic form, is up to the 
present time not large. There is, however, such uniformity in the results 
obtained that while it is perhaps not to be considered as established for 
all, yet the majority of cases appear to be caused by an organism which, 
in its morphological characters and biological properties, is not to be dis- 
tinguished from the micrococcus lanceolatus. 
During our stay at Lonaconing two deaths occurred, and we were per- 
mitted to make autopsies. The first was a child of nine years, who died 
on the third day of the disease. The autopsy showed an extensive con- 
vexity-meningitis with spinal meningitis. The second autopsy was on a 
girl of sixteen who died in the third week of the disease. In this case 
there was an extensive exudate over the base with effusion into the pos- 
terior fossa. 
Pathological Anatomy.— The changes in the central nervous 
system in cerebro-spinal meningitis have been studied, among others, by 
Strumpell, v. Campe, and Hagelstara. They are not always of the same 
kind or extent, and depend in part, at least, upon the duration of the 
disease. In the explosive cases the evidence of more than hypersemia 
and serous exudation can often not be appreciated by the naked eye; 
but the microscopical examination of such cases shows that a tolerably 
rich emigration of leucocytes into the pia-arachnoid has already taken 
place. In the cases in which death has been longer delayed the inflam- 
matory alterations are often pronounced, and they are not necessarily 
limited to the lepto-meninges. The substance of the brain and cord, 
as shown by Strumpell, are commonly involved, and the legitimacy 
of the terms meningo-encephalitis and meniugo-myelitis has been sug- 
gested by him. While the inflammatory processes in the substance of 
the brain and cord are generally to be made out only with the micro- 
scope, yet in some instances, as pointed out by Zenker and Klebs, and 
more recently by Striirapell, abscesses of comparatively large size may 
exist. 
In the substance of the central nervous system the invasion may take 8 
FLEXNER, BARKER: CE RE B RO-SPIN AL MENINGITIS. 
place in three ways : (1) by direct extension from the meninges; (2) 
along the vessels entering from them; and (3) through the development 
of independent foci. These several modes were observed by Strumpell, 
whose observations were confirmed in our cases. Hemorrhages, espe- 
cially into the substance of the cord and into the central canal, have 
also been observed. 
The exudate in the meninges consists of pus cells, red blood-cor- 
puscles, fibrin, and serum in varying proportions. The amount of serum 
may be considerable, as in the case reported by Stills, in which three 
pints were present, death having taken place on the thirty-fifth day of 
the disease. The exudate fills the meshes of the pia-arachnoid, dips 
down between the convolutions, enters the ventricles of the brain and 
the central canal of the cord, and appears in the form of a cellular infil- 
tration in the substance of the brain and cord. Finally, the extension 
of the process along their course gives rise to the symptoms referable to 
the involvement of the nerves. 
The alterations found in other organs of the body cannot be said to 
be peculiar to this disease, but are such as attend infectious diseases in 
general. Among these may be classed the hemorrhages into the serous 
membranes and into the substance of certain organs; the swelling, in- 
creased granulation, and even fatty degeneration of the cells of paren- 
chymatous organs, and the hypergemia and degeneration of the voluntary 
muscles. 
In our two autopsies the acute and subacute, as well as the convexity 
and basal forms of the disease, were represented. The first was the girl 
of nine, dying on the third day of the disease. Autopsy two hours after 
death. There were no adhesions between the dura and the skull-cap ; 
the outer surface of the dura was smooth, the longitudinal sinus con- 
taining dark fluid blood ; the dura and pia-arachnoid were not adherent; 
the vessels of the pia were greatly dilated and filled with blood of a dark 
color. The soft meninges were swollen, but no considerable quantity of 
fluid escaped from them; they were opaque, especially over the con- 
vexity of the brain, and in the depressions between the sulci heavy 
opaque white streaks and bands were visible. This exudation into 
the meninges was confined to the convex surface of the brain, the base 
being free from it, but the ventricles were somewhat dilated, and con- 
tained an excessive amount of clear serum. 
The dura covering the spinal cord, especially in its inferior part, was 
wide and bulging. On incising it near the middle of the lumbar region 
about 40 c.c. of slightly turbid fluid escaped. The spinal dura was not 
adherent to the pia. In the meshes of the latter was an exudate which 
was not uniformly distributed, but was most abundant posteriorly and 
corresponded for the most part with the lower cervical and dorso-lumbar 
regions. This exudate was white and opaque and resembled that present 
in the brain. The vessels of the pia of the cord were likewise injected, 
their contents being dark in color. On section of the cord the substance 
presented a vivid pinkish tint. 
There were subserous hemorrhages into the pleura and pericardium, FLEXNER, BARKER: C E REB RO-SP IN AL MENINGITIS. 
9 
and beneath the capsule of the kidney there were punctiform hemor- 
rhages. The cut surface of the kidneys and liver presented an opaque 
appearance. There was no pneumonia and the nasal sinuses were free 
from perceptible inflammation. The spleen was only slightly enlarged, 
the color was darker than normal, its substance somewhat softened, and 
the Malpighian bodies were swollen and strikingly distinct. The mucous 
membrane, especially of the small intestine, was congested, and the 
follicles were swollen. 
The voluntary muscles were intensely red, and this was especially 
noticeable in those along the spine, and a large amount of blood escaped 
from them on incision. 
The bacteriological examination of the pus in cover-slips from the 
exudate in the meninges of the brain and cord showed the presence 
there of the micrococcus lanceolatus without admixture with any other 
organism. The micrococci occupied pus cells and were also present in 
the fluid among the cells. They were fairly numerous. 
Cultures were made in plain agar agar, in glycerin-agar, and in Guar- 
nieri’s medium (Prof. Welch’s modification). Owing to circumstances 
they could not be brought into a thermostat for forty-eight hours. 
Tissues were placed immediately after the autopsy in various hardening 
agents, Flemming’s solution, bichloride of mercury, and absolute alcohol. 
Inoculation of animals with the exudate could not be practised at Lona- 
coning. The tissues were sent to the laboratory in Baltimore by express, 
where inoculations of mice and rabbits were made. 
We had been at Lonaconing several days before a death occurred. 
Before our visit there had been deaths almost every day, but the 
mortality diminished for a while, and during those days no new eases 
developed. The death of the child of nine years took place at seven 
o’clock on the last evening we spent at Lonaconing, and the autopsy was 
made at nine. Cultures from the exudate were made at once on ex- 
posing it by drawing back the dura. Additional cultures were made an 
hour or more later. The first cultures were made at the moment the 
exudate was exposed, without disinfecting the surface, by inserting the 
needle under the raised dura; the second set, which included cultures 
from all the organs, was made in the usual manner after burning the 
surface of the organs. It is necessary to state that the second set of 
cultures was made in a carriage-house next a stable in which horses 
were kept. 
On the afternoon of the day following the autopsy we left for Balti- 
more carrying with us fresh tissues for inoculating animals, the culture 
tubes, and the preserved tissues. We had proceeded as far as Cumber- 
land, Md., when we received a telegram asking us to return to Lona- 
coning, as another death had occurred. The organs of the first case were, 
therefore, despatched by express to Baltimore, so that no unnecessary 
delay should occur before the inoculation of animals could be made 
They reached Baltimore about noon on the following day, some forty 
hours after the autopsy. The animals inoculated (mice and rabbits) all 10 
FLEXNER, BARKER: CEREBRO-SPINAL MENINGITIS. 
recovered. The cultures were not sent at this time, but as a precaution 
were kept and carried by us to Baltimore, and placed in the thermostat 
just fifty hours after the autopsy. 
The first cultures made at the time of the autopsy showed a very feeble 
growth of diplococci, but on transplantation no further growth could be 
obtained. All other tubes from the brain or cord showed either no 
growth or an abundant one of a tolerably coarse bacillus. This bacillus 
is probably to be regarded as a contamination, which is believed to have 
gotten into the tubes at the time of the inoculation. This would not be 
surprising considering the disadvantageous circumstances—above noted 
—under which the cultures had to be made. Culture-tubes from the 
organs remained sterile with the exception of those from the spleen. 
From this a growth was obtained of pure streptococci, which formed 
tolerably long chains, and were devoid of pathogenic effects when intro- 
duced in large quantities into mice and rabbits. 
The cultures from the second case could not be made until Baltimore 
was reached. The autopsy was made at 10 a.m. (twelve hours after 
death), and the cultures at midnight of the same day. The tubes 
inoculated from brain, cord, and viscera remained sterile. Plain agar, 
glycerin-agar, and Guarnieri were the media used. Mice and rabbits 
were inoculated from the exudate in the brain and cord. None suc- 
cumbed.1 
The histological examination of the tissues from the first case showed 
that an abundant exudation had taken place into the membranes of the 
brain and cord. It will be well, perhaps, to go more in detail into the 
microscopical characters of this exudate and of the lesions of the cord 
and brain. While the tissues were still warm they were placed, as has 
before been mentioned, in various hardening agents, including Flem- 
ming’s solution, bichloride of mercury, and absolute alcohol. 
For the study of the cellular elements in the exudate, the tissues fixed 
in bichloride of mercury and afterward hardened in alcohol, and those 
placed directly into absolute alcohol, gave the best results. The cord 
fixed with bichloride of mercury also showed well the alterations in the 
axis cylinders of the nerve roots, to be presently described. Sections 
from various levels were studied, and variations were noted ; but they 
were hardly great enough to merit separate description. On the other 
hand, the pictures presented by the tissues prepared with HgCl2, as con- 
trasted with those hardened in alcohol, merit separate consideration, and 
we are the more disposed to treat them separately on account of the 
1 In view of these experiments, it may be questioned whether the organism found by us in 
the exudates was really the micrococcus lanceolatus. It is, however characteristic of the 
lanceolate diplococci to show a variable vitality and great variation in their pathogenic 
effects on animals, and from these well-established facts we are the more disposed to regard 
the bacteria we found as being identical with the lanceolate cocci which give rise to acute 
lobar pneumonia. FLEXNER, BARKER: CEREBRO —SPINAL MENINGITIS. 
11 
general significance which may attach to the variations of cell appearance 
depending upon hardening and staining reagents. 
The cord treated with HgCl2 is well preserved, the morphological 
elements staining sharply. The anterior half: The membranes are 
swollen, the swelling being due to (1) the dilatation of the bloodvessels, 
and (2) an exudate in the meninges composed of serum and cells. The 
evidence of fluid is not to be made out everywhere with certainty, but 
areas occur in which the tissues are found pressed widely apart. The 
pia extending into the anterior fissure is swollen, and the bloodvessels 
are distended and filled with blood. This dilatation of the vessels is 
best seen at the anterior margin, where the fissure is widest, and again 
just before its termination at the white commissure, but it occurs else- 
where in the cord. The swelling of the tissues in the fissure is not due 
altogether to the increased accummulation of blood in the vessels and 
the transudation of fluid, but is in part dependent upon an increased 
number of cells in the tissue. These cells vary in size and possess 
nuclei which are of different sizes and forms. The majority of these 
cells have not the appearance of leucocytes with polyform nuclei—in 
fact but few cells having the form characteristic of these are to be 
seen Moreover, in the dilated bloodvessels few polynuclear leucocytes 
are present. The cells which make up the increase in the tissue are 
chiefly small cells with round, deeply-staining nuclei and a small 
amount of protoplasm; the others are all of an epithelioid type. The 
latter are in small numbers only, and perhaps not to be regarded as 
essentially increased. Single red blood-corpuscles are free in the tissues 
and a small quantity of blood pigment is to be found deposited there. 
Finally, in the meshes of the membrane there are small globular masses 
varying in size from one-third to one-half the diameter of a red blood- 
corpuscle. In eosin these stain pale pink, while the red blood-corpus- 
cles take on a bright yellowish-red color. The globular masses are less 
refractive than the red blood-corpuscles, which stain well; but they 
approach more nearly in staining and refraction shadows of red blood- 
corpuscles, some of which are also occasionally seen. It is not unlikely 
that they represent partly disintegrated red corpuscles, if indeed they 
are not globular masses of haemoglobin. In tbe depth of the fissure the 
extravasation of blood is more decidedly marked than is the case near 
the surface. 
Passing from the anterior fissure toward the anterior roots, at first a 
slight diminution of the cellular infiltration is noted, but at the roots 
the exudate is more abundant. In the angles between the roots and 
the cord dense accumulations of cells may be found. The forms which 
predominate here in the exudate are again the small round cells, 
although a larger proportion of cells with vesicular nuclei, some leucocytes 
with polymorphous nuclei, and a few red blood-corpuscles are present. 
This mass of cells is on the surface, and it can be seen that a prolifera- 
tion of the cells of the lymph spaces has taken place in the pia beneath; 
in these spaces an occasional “polynuclear” leucocyte is seen. There 
is an almost uniform layer of cells between the anterior lateral and the 
posterior lateral fissures. At the posterior roots the increase in the 
exudate is marked. The cells fill the tissues of the membranes, and 
about the veins of the pia there are occasional accumulations of round 
cells. The polynuclear leucocytes are relatively slightly increased in 12 
FLEXNER, BARKER; CE REB RO-SPIN AL MENINGITIS. 
number in this portion of the cord, and are correspondingly more 
numerous in the bloodvessels. The predominating cells, however, resem- 
ble lymphocytes or the mononuclear cells of granulation-tissue. Toward 
the posterior median fissure the exudate becomes still thicker, the mem- 
branes are obscured, and more red blood corpuscles are mixed with the 
exudate. In this situation there are cells equal in size to four or six of 
the round cells; they are thin and transparent, are round or polygonal 
in shape, have a feebly staining protoplasm and vesicular nuclei, and 
often contain other cells, especially leucocytes with polymorphous nuclei, 
within them. 
The bloodvessels of the cord itself are dilated. This is the case both 
in the gray and in the white matter. Just beneath the pia hemor- 
rhages have occurred, some of which extend into the substance of the 
cord, and in the anterior lateral columns small hemorrhages have taken 
place independently of those under the pia. There is no perceptible 
tendency of the process of the membranes in this instance to pass into 
the cord. Separate foci of leucocytic accumulation do, however, occur; 
but they are neither large nor numerous, nor, as far as could be deter- 
mined did they have any connection with bloodvessels. The largest 
collection observed was in size a little smaller than a miliary tubercle 
(Fig- 1). 
Fig. 1. 
Section of spinal cord showing collection of leucocytes in its at a. 
The ganglionic cells show certain differences among themselves, 
consisting of variations in the granulation of the protoplasm, the 
clearness of the nuclei and nucleoli (these being in some cells quite in- 
distinct), but especially in the sharpness of the cell margins. In some, 
particularly in those in which the nuclei are indistinct, the margins of 
the cells are very indefinite. These are the only changes observed in 
the large multipolar cells of the anterior horns. In the posterior horns 
an occasional cell may be seen in which the refraction of the proto- 
plasm is increased, and these cells are swollen and the lymph spaces 
surrounding them obliterated. FLEXNER, BARKER: CEREBRO —SPINAL MENINGITIS. 
13 
The changes described by Striimpell and Hagelstam in the axis-cyl- 
inders of the cord were not observed by us in these specimens, probably 
for the reason that, although all other parts of the cord were well pre- 
served and stained perfectly, the axis-cylinders did not stain satisfac- 
torily. However, in the nerve roots these as well as interstitial changes 
were observed, and in some instances were quite marked. 
Swelling of the axis-cylinders in the cord has been noticed in nephri- 
tis, tuberculous meningitis, and leuksemia by F. Schultze, by Kohler 
in the oculo-motorius in tuberculous meningitis, and Hoche found it 
both in the cord and nerve roots in tuberculous meningitis, and describes 
in addition a cellular proliferation of the peri- and endoneurium of the 
latter. The swelling of the axis-cylinders also occurs in variola, typhoid 
fever and septicaemia. (Hoche.) 
The anterior roots show fewer alterations than the posterior. The 
bloodvessels in the perineurium are swollen and a few red blood-corpus- 
cles are found free between the nerve bundles. There is no marked 
proliferation in the interstitial tissue. The majority of the nerve fibres 
are unaltered, but still not a few are swollen and stain in haematoxylin 
feebly, those which are unchanged staining more deeply. These swollen 
fibres have on an average a diameter more than twice that of the 
others. 
The normal axis-cylinders lie in a space which has apparently been 
formed either by the disappearance in part, or the contraction, of the 
myelin sheath, a faint line of myelin being still visible just inside 
Schwann’s sheath; in some instances the myelin entirely fills the space 
between the axis-cylinder and the sheath of Schwann. On the other 
hand the swollen cylinders, which occur singly or in groups, always fill 
the space inside the myelin sheath, being distinguished from the latter 
by their larger size and by their staining properties. It is worthy of 
note that in those nerves in which a cellular proliferation, especially 
around the veins, can be made out, more axis-cylinders show this change 
than where the cellular increase is not so apparent. 
The posterior roots show the same changes as the anterior, only in a 
more pronounced manner. It is not uncommon in these to find as many 
as twenty or thirty swollen axis-cylinders lying close together. The 
interstitial tissues of the nerves and the epiueurium are also affected. 
A considerable cellular collection occurs at times in these situations, 
and the increase in the peri- and endoneurium reaches so high a degree 
as to obscure the nerve fibres. This, however, seldom happens. The 
cells forming the collections are principally of the type of small round 
cells. 
Specimens of the cord hardened in absolute alcohol were found well 
suited for the study of the cellular elements making up the exudate. 
Sections stained in aqueous solution of fuchsin or magenta show, as the 
important difference between them and those of the tissues hardened in 
solutions of bichloride of mercury, that more polynuclear leucocytes are 
present in the exudate than was before apparent. These cells are found 
on the anterior but in larger numbers on the posterior aspect of the 
cord, and in the cell masses in the latter, leucocytes presenting the most 
irregular nuclear forms are met with. Nuclear fragments are to be 
found in small quantity. Notwithstanding this difference, the cell- 
forms which are usually regarded as being derived from the fixed cells 
are still present in large numbers. In one section a small collection of 14 
FLEX NER, BARKER: CEREBRO-SPINAL MENINGITIS. 
polynuclear leucocytes, not associated with a bloodvessel, was found in 
the lateral horn. Again, in a section of one of the anterior roots a 
small collection of polynuclear leucocytes, and near by an evident pro- 
liferation of the nuclei of Schwann’s sheath, was observed. Single 
polynuclear leucocytes are found between the nerve fibres, and in the 
bloodvessels there is an evident leucocytosis. 
Specimens taken from various parts of the brain were hardened in 
the same way as the cord. The tissues from bichloride and absolute 
alcohol again gave very good preparations. Various staining reagents 
were employed—hseraatoxylin and eosin, fuchsin, magenta. For the 
study of the bacteria, the methods of Gram and Weigert were used, as 
well as solutions of methylene-blue and gentian-violet applied in the 
ordinary way. 
The thickness of the exudate is not only less on the convexity than 
in the sulci, but it is not uniform over the convolutions themselves. In 
some places the exudate over the convolutions is two or three times as 
deep as in other places. But it is in the sulci (Fig. 2) that the greatest 
accumulations of cells have taken place. The characters of the exudate 
are not essentially different from those described in the cord, but the rela- 
tive number of the different kinds of cells is not the same. There is dila- 
tation of the bloodvessels of the pia, and an increase of leucocytes with 
polymorphous nuclei in these vessels is more common than in those of 
the cord. Hemorrhages are also found, amounting at times to con- 
siderable extravasations and at others to the escape of a few corpuscles 
only. A very little golden-yellow pigment is seen now and then. In the 
section the pia is lifted up from its connections with the underlying 
brain substance in many places, although the brain substance beneath 
is intact. 
The cells composing the exudate consist of polynuclear leucocytes 
in considerable, perhaps predominating, numbers, but many other 
cells are also present. Among these latter are cells of the type of 
lymphoid cells, larger cells with vesicular nuclei, and, finally, cells 
much larger than either of these, which in certain situations are so 
numerous as to make up a considerable part of the exudate. These 
cells, as indicated, are not uniformly distributed. They may be found 
on the convexity, but are more common in the sulci. In size they 
equal several of the ordinary cells with vesicular nuclei, and they them- 
selves possess nuclei of this type. They are either circular or polygonal 
in outline, thin and translucent, and what especially characterizes 
them is the fact that they often contain enclosed in their protoplasm 
other cells, principally polynuclear leucocytes. The number of cells 
which are included varies. Sometimes only two or three are seen, but as 
many as fifteen have been counted in one cell. Besides the leucocytes 
small round cells and red blood-corpuscles may be enclosed in these larger 
cells. (Fig. 3.) As stated, these large cells have vesicular nuclei and 
abundant protoplasm, and present the appearances of epithelioid cells. 
While regarding them as proliferated endothelium derived from the pia, 
we can offer no explanation of the purpose which they serve in taking 
up other cells. The cells which they contain are practically normal; 
they possess nuclei which stain well and are of normal appearance. On 
the other hand, the large cells themselves are apparently normal. 
Sometimes it happens that the nucleus of one of the large cells is not 
sharply defined, or that the cell protoplasm stains in eosin a little more 
deeply than is usual with endothelium. Section of the brain from Case 1., showing dilatation of bloodvessels and 
the relative amount of exudation on the surface and in the sulcus. 
[To face page tt FLEXNER, BARKER: GBR EBRO —SPINAL MENINGITIS. 
15 
In the brain, besides inconsiderable hemorrhages, the cellular infiltra- 
tion of the meninges has advanced to a slight extent into the substance 
along the vessels, and a few scattered leucocytes without vascular con- 
nection can be made out. In addition there is slight oedema, as indi- 
cated by the rarefied appearance of the cortex. Fibrin plays a very 
small part in the exudate, sections of the tissue hardened in alcohol 
stained by Weigert’s method showing only a small amount. 
From the exudate in the meninges in Case I. Polyform leucocytes, endothelioid cells, red 
blood-corpuscles, and the larger cells with inclusions. A few cells with fragmented nuclei, 
and free nuclear fragments, also present. 
Cover-slip preparations made at the time of the autopsy from the 
exudate in the brain and cord showed a fair number of diplococci, 
usually lancet-shaped and always surrounded by capsules, and, as 
previously stated, they were sometimes free and sometimes enclosed in 
cells. The results of our attempts to cultivate the organisms, as well as 
the inoculations of animals, have already been mentioned. In the tissues 
stained for bacteria by the methods of Gram and Weigert, as well as 
with gentian-violet and methylene-blue, typical diplococci were found. 
They were not particularly numerous, but wrere present there to the 
exclusion of other organisms, so far as could be determined by these 
staining methods. 
The changes in the other organs may be summed up in a few words. 
In the kidney the bloodvessels generally are dilated, and small hemor- 
rhages have occurred into the tubules. The tubes containing blood 
preserve their epithelium, but this is compressed. The epithelial cells 
of the convoluted tubes are swollen and granular, and here and there 16 
FLEXNER, BARKER: CEREBRO-SPINAL MENINGITIS. 
contain fine fat-droplets. An occasional epithelial cell devoid of a 
nucleus is seen. The spleen is congested and the lymphatic tissue of the 
nodules increased in amount. 
The second case was that of a girl of sixteen who died in the third 
week of the disease. The autopsy was made twelve hours after death. 
The dura was strongly adherent to the skull-cap, and on removing it 
about 200 c.cm. of slightly turbid fluid containing white flakes escaped 
from the posterior fossa. The longitudinal sinus and the veins over the 
convex surface of the brain were distended with dark fluid bkod, and 
the arteries were prominent. The fluid in the pia over the cortex, which 
was increased in amount, was turbid. On the base, covering the pons 
and the upper half of the medulla, was a firm white deposit which was 
intimately adherent to the underlying tissues. Over the base, from the 
pons to the optic chiasm inclusive, there was in the pia a fluid, milk-white 
in color, which was especially abundant in the anterior perforated space 
and over the optic commissure. The fourth ventricle and the lateral 
ventricles contained greenish-yellow gelatinous pus—indeed the former 
was completely filled with it. Both the lateral ventricles were dilated, 
and the choroid plexuses covered with an opaque exudate. A similar 
opaque exudate extended along the sheath of the auditory nerve into 
the bony canal. 
The pia-arachnoid, throughout the entire length of the cord on the 
posterior surface, contained a gelatinous exudate fully two milli- 
metres in thickness, the exudate on the anterior surface being less 
marked. 
The kidneys were swollen, cloudy, and cyanosed. The liver was 
cloudy and of very flabby consistence. The spleen was somewhat 
swollen, softened, and- deep reddish-brown in color, the Malpighian 
bodies being very distinct. The mucous membrane of the intestines was 
swollen throughout, congested, and its lymphatic apparatus was hyper- 
trophied. There was no pneumonia. 
From the pus in the ventricles and from the exudate over the base 
of the brain, the micrococcus lanceolatus was obtained on cover-slips. 
The organisms were present in much smaller numbers than in the 
previous case. In the other organs no bacteria were found. The re- 
sults of cultures and inoculation of animals from this individual have 
already been mentioned. 
The tissues from this case were hardened in the same manner as those 
from the previous one, although they were not obtained in so fresh a 
condition. This fact is evident from the preservation, especially of the 
the cord. The exudate in the meninges stains well, while the substance 
of the cord does not stain satisfactorily. As in the previous case, the 
largest accumulation of cells on the anterior aspect of the cord is at 
the fissure, and the two points of greatest accumulation are on the 
surface and in the depth of the fissure. Laterally the exudate is not. 
uniform, but is gathered into foci, and is more abundant where the 
anterior roots are given off At this place the exudate passes along the 
roots as they leave the cord. The exudate becomes thicker still over 
the posterior aspect of the cord, but it is not uniform. The section has 
been carried through the dura, and where no mechanical separation has 
taken place the exudate is found to be in contact with this membrane. FLEXNER, BARKER: CEREBRO —SPINAL MENINGITIS. 
17 
The thickness of the exudate over the posterior is several times that 
over the anterior aspect of the cord, and where the posterior roots come 
off the exudate surrounds them. 
The cells which compose this exudate are again recognized as round 
cells, larger cells with vesicular nuclei (these varying in size, and often 
including other cells in their substance), and polynuclear leucocytes. 
There are fewer of the large cells present than in the sections of the 
brain from the acute case. The polynuclear leucocytes do not predomi- 
nate in number over the other cells. In addition to the cells on the 
posterior aspect of the cord, where the exudate is thicker, it contains a 
material which stains very deeply in hsematoxylin, and has an amorphous 
appearance. In this mass cell-forms can still be made out at times, but 
they do not stain. Nuclear fragments are also seen. This amorphous 
material may reach a considerable amount, and it is doubtless derived 
from the softening and disintegration of the exudate. 
The pia is thickened in places by an actual new growth of connective 
tissue. This thickening is next to the cord, and is represented by |pci of 
young and cellular connective tissue; in some of these there are already 
well developed fibres with intercellular substance. 
The nerve roots are not unaffected. Surrounding the veins are collec- 
tions of round cells and the number of cells in the perineurium of the nerve 
bundles and in the epineurium is much increased. This cellular prolifera- 
tion is sometimes so extensive that it must have offered some interference 
to the functions of the nerve by the pressure exerted. The cellular pro- 
liferation in the nerve may actually obscure the nerve fibres. The fibres 
themselves show changes similar to those already described in the acute 
case. Following the vessels as they enter the cord, a cellular prolifera- 
tion is often seen about them. 
The meninges of the brain show in general the same condition as those 
of the cord. Sections made from various parts of the base covered with 
exudate show the latter to be composed of the same elements. Where the 
exudate is thickest the amorphous layer staining deeply in hsematoxylin 
is also most pronounced. The pia is thickened by a new growth of tissue 
as well as by the exudate contained within its meshes. This new tissue 
is young, and where it occurs the pia is intimately adherent to the brain 
tissue. The vessels which pass in from the pia often show a proliferation 
of round cells in the perivascular lymph spaces, and such vessels may be 
followed for a considerable distance into the brain substance, the largest 
aggregations of these cells being seen in the neighborhood of the lateral 
ventricles. Here they reach a considerable size, are always associated 
with vessels, and are composed almost entirely of small round mono- 
nuclear cells, although a few polynuclear leucocytes may be seen among 
them. The lateral ventricles were, as previously stated, filled with pus. 
The epithelium of the ependyma is only in part preserved, and where it 
is deficient, cells with nuclei of a vesicular type forming a layer two or 
three cells thick are seen. In the pus adhering in the section to the 
ependyma, many fragmented nuclei exist. A single calcified area the 
size of a millet-seed was observed. 
Sections of the brain and cord stained by Weigert’s method showed 
fibrin to be absent. In sections the diplococci lanceolati were found, but 
only in small numbers. 
The liver shows small collections of leucocytes (polynuclear) in the 
neighborhood of the portal spaces. The spleen is congested, and hem- 18 
FLEXNER, BARKER: CEREBRO-SPINAL MENINGITIS. 
orrhages have taken place into the parenchyma. There is, in addition, 
a general hyperplasia of the lymphatic apparatus. A few “ red blood- 
corpuscle-carrying cells ” are to be seen, and many of these contain blood 
pigment as well. 
Symptomatology. 
Regarding the symptomatology, we shall content ourselves with 
giving a very brief resume of the notes taken, paying most attention to 
the symptoms most prominent in this epidemic. We shall lay especial 
stress upon certain of the clinical features (e.g., the blood examination) 
which heretofore have been insufficiently studied. The peculiar con- 
ditions which obtain in an infectious intra-cranial disease are such as to 
render the clinical picture very complex. In local infections elsewhere 
in the body (e.g., pneumonia, diphtheria) it is comparatively easy to 
separate clinically the symptoms and physical signs due to the local action 
of the infectious agent on the one hand from those dependent for their 
origin on the absorption and distant action of its toxic products. In 
diseases within the skull, however, more than anywhere else in the body, 
it is the size of the pathological new production and the quickness of its 
development which are of significance for the severity and course of the 
disease. Quincke has recently again emphasized the fact that even the 
simple serous accumulations within the skull-cavity, no matter where 
they are situated, if sufficiently extensive, may produce the most severe 
symptoms, or even cause death. 
In epidemic cerebro-spinal meningitis we have to think of the results 
which may follow, not only the more or less sudden outpouring of an exu- 
date (cortical, basal, or intra-ventricular), but also those which are 
consequent upon the direct and remote action of the toxines which are 
produced by the micro-organisms, and we have to decide whether the 
lesions in distant organs (lungs, heart, joints) are to be looked upon 
as absorption-effects or as a localization of the same organism in these 
parts, or as complicating infections due to other bacteria. As Leyden 
has pointed out, the gravity lies more often in the evil effects of the exu- 
dation on the functions of the brain than in the severity of the infection; 
if the meningitis be cortical, epileptiform convulsions endanger life; if 
there be marked exudation into the ventricles, then coma and brain 
paralysis too often ensue. 
From what we have said, and from the results of pathological exami- 
nations, the complexity of the question becomes easily evident, and an 
attempt to analyze the different disturbances in function, and to connect 
each definitely with its pathological basis would seem at first to be well 
nigh hopeless. Nevertheless, with the constant acquisition of facts and 
better methods of technique, we need not despair of finally arriving at a 
position in which we shall be able to cope more or less successfully with 
these problems. FLEXNER, BARKER: CEREBEO-SPINAL MENINGITIS. 
19 
It was possible at Lonaconing to make out most of the different types 
of the affection which have been described—fulminating, acute, subacute, 
intermittent, and abortive. The onset of the disease was, in the majority 
of the cases, sudden, the individual being attacked without warning with 
severe headache and vomiting, symptoms which were often followed in a 
few hours by delirium, stiffness and retraction of the neck, and severe 
constitutional disturbances. In only a few cases was there a definite 
recognizable prodromal stage, with general malaise, headache, and 
dragging pains in the limbs. 
Compared with other epidemics, the number of fulminating cases (cas 
Joudroyants) was large, no less than ten patients dying within forty-eight 
hours after seizure, one child indeed succumbing in eight and another 
in ten hours after the appearance of the first symptoms. In the less 
violent but still severe cases the symptoms lasted from six to fourteen 
days, when either death occurred or signs of slow improvement ensued. 
Many abortive cases were observed in which, after a sudden onset, with 
perhaps severe symptoms, the patients recovered with striking rapidity. 
Several cases of the “intermittent type” occurred during this epi- 
demic, and in these periods of comparative well-being alternated with 
marked exacerbations. The convalescence was often tedious, and the 
danger was by no means over when the acute symptoms had subsided. 
Even after there was good reason to believe that the causative bacteria 
were all dead and convalescence seemed to be established, serious symp- 
toms would reappear, which would suggest that as long as the exudate 
is not completely reabsorbed there is danger. 
The symptoms in general, we may say, presented no regularity. The 
disease is full of surprises, and the clinical phenomena of one day or hour 
may differ greatly from those of the next. 
Especially inconstant was the course of the fever, and the temperature 
charts are interesting, chiefly in that they show that no fixed type of 
pyrexia can be definitely assigned to this disease. Nor did the height 
of the fever bear any relation to the severity of the other symptoms; the 
sudden and often marked elevations and depressions of the temperature 
independent of general symptoms could be explained only by assuming 
a direct interference with the functions of the thermo-regulatory centres. 
Even the absence of pyrexia did not permit the making of a favorable 
prognosis. 
The other symptoms referable to disturbances of the central nervous 
system, the headache, the vertigo, the delirium, the paralysis of the eye- 
muscles, the deafness, the general hypersesthesia, and the twitchings 
showed almost as great irregularity as did the temperature curve. 
Among the clinical appearances noted which were due to lesions of the 
cranial nerves and their centres in the different cases may be mentioned 
anosmia, strabismus (almost always divergent), nystagmus (usually hori- 20 
FLEXNER, BARKER: CEREBRO-SPIN AL MENINGITIS. 
zontal or vertical), inequality of pupils, photophobia, ptosis, defects of 
vision, facial rigidity, trismus, slowed respiration, Cheyne-Stokes breath- 
ing, deafness and disturbances of speech. 
On account of its rarity, it is interesting to record one case in which 
we observed definite rotary nystagmus. The patient was a girl of 
seventeen, who had severe general symptoms with distinct evidence of 
a basal exudate. During a part of one day the left eyeball was rotated 
definitely in its socket, the excursions apparently corresponding to the 
limits of the movements of rotation. On reviewing the literature, we 
have been able to find reference to only one similar instance—a case 
mentioned by Jaffe. 
The intra ocular changes have been especially studied in this epidemic 
by Dr. R. L. Randolph. Out of thirty-five cases in which he examined 
the fundus, it was normal only in seven. The most frequent alteration 
was passive congestion in the retinal veins, with congestion of the optic 
disks. In several cases there was a distinct optic neuritis, and in one 
instance the central vein was thrombosed. 
The retraction of the neck was very commonly present; in some cases 
the occiput was drawn well back between the scapulae. The thighs and 
legs were frequently flexed, but extreme opisthotonos was not often seen. 
There was general hypersesthesia of the skin, and attempts to change the 
position of a patient gave rise to severe pain. In the graver cases there 
were marked twitellings of the muscles and tendons, and in some, espe- 
cially a short time before death, convulsions and coma. 
The tendon reflexes varied much, but in many cases were diminished, 
which is to be attributed, no doubt, to the extent of the interference with 
the posterior roots of the spinal nerves. 
Beyond the nervous arythmia, the respiratory organs were not mark- 
edly implicated, and it was only rarely that one met with an associated 
bronchitis or broncho-pneumonia. General cyanosis was not uncom- 
mon. A very frequent feature in the epidemic was epistaxis, a symptom 
which does not seem to have often attracted the attention of observers 
elsewhere. 
The pulse was sometimes slowed, sometimes accelerated, and often 
intermittent. Beyond the blowing systolic murmurs so frequently 
heard over the cardiac area in children in febrile affections, there were 
very few symptoms referable to the heart or pericardium. 
The lips, teeth, and tongue were covered with sordes, especially in the 
graver and more protracted cases. A few patients showed mild anginas, 
and the tonsillar crypts were not infrequently filled with white cheesy- 
looking plugs. The chief symptom pertaining to the digestive system 
was the vomiting, which, in some cases, was persistent and imtractable, 
leading to inanition and emaciation. Where the retraction of the neck 
was great there was often difficulty in swallowing; in some cases the FLEXNER, BARKER: CEREBRO —SPINAL MENINGITIS. 
21 
dysphagia appeared to be due to interference with the normal innerva- 
tion. The bowels were, as a rule, constipated, although diarrhoea occa- 
sionally occurred. Indeed, in four cases a well-marked dysentery was 
observed, the feces containing mucus, pus, and blood. Occasionally 
in a grave case there would be incontinence both of the urine and the 
feces. 
In one case of dysentery the feces were carefully examined. The 
reaction was found to be alkaline, the odor very foul, and mucus, pus, 
and blood were visible to the naked eye. A fresh specimen of the muco- 
purulent portion, examined microscopically, showed, besides the epithe- 
lium from the surface of the mucous membrane, many round cells of 
variable size, which were often fatty and vacuolated. Some of these 
were certainly polynuclear leucocytes, others resembled rather lymphoid 
cells. In the protoplasm of several cells which had the size of poly- 
nuclear leucocytes, besides large vacuoles, one could make out single 
included cells of small size. Red blood-corpuscles were also present. 
Smear cover-glass preparations, dried and stained in various ways, 
showed as the predominating organism lancet-shaped cocci in pairs, 
apparently encapsulated. In addition, there were slender bacilli, a few 
shorter, thicker bacilli (resembling B. coli communis), and short chains 
of streptococci. It must be mentioned that in the two cases which came 
to auptosy large lumbricoid worms were found in the alimentary canal, 
and, on inquiry, we learned that they had been observed in many of the 
cases, both in the vomit and in the feces. 
The spleen was at times slightly enlarged, as shown by percussion; 
the splenic dulness, however, did not pass beyond the costo-articular 
line, and in no instance was the border of this organ palpated. Ab- 
dominal retraction was not a prominent symptom on the whole. The 
only symptom referable to the liver was the occurrence of mild jaundice 
in two of the cases. 
The cutaneous changes were widely divergent. Many of the cases 
ran their course without any apparent exanthem, and if one were to be 
guided only by the majority of cases in this epidemic he would be com- 
pelled to discard the name “ spotted fever ” for the disease. Herpes was 
very common, and formed an early and important symptom. It was 
situated chiefly on the lips, nose, ears, and neck following the distribu- 
tion of the cutaneous vessels and nerves. Purpuric and petechial erup- 
tions were seen in a comparatively small proportion of the patients; one 
of the commonest forms of eruptions was an indistinct purplish mottling 
over the surface of the body, which appeared and disappeared almost 
under the eyes. 
The urine varied in amount in different cases and in different stages 
of the disease. As a rule it was concentrated, but occasionally a patient 
would pass large quantities having a low specific gravity. In the severer 22 
FLEKNER, BARKER; CEREBRO —SPIJSTAL MENINGITIS. 
cases, and especially in those running an acute course with high fever, 
slight albuminuria was common, and microscopical examination of the 
sediment showed the presence of hyaline and granular casts. Erhlich’s 
diazo-reaction was negative in every case in which it was applied. The 
reaction has, however, been present in the urine in a few instances in 
meningitis, but only according to Ehrlich in very severe cases. The 
urine contained an excess of phosphates, a point to which several ob- 
servers, notably v. Grimm, have called attention. In many cases there 
was a white precipitate of triple phosphates equal to one third or more 
of the volume of urine passed. In none of the specimens examined 
could the presence of sugar be demonstrated. 
The Joints.—Nearly twenty per cent, of the severe cases suffered 
from complicating joint affections, the knees being most frequently 
attacked, the elbows, wrist, and ankle following in frequency in the 
order named. The effusions were peri-articular as well as intra-articular, 
and the joints were swollen and reddened, resembling closely those of 
acute articular rheumatism. Indeed, there were cases which, had it 
not been for certain initial symptoms indicating a meningeal process, 
could easily have been diagnosed as nothing more than attacks of rheu- 
matism. Similar cases have been noted in other epidemics, and there 
are references in the literature which draw attention to the prevalence 
of meningitis and of rheumatism in the same community at the same 
time.1 
Speaking generally, it may be said that for this epidemic at least, 
complications in the joints occurred more frequently in the better class 
of patients, and it is interesting to note that the meningeal symptoms 
appeared to be favorably influenced by their appearance. 
Kernig, of St. Petersburg, has described a symptom which he believes 
to be pathognomonic of meningitis. In thirteen cases he observed a 
peculiar flexion-contracture (Beuge-kontrahtur) of the knee-joints which 
1 These facts are, we think, not without importance as bearing upon the etiology of acute 
rheumatism. There can be little doubt, it seems to us, although for the proof we must look to 
cultural experiments, that in the joint complications in epidemic meningitis, the articular and 
the peri-articular inflammations are due to local infections with the same bacterium which has 
set up the meningitis. Moreover, in at least one case of genuine acute rheumatism the micro- 
coccus lanceolatus has been isolated in pure culture from the joint effusion, and Foa and 
Bordoni-Uffreduzzi have been able to set up a polyarthritis in rabbits by subcutaneous inocu- 
lation of this diplococcus. The frequent association of rheumatism with endocarditis, and 
with inflammation of the pleura, pericardium, and peritoneum lend support to the view that 
at any rate in a certain proportion of the cases the pneumococcus may be the cause. Never- 
theless it is probable that acute articular rheumatism will, ere long, be proven to have no 
etiological unity, just as has already been proven for the inflammations of the serous mem- 
branes generally. It seems probable that the entrance of pyogenic organisms of different 
varieties into the circulation, under circumstances which are inconsistent with the develop- 
ment of the phenomena of a general septicaemia, may give rise to inflammations in some one 
or more of the serous membranes of the body—be it meninges, pleurae, pericardium, perito- 
neum, or joint surface, the particular ones attacked depending on certain peculiarities either 
in the virulence of the invading organism or in the lessened resistance at the moment of the 
serous membrane implicated. 23 
FLEX XE R, BARKER: CEREBRO-SPINAL MENINGITIS. 
could not be reduced when the patient was in the sitting position. In 
attempting to extend the knee, the leg could not be straightened further 
than a point where it made an angle of about 135° with the thigh, 
although when lying or standing this contracture was completely absent. 
If the patient lay on his side with the thighs drawn up the symptom was 
still present. It has been claimed that the same phenomena may be 
seen in many other conditions (old age, chronic alcoholism, etc.), but 
Kernig asserts that he has examined thousands of individuals with par- 
ticular reference to this point, and has never found this contracture 
except in cases of meningitis. Unfortunately we were not familiar with 
this suggestion when at Lonaconing, and so cannot say anything as to 
the value of “ Kernig’s symptom.” 
The Condition of the Blood.—There have been very few oppor- 
tunities for studying the blood in cases of epidemic cerebro-spinal men- 
ingitis since the more general employment of the finer methods of 
hsematological technique; and in the literature we have been able to 
find only meagre references to the subject by Halla, v. Limbeck, and 
Rieder. The two former found a leucocytosis in cases of suppurative 
meningitis, while Rieder observed two cases of epidemic cerebro-spinal 
meningitis, one having 20,100 white corpuscles, the other 17,500 to the 
cubic millimetre. We were fortunately able to examine the blood of 
several of the cases at Lonaconing, but shall include in this report only 
a few typical examples. 
In order to avoid error, every precaution was taken in these examina- 
tions. The blood in all cases was taken with the aid of a ste’rile lancet 
from the lobule of the ear, previously thoroughly cleansed with alcohol 
and ether. The blood was examined fresh in each case, care being taken 
to secure specimens which spread out into a layer of only one corpuscle 
in thickness. These were examined immediately with an oil immersion 
lens. The haemoglobin was estimated by the instrument of v. Fleischl. 
The readings were made in a dark room, with artificial light, and 
through a cylinder of paper some twelve inches in length. Moreover, 
the readings were made by two individuals, and where the results dif- 
fered at all the mean of the readings was recorded. By this method of 
control any gross error was avoided. For the enumeration of the cor- 
puscles the blood-counter of Thoma-Zeiss was employed, the methyl- 
violet solution of Toison being used as a diluting fluid. Finally cover- 
slips were prepared for drying and staining by the methods of Ehrlich. 
For this purpose particular care was taken to secure good specimens, 
and on subsequent examination all imperfect preparations were dis- 
carded. We shall epitomize the results of our examinations. ' InThe 
fresh blood slide no marked variations in size or shape of the red cor- 
puscles could be made out; in some of the cases, however, there was 
distinct pallor of the red cells. The increase in the number of the 
leucocytes was quite evident in many cases in the examination of the 
fresh drop of blood, and a greater number of white corpuscles appeared 
to be motile than one sees under normal conditions. Many of the leu- 
cocytes presented a striking vacuolation, a condition which, we believe, 24 
flexner, barker: cerebro-spinal meningitis. 
is not uncommon in the leucocytes dependent on other causes. The 
blood-platelets were present in clumps, but did not appear to be decidedly 
increased or diminished in numbers. 
As to the number of corpuscles present, the average of a number of 
counts shows that a diminution of the red cells is not a marked feature 
of the disease. In some of the advanced cases, with emaciation there 
was a moderate oligocythsemia, but in the majority of instances the full 
complement of red blood-corpuscles was present. The haemoglobin, 
however, in all cases examined was somewhat diminished in amount, so 
that the individual corpuscular holding in haemoglobin (yaleur glohu- 
laire) was below par. A well-marked leucocytosis is, we believe, a con- 
stant phenomenon in the disease during its active stages. In no case 
examined, except in convalescent patients, was it absent. The number 
of white corpuscles varied in different cases in our experience, between 
12,000 and 32,000 to the cubic millimetre. That the degree of variance 
is greater, however, there can be little doubt, and it is probable that 
further investigations will prove that still larger leucocytoses may exist, 
especially in cases of meningitis associated with complications in the 
lungs or joints. The dried specimens were fixed by heating for an hour 
and a half on a copper bar at 120° C., and then stained, some of them 
in solutions of eosin and methylene-blue, some in the triple stain of 
methylene-green, acid fuchsin and orange green. 
In none of these specimens were micro-organisms found, although they 
were patiently looked for. The “color analysis” of the leucocytes 
showed in every case the increased number of white blood-corpuscles to 
be due to an increase in the cells with neutrophilic granules and poly- 
morphous nuclei. The mononuclear cells (small and large) were rela- 
tively diminished in number. It will be seen that these changes in the 
blood are not peculiar to meningitis, but are quite in accord with the 
leucocytoses associated with suppurative inflammations, or inflammations 
accompanied by well-marked local exudation anywhere in the body. 
As examples the following four cases may be cited : 
Bessie B. (Case XVII. of Dr. Porter’s series), aged four years, always 
healthy before ; had been a bright, stout, well-nourished girl. One evening 
in the last week in Jannary felt cold and chilly, and had distinct rigor during 
the night, followed by vomiting and severe pain in the head. During first 
week she was very restless, had muscular hypersesthesia, inequality of pupils, 
rapid pulse, and uttered a sharp cry from time to time. Two purpuric spots 
appeared on buttocks. Retraction of the neck began about the eighth day. 
Up to this time the patient ate and drank well, and appeared rational. The 
mother now noted that the child could not use the right arm, and on exami- 
nation it was found rigid and swollen. Herpetic eruption appeared about 
the tenth day. 
Note dictated February 14: Child lies on left side, moderately emaciated, 
legs drawn up, thighs flexed, right arm rigid, resists movement; head 
retracted ; whole body held stiff and rigid; attempts to move the child cause 
her to cry out; face slightly mottled and has a bluish tint; lips bluish-red 
and covered with sordes ; remains of herpetiform eruption visible. Tongue 
grayish-yellow, moist coating thicker in the centre than at the edges; pupils 
even, midway between contraction and dilatation. No ocular paralyses; 
veins in forehead rather prominent; thorax symmetrical; expansion equal; 
marked pulsation in vessels of neck; resonance clear throughout front, FLEXNER, BARKER: CEREBRO —SPINAL MENINGITIS. 
25 
axillae, and back; a few whistling rhonchi heard at bases. Pulse equal at 
the two wrists, 18 to the quarter, very irregular and arrhythmical. Some- 
times there would be two or three beats of varying intensity followed by a 
pause corresponding to the time of from two to four beats; volume of pulse 
rather small. Apex beat of heart in fourth interspace 1 cm. inside the left 
nipple line. Dulness not increased; loud blowing systolic murmur heard 
over whole cardiac area, greatest intensity at the third left interspace 1 cm. 
from sternal margin. Pulmonic second sound relatively accentuated. 
Splenic dulness begins at the eighth rib and extends to the costal margin ; 
does not pass the costo-articular line. Border not palpable, possibly owing 
to rigidity of abdomen. Liver dulness begins at the seventh rib in right 
mamillary line and extends to costal margin; border not palpable. Skin 
dry, no cedema; no marked change in tendon reflexes; no lymphatic 
enlargement. 
The blood examination was made on February 14. Even in the fresh 
drop of blood the increase in the white elements could easily be made 
out. The count showed 4,448,000 red and 24,000 white blood-corpuscles ; 
haemoglobin, 72 per cent. Dried and stained preparations showed a 
marked increase in the number of polynuclear leucocytes with e-granules, 
and a relative diminution in the number of lymphocytes and large mono- 
nuclear leucocytes. 
Florence D., aged sixteen years. The onset in this case had been gradual, 
the patient having pain in the head and back for several days before any 
serious symptoms appeared. On January 29, at 1 p.m., she had a severe 
chill followed by excruciating pain in the head, causing loud shrieks and 
restlessness; this was associated with vomiting and excitement. Next day 
the patient was decidedly deaf and more or less stupid. Later she became 
delirious, and often had to be held in bed. She picked her nose from time 
to time , and had several attacks of epistaxis. Distinct purpuric eruption 
appeared on face and neck and a few spots on body. None of them were 
very bright and none of them turned yellow or green afterward. During 
part of her illness she had retention of urine and had to be catheterized. 
Her bowels were constipated. Spleen and liver not distinctly enlarged. 
The temperature never went higher than 103.5°. She had marked eye 
symptoms, including divergent squint, paralysis of accommodation, and nys- 
tagmus. On ophthalmoscopic examination there was a definite optic 
neuritis in the right eye (Dr. Randolph). The girl died at the end of the 
third week of the disease. Toward the end she was much cyanosed and 
showed well-marked Cheyne-Stokes respiration. Her urine was examined 
several times and found to contain a trace of albumin and numerous hyaline 
and granular casts. 
The blood was examined on two successive days in the third Aveek. 
As the results of the two examinations were practically the same, we 
give that made on February 15. In the fresh blood slide, the examina- 
tion of two or three fields sufficed to show that the leucocytes Avere dis- 
tinctly increased in number. The vacuolation of the leucocytes was 
especially striking in this ca§e. Haemoglobin (v. Fleischl), 45 per cent. 
Blood-count: red blood-corpuscles, 4,896,000; white blood corpuscles, 
24,500. The dried and stained specimens showed a marked relative 
increase (over 85 per cent.) in the neutrophiles Avith polymorphous 
nuclei, and a relative decrease in the different mononuclear forms. 
Several typical normoblasts seen. 
Agnes S., aged nine years, taken ill on February 7, 1893. Complaining 
of chill, severe pain in the head, and vomiting. The temperature, as will 
be seen by referring to the accompanying chart, was not high at the 26 
FLEXNEE, BARKER: CEREBRO-SPINAL MENINGITIS. 
beginning. There was severe pain in the neck and inability to move mus- 
cles of limbs on account of pain. No marked retraction of neck. She con- 
tinued with comparatively mild symptoms for some ten days when, on Feb- 
ruary 17, she had diarrhoea, cramp-like pains in the abdomen, with a little 
blood and mucus in the stools. These symptoms were relieved the next 
day, but on the 18th she suffered from extreme pain in left ear, requiring 
morphine for its relief. On the 20th it was noticed that she had no power 
in right arm and leg, and there was some incontinence of urine and feces. 
Paralysis of right side of face. On 23d temperature rose to 101.8°. Next day 
well-marked evidence of complicating bronchitis and broncho-pneumonia. 
Pulse and respiration became more rapid and temperature higher. Death 
on evening of February 25. Temperature, 105°; pulse estimated at over 200. 
Fig. 4. 
The blood examination in this case was made on February 14th. In 
the fresh blood slide the increase in the white elements was easily de- 
monstrable. Marked vacuolation of the leucocytes. Haemoglobin (von 
Fleischl) 72 per cent. Blood-count, red blood-corpuscles 5,032,000 ; 
white corpuscles 29,500. Cover-glass preparations from this case dried 
and stained in the “ triple stain,” gave the following “ differential count” 
of white elements: 
Proportions in 
normal blood. 
Per cent. Per cent. 
Small mononuclear 53 4.9 15 to 25 
Large mononuclear and transition forms . 74 6.8 4to 6 
Neutrophiles with polymorphous nuclei . 946 87.3 70 to 76 
Eosinophiles 0 0.0 1 to 5 
Myelocytes 10 1.0 
Total number counted . . . 1093 100.0 
Only one nucleated red blood-corpuscle (typical normoblast) seen in 
the whole slide. 
In making the differential counts it was thought best to adopt the 
simple classification given above rather than the more complicated one 
of Uskow. According to the suggestion of Thayer, we have made the 
counts so that the small mononuclear elements correspond to the small 
and large lymphocytes, the small transparent forms and some of the 
smaller transitional forms of Uskow; the large mononuclear and transi- 
tion forms including all other non-granulated forms, with the exception 
of transparent polynucleur leucocytes. In terms of Uskow’s classifica- 
tion the characteristic change in these leucocytoses consists of an increase FLEXNER, BARKER: CEREBRO —SPINAL MENINGITIS. 
27 
in the ripe, and especially in the over-ripe elements with a relative de- 
crease in the number of the young or unripe elements. 
The complete absence of leucocytes with eosinophilic granules did not 
hold for the other cases examined. The number of typical myelocytes 
seen in this case was rather striking, and, had the patient been an adult, 
would perhaps have been of considerable pathological significance. In 
the blood of children, however,one often sees, even under normal condi- 
tions, a variable number (nearly always, however, under 1 per cent.) of 
these cells. 
For comparison, we give the results of a differential color analysis of 
the blood taken from a woman, thirty-eight years of age, who had suffered 
from a prolonged attack of meningitis, and had a moderate leucocytosis : 
Per cent. 
Small mononuclear elements 10.9 
Large mononuclear and transition forms ...... 2.1 
Eosinophiles 0.6 
Neutrophiles with polymorphous nuclei ...... 86.4 
Myelocytes 0.0 
100.0 
Lizzie L., aged fifteen years (service of Dr. Skilling), was seen during con- 
valescence. She had suffered from a severe attack, the temperature at the 
beginning reaching nearly 105°. There had been retraction of the neck and 
delirium for some four or five days, and excessive vomiting. Abundant 
herpatic eruption on lips, cheeks, hands, and wrists, the discoloration still 
remained. Marked constipation at first. No paralysis, no joint complications, 
no tenderness below neck. Had been sitting up the day before blood exami- 
nation was made. 
In the fresh blood-slide the red corpuscles were noticed to be distinctly 
paler than normal. No apparent increase in number of white elements. 
Haemoglobin 55 per cent. Red blood-corpuscles, 5,004,000. White 
blood corpuscles, 9000. In the dried and stained specimens the different 
varieties of leucocytes were present in about normal proportions, the over- 
ripe (multinuclear) elements being still, however, slightly in excess. A 
few tyjiical normoblasts seen. This count is given in that it shows the 
disappearance of the leucocytosis with the advent of convalescence. 
2--sl .StT M i M I 
SB S .2 3ts o 8 o" R Tn §S a 
\ .s| -3 g2 § 1 ~-| 8 S “ 38s 
o | "g '33 o j p,"3 S| § g So,!- p ® So,® W. 11. Remarks. 
.2 *2 q =3 S . ®.2 
tS §> S-g. S-iS g »£, |S3 ** SS 2 
PL, < | -P 
I , 
i p. ct. 
B. B. 4 Dr. Porter 17th ... | 74 4,448,000 0.84 24,000 1 :1851 Dysentery as a com- 
i plication. 
F. D. 16 Dr. Porter 18th 101.2° I 45 4,896,000 0.47 24,600 1 ; 199 j Albumin and casts 
j in urine. 
A. S. 9 1 Dr. Porter 7th 100.5 j 72 5,032,000 0.7 29,500 1:170 
L. L. 15 Dr. Skilling ... 99.2 1 55 5,004,000 0.55 9,000 1 :556 Convalescent. 
Table. 
A word of explanation is necessary with regard to the low percentage 
of haemoglobin found in the blood of Florence D. and Lizzie L. Both 
these girls showed clinically a decided pallor of the skin and mucous mem- 28 
FLEXNER, BARKER: CEREBRO-SPINAL MENINGITIS. 
branes, although as the blood-counts show the red corpuscles were present 
in nearly normal numbers. The marked diminution in the valeur glohu- 
laire, taken with the age and sex of the patients, made us think of a pre- 
existing chlorosis, and on inquiry we learned that both had been noticed 
to be slightly pale for some months previous, and that both had com- 
plained of more or less constipation and certain menstrual irregularities. 
It is almost certain, therefore, that the low percentage of haemoglobin 
observed in these two cases was not entirely dependent upon the meningeal 
inflammation. 
And finally, in this connection, it will not be out of place, in view of 
the many interesting observations which have been made regarding the 
bearing of the presence or absence of a leucocytosis in diseases due to the 
lanceolate diplococci (acute lobar pneumonia, pneumococcus-infections 
in rabbits) upon the severity of a given infection and upon the prognosis, 
to state that, in the fatal cases which we have had the opportunity of 
examining during life the presence of a leucocytosis was always de- 
monstrable. While for confirmation of this point it will be necessary to 
study many more cases in future epidemics, yet the evidence, as far as it 
goes, is in favor of the view which we have already mentioned, that death 
in cerebro-spinal meningitis results from the local intra-cranial mischief, 
rather than from the infection per se. 
The death-rate at Louaconing corresponded to that of an epidemic of 
moderate severity, about 40 per cent, of the cases (excluding those classed 
as abortive) proving fatal. Hirsch, in his monograph, states that out of 
15,632 cases 37 per cent. died. v. Ziemssen placed the mortality of mild 
epidemics at 20 per cent., and of the severest epidemics at 70 per cent. 
Pathogenesis. 
The disease, then, being known to be due, at least in the majority of 
instances, to the action of a specific micro-organism, viz., the micrococcus 
lanceolatus, we have next to consider by what mode the infectious agent 
gains entrance to the body, and more particularly into the meninges of 
the brain and cord, and in what way, if at all, it is thrown off. Again 
we have to inquire whether, if it can be thrown off, it will ever fab-an be 
in a condition to infect other individuals. 
Unfortunately a wholly satisfactory answer cannot at this time be given 
to these questions. We are not yet in possession of sufficient data based 
on a close study of the epidemiology and bacteriology of the disease, to 
enable us to more than indicate the probable mode of infection and the 
conditions which predispose to the origin and propagation of the disease. 
The simultaneous prevalence of other infectious diseases in the locali- 
ties in which epidemic cerebro-spinal meningitis existed, has been held to 
be of some significance. The occurrence of pneumonia at such times 
must be regarded as of special importance, for, as we have said, the same 
infectious agent is the cause of both diseases, and in the epidemic of FLEINER, BARKER; CEREBRO-SPINA L MENINGITIS. 
29 
cerebro-spinal meningitis studied by Foa and Bordoni-Uffreduzzi the 
most of the cases were complicated by pneumonia. Epidemic parotitis 
has been noted as occurring in a community in connection with or just 
before the outbreak of this disease. Parotitis was epidemic at Lonaconing 
at the time of the prevalence of meningitis, and we may remark that 
there are in the literature references which go to show that the micro- 
coccus lanceolatus may be the cause of this disease also. 
Again, other infectious diseases, scarlet fever, measles, typhoid fever, 
influenza, and coryza, have been mentioned by different writers as con- 
comitant epidemics. 
While in pneumonia, and probably a certain number of cases of paro- 
titis and coryza, the same organism as that found in meningitis is known 
to occur, yet in the other infectious diseases mentioned, the infectious 
agent, so far at least as is known at present, is in none of them the mi- 
crococcus lanceolatus. Moreover, it is to be remembered that meningitis 
does not attack by preference those suffering or just recovering from 
other infectious diseases, if we exclude pneumonia. These diseases occur 
as concomitants or as precursors only. 
Hence it is clear that in the search for predisposing factors we must 
look further than the infectious diseases with which epidemic meningitis 
may coexist. And it is not improbable that we shall find that, although 
one disease does not depend upon the other for its development, yet the 
same conditions of life which permit one to flourish may also engender 
the other. 
It has been suggested by Striimpell that there may be some relation 
between coryza and epidemic meningitis. This, he thinks probable, on 
account of the observations of Weigert, that in some cases of the disease 
there is a purulent inflammation of the nasal sinuses. Weichselbaum 
found in some of his cases of meningitis purulent inflammation of the 
nasal and sphenoidal sinuses and the middle ear, and in all these he 
demonstrated diplococci. One must, we think, hesitate before accepting 
it as even highly probable that the majority of cases originate in this 
way. On the other hand, a sharp line of distinction must be drawn 
between those cases which are definitely primary and those which are 
secondary. There are, undoubtedly, cases in which there has been an 
extension of disease in the middle ear to the meninges, and why should 
not the same thing happen in diseases of the nasal sinuses? Such cases 
may simulate the sporadic form of the disease. But what is necessary is 
to see whether or not cases associated with diseases of the middle ear and 
thtise of the nasal mucous membrane occur in such numbers during an 
epidemic as to make this mode of origin the probable one in all. In the 
acute case in which we performed an autopsy no disease of the nasal 
sinuses existed. 
With our present knowledge it seems more probable that we have to 30 
FLEXNEE, BARKER; CEREBRO-SPINAL MENINGITIS. 
do with an infection by the way of the blood current rather than by con- 
tinuity from the nose or ear. The common occurrence of meningitis in 
pneumonia indicates the possibility as well as the frequency of this mode 
of infection. In those cases in which pneumonia does not occur, other 
sources of entrance for the infectious agent must be sought; and to this 
category belongs especially the epidemic form. In any consideration of 
this subject at the present time, infection from the nasal1 and oral cavi- 
ties, in the latter case by lymphatic communication, as suggested by 
Ortmann, is a possibility which cannot safely be rejected. Nevertheless, 
the writers have been led to believe that the intestinal tract may be re- 
garded as the way of entrance into the blood-current, if not in all, at 
least in many of the cases. 
In two of the cases which we observed clinically, and which afterward 
proved fatal, there was dysentery. Cultures and cover-slip preparations 
were made from the evacuations of one of these, and the predominating 
organism present was the micrococcus lanceolatus. In both of the cases 
which came to autopsy there was enteritis. And in other epidemics the 
occurrence of dysentery has been noted. Yet constipation as a feature 
of the disease is of more common occurrence than diarrhoea. This may 
be considered at first as militating against the conception of the intestinal 
tract as the place of entrance into the body of the infectious agent. But 
it is perfectly conceivable that the organisms may enter through the in- 
testinal canal without first producing a demonstrable lesion therein, and 
find in the meninges of the central nervous system a locus minoris 
resistentice. The case of meningitis, as reported by Ortmann as due to 
the micrococcus lanceolatus secondary to typhoid fever is important as 
indicating the possibility of entrance from the intestine. Here, however, 
undoubted lesions of the mucous membrane were present. 
Owing to the slight vitality of the organism in acid media, and as the 
intestine must become invaded after the infectious material has first passed 
through the stomach, it is necessary to draw attention to one point that 
may be of significance. Whether in all the persons attacked there is an 
alteration in the gastric juice by which its acidity is either diminished 
or altogether abolished, we cannot say, as we were unable to obtain the 
contents of the st miach from a number of cases. But in the vomit ob- 
tained from one child sick of the disease, free hydrochloric acid was 
demonstrated to be absent. Still, were this not the rule, there are periods 
in health during the fasting hours, when the stomach is free, or nearly 
so, from acid contents. In this connection the observations of Ewald are 
full of interest. He found that when water was introduced into the 
stomach a small amount passed immediately into the intestine; after 
about an hour the rest went suddenly over into the duodenum, and this 
1 The lymphatics of the mucous membrane of the nose can he injected from the sub- 
arachnoidal lymph space (Schwalbe, Key. and Retzius.) FLEXNER,BARKER: CEREBRO-SPINAL MENINGITIS. 
31 
part had no acid reaction, so that any bacteria present were not subjected 
to the harmful influence of an acid medium. Fliigge has recently 
emphasized this point when dealing with the method of spread of cholera 
through drinking-water. In our disease the diplococci are of course not 
necessarily in the water imbibed, but in the process of swallowing it is 
easy to understand how they could be washed from the mouth and throat 
(their constant habitat), and so gain entrance to the stomach, and finally 
to the intestines uninjured. 
The importance of considering the intestine as a probable infection- 
atrium in epidemic cerebro spinal meningitis becomes evident when it is 
remembered that about 80 per cent., and according to some authors 
(Kruse and Pansini) 100 per cent., of all persons in health carry about 
constantly in their mouths the micrococus lanceolatus, and according to 
Ketter, in 20 per cent, of these the organisms possess sufficient virulence 
to kill animals when injected into them. This fact removes the necessity 
of searching for the infectious agent outside the body, in, for example, 
the soil or the water. 
Most writers on the subject now agree that the disease is not contagious, 
but is rather of “ miasmatic ” origin. The localization of the infectious 
agent in the closed cavity of the central nervous system certainly does 
not favor the infection of the surroundings. Still in some epidemics, 
that in Hamburg for example, the disease was known to appear in a 
locality in which it previously existed, but from which it had disap- 
peared ; and the interval of time which had elapsed was in some instances 
considerable. These facts would seem at first to be irreconcilable with 
the view that there is no infection of locality. We have shown that an 
organism possessing the and morphological properties of the mi- 
crococcus lanceolatus is thrown off with the dejections in some cases of 
cerebro-spinal meningitis, and as indicated by the experiments of Bor- 
doni-Uffreduzzi, Guarnieri, Netter, Patella, Nikiforoff, Sirenayand Alessi, 
and Kruse and Pansini, the organisms may retain their vitality and even 
virulence when dried in sputum, blood, etc., sometimes for four months. 
Hence we are not at this time justified in excluding the possibility of the 
infection of locality. This assumption seems, however, in view of the wide 
distribution of the organism in nature, to be hardly necessary. It is, we 
think, more probable, that the local conditions which enabled the first 
cases to appear, persisting, other susceptible individuals are attacked, so 
that fresh cases appear in the site of the previous ones, in fact that we 
have to do with a “ predisposition of community ” rather than an “ infec- 
tion of locality.” 
If we are then to believe that the disease is, in the majority of instances, 
the result of an auto-infection, and this would be equally true whether 
we conceive it to be due to the entrance of the bacteria from the nose or 
pharynx or from the intestinal canal, it still remains for us to determine  FLEXNER, BARKER; CEEEBRO-SPIKAL MENINGITIS. 
the nature of the unusual conditions which render the system vulnerable 
to the invasion of the micro-organism, and what it is that brings about 
the localization by preference of the morbid process in the cerebro-spinal 
meninges. 
When excluding air, water, soil and food, as carriers of the infectious 
agent, we by no means intend to deny that they may play an important 
role in the causation of the disease. And concerning Lonaconing, the 
local conditions are such as would naturally produce a lessening of the 
powers of resistance of a number of individuals, and thus render them, 
although apparently in good health, susceptible to the disease. While 
in this epidemic, as we have already said, the more prosperous classes 
were by no means exempt, it was chiefly the poor that suffered, and the 
disease prevailed particularly in localities in which the houses were close 
together, and in which overcrowding existed, with the attendant evils of 
unsanitary arrangements, improper and insufficient food, and unclean 
bedding and clothing. 
Nevertheless, although the facts pointed to a predisposition of the 
whole community outside the merely personal predisposition, in the end 
the resistance of the tissues of each individual must necessarily be of 
prime importance in determining infection or immunity. 
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