NEONATAL
MENINGITIS
A
Clinical
and
Pathological
Study
of
29
Cases
Peter H. Berman, M.D., and Betty Q. Banker, M.D.
Department of Pathology, Cleveland Metropolitan General Hos-pital and Western Reserve University, School of Medicine, Cleveland, and the Department of Pathology, Children’s Hospital Medical Center
and Department of Neuropathology, Harvard Medical School, Boston
(Submitted November 5, 1965; accepted for publication January 8, 1966.)
This work was supported in part by a research grant from the Muscular Dystrophy Associations of
America.
P.H.B. was Special Fellow in Pediatric Neurology (BT 595), National Institute of Neurological Diseases
and Blindness. PRESENT ADDRESS: Department of Neurology, New York University, School of Medicine,
550 First Ave., New York, New York.
B.Q.B. is Career Research Development Awardee, National Institute of Neurological Diseases and
Blindness. ADDRESS: Cleveland Metropolitan General Hospital, 3395 Scranton Road, Cleveland 9, Ohio.
ARTICLES
6
PEDIATRICS, Vol. 38, No. 1, July 1966
P
URULENT MENINGITIS is considered tobe an infrequent disease in the
new-born infant.1’2 Cruickshank noted that
acute meningitis accounted for less than
5% of 800 consecutive neonatal deaths in
a large
maternity
hospital.3 According toGroover and co-workers4 the incidence of
meningitis is 0.13 cases per 1,000 full-term
births and 2.24 cases per 1,000 premature births. Smith, however, who analyzed 409 cases of meningitis in infants and children,
recognized the relative frequency of this
disease in the newborn; he also
empha-sized that meningitis had its onset more
frequently in the first month of life than
in any subsequent 30 day period.5 Sherer’s
description6 of three fatal cases of B. coli meningitis, published in 1895, was the first dealing exclusively with this disease in
the neonate. The first account of neonatal
meningitis in this country was given by
Hinsdale.7 The mother of his case had a
purulent endometritis at term, and gram-negative colon bacilli were isolated from the infant’s spinal fluid. Since that time,
the literature has consisted predominantly
of reports of single cases and small series
which primarily have dealt with the
clin-ical and bacteriological findings peculiar to
the
neonate.8-’4 In 1943 Flemsborgwas
able to collect only 150 cases from the
lit-erature.15 In more recent years, several
reports have reflected the large experience gained in single institutions.1’2’ 16-19 These
studies have stressed a number of distinc-tive features of meningitis in the newborn
period, namely, that the symptoms and signs of meningeal irritation may be ab-sent, that gram-negative intestinal organ-isms are the most frequent etiologic agents,
and that, despite antibiotic therapy, the mortality rate remains high. None of these reports has considered the pathology of neonatal meningitis in any detail. The
pur-pose of this paper, therefore, is to describe the neuropathological features of menin-gitis in the neonate and to correlate these features with the clinical and
bacteriologi-cal findings. Several factors that may be related to the continued high mortality rate of this disease in the newborn infant
will be discussed.
This study is based on a review of the clinical records of all infants who devel-oped a meningitis in the first month of life during the years 1958 to 1962 at the
Chil-dren’s Hospital Medical Center in Boston
and 1963 to 1965 at the Cleveland Metro-politan General Hospital. Included were
and decreased sugar content, (2)
pleocy-tosis and decreased sugar, (3) bacteria and decreased sugar. In addition, all infants with pathological evidence of a purulent
meningitis in the neonatal period were in-eluded in this study, even though the cere-brospinal fluid had not been adequately
studied during life or had been reported
as normal. Many cases were eliminated
because a review of the clinical and patho-logical data failed to corroborate the clini-cal diagnosis of bacterial meningitis. In many of these cases, it appeared that vary-ing amounts of subarachnoid hemorrhage had resulted in a mild leukocytic pleocy-tosis in the spinal fluid; the sugar was
nor-mal and the cultures sterile.
From a review of these case records and pathological material, 36 infants were con-sidered to have developed a purulent men-ingitis during the first 28 days of life.
Seven of the 36 patients were excluded from this study, since the meningitis was
a direct consequence of a central nervous system anomaly. In 25 of the remaining 29 patients postmortem examinations were made, the results of which will be
pre-sented in detail.
CLINICAL DATA
The clinical findings are summarized in
Tables I, II, and III, and only some of the salient features will be mentioned here. Twenty-two of the 29 infants (76%) were male. Ten infants (including one set of
twins) were of low birth weight (under
2,500
gm). Definite perinatal infections oc-curved in 12 mothers. Infection of the uri-nary tract was most frequent and there were single instances of purulent endo-metritis, furunculosis of the vulva, pustular facial acne, and finger infection. In one case, following Caesarean section, theab-dominal wound became infected. In 7 of the 12 infected mothers, a bacteriological diagnosis was established, and in 5 of these the offending organism proved to be identical with that isolated from the in-fant’s cerebrospinal fluid. In another case a direct relationship probably existed
be-tween
the mother with vaginal furunculo-sis and her infant with staphylococcalmeningitis. In addition, four mothers had unexplained fever during the perinatal period. Thus, 16 of the 28 pregnancies were associated with definite or probable
maternal infections during the perinatal period. Premature rupture of the fetal membranes had occurred in seven in-stances.
Infections other than those of the
cen-tral nervous system had occurred in nine
infants before the diagnosis of meningitis became apparent.
Seven infants were apneic upon delivery with Apgar scores at 1 minute of 6 or less. Although they required active
resuscita-tion, spontaneous breathing occurred within several minutes and improvement in color, tone, and reflex activity were noted before their transfer from the delivery room.
An impairment of the infants’ reactions
to stimuli, and particularly irritability, were the most frequent abnormalities.
Characteristically these were of short dur-ation, lasting 24 hours or less, and were followed by lethargy. In others, the initial
manifestation of illness was excessive lethargy. Feeding difficulties and respira-tory distress were frequently encountered
throughout the course of the disease and
convulsions occurred in the majority of the
infants.
The signs of meningitis usually seen in
older age groups were relatively infre-quent in the neonate. A tense fontanelle was reported in only five infants. Eleven patients were observed to have opistho-tonus or a stiff neck. Fever was the pre-senting symptom in only 10 infants and was recorded in the course of the illness in 10 others. Some infants were actually hypothermic through much of the illness.
In the majority of the infants, symptoms
developed during the first week of life and
the course of the disease was fulminant,
complica-r.
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TABLE III
BACTERIA CULTURED FROM THE
CEREBROSPINAL FLUID
tions following repeated ventriculo-atrial shunt procedures for hydrocephalus, and a fourth died at 23 months of age during
carotid arteriography, performed for the investigation of a persistent seizure
dis-order. The only survivor is developing normally at the age of 20 months.
Three patients (Cases 15, 20, and 22) were of particular interest since their men-ingitis was probably masked by the
admin-istration of antibiotics for other infections.
One patient had an E. coli septicemia on
the first day of life. Penicillin, Colistin and Chloramphenicol were administered for 2 weeks. On the fifteenth day of life there was a sudden onset of fever and convul-sions. A lumbar puncture established the
diagnosis of E. coli meningitis. Death oc-curved on the following day. Postmortem examination disclosed a subacute menin-gitis, more than 1 week in duration. The second patient developed marked
respira-tory distress shortly after birth and a chest film revealed a left lower lobe pneumonia.
After antibiotic therapy was instituted, the respiratory difficulties subsided. During the following 5 weeks the infant thrived
and appeared normal, and he was
circum-TABLE II
ETIOLOGIC ASSOCIATION BETWEEN INFECTION OF THE MOTHER AND HER INFANT
Case
,
?%umber
.
Maternal Infection
Organi..m I8Olated From Mother
From CSFof Infant
21 Endometritis Pseudomonas Pseudomonas
‘p. ep.
4 Urinary tract infection F. coil F. coil
8 Urinary tract infection F. coil E. coil
11 Urinary tract infection E. coil E. coil
7 Urinary tract infection E. roil F. coil
19 Urinary tract infection E. coil Paracolon
22 Urinary tract infection A. aerogenes E. coii
28 Urinary tract infection x Listeria
15 Infected wound x A. aerogenes
16 Pustular acne x Staphyincoccua
aurevs
9 Furunde (vulva) x
Streptococcus-Beta hem.
24 “Finger infection” x Unknown
S Perinatal Fever x Paracolon
2 Perinatal Fever x Paracolon
25 Perinatal Fever x E. coil
23 Perinatal Fever x F. coii
20 Perinatal Fever x Paracolon
Gram-Negative Intestinal
.
Bacteria Number
Total
Number
E. coli 11
A. aerogenes 5
Paracolon sp. 4
B. proteus 2
Pseudomonas sp. 2
924
Others
Listeria monocytogenes 1
Staph. aureus 92
Streptococcus (beta hernolytic) 1
Unknown 1
5
cised prior to anticipated discharge from the hospital. Two days later fever
devel-oped, at which time the spinal fluid con-tamed six monocytes and 75 mg/100 ml
protein. Two days later, after a second elevation of temperature, there were 1,300
leukocytes (66% were mononuclear cells), the protein was 430 mg/100 ml and the
sugar 16 mg/100 ml. He died on the fol-lowing day. The neuropathological changes were those of a smoldering chronic men-ingitis with a superimposed acute purulent
reaction. Antibiotics were given intermit-tently to the third infant during his 68 days of life for recurrent E. coli pyelonephritis and septicemia. The spinal fluid was not
examined until the twenty-ninth day, at which time it was clear and sterile,
con-taming only 1 granulocyte. The protein content was 136 mg/100 ml. The spinal fluid remained sterile and the protein ac-tually fell to 68 mg/100 ml. Postmortem
examination disclosed a severe chronic meningitis with marked thickening of the subarachnoid space over the cerebral hem-ispheres, brain stem, and spinal cord. Bac-teria were demonstrated in smears of the exudate. Although the presence of a
12 NEONATAL MENINGITIS
In all, 21 infants succumbed to the initial
illness, 3 had a subacute meningitis, 4 died
from neurological sequelae, and only 1
survived without apparent neurological
deficit.
The treatment consisted primarily of the
administration of antibiotics as soon as the
infection was discovered. Although these
infants were not treated according to a
standard plan, combinations of two or
more parenterally administered drugs in
dosages recently recommended as
opti-ma120’2’ were utilized in each case. In two
infants spinal fluid cultures were
persist-enfly positive despite the fact that the
of-fending organism initially showed in vitro
sensitivity to at least one of the drugs em-ployed. In two infants, intraventricular injections of polymyxin B complimented the use of other drugs with remarkably
favorable results.
Cultures of the spinal fluid established
the etiologic diagnosis in 28 cases. In two of these, the responsible organism was iso-lated only from cultures made postmortem.
Gram-negative intestinal organisms were most frequent (Table III).
PATHOLOGICAL FINDINGS
Postmortem examinations were
per-formed in 25 infants (Table I). The brain
and spinal cord were examined in the fresh
state and again after 10 to 14 days of
fixation in 10% formalin. Coronal sections
of the brain were examined after fixation. Celloidin and paraffin sections were stained with hematoxylin and eosin, cresyl violet,
phosphotungstic acid-hematoxylin, peri-odic acid Schiff, and for bacteria by the gram stain. Other viscera were examined
in the usual manner.
General Pathological Findings
Infectious foci outside of the central
nervous system were found in 17 of the 25 infants. The widest dissemination of these
foci occurred in the two infants with
gram-positive infection (Cases 16 and 9). In the
former, foci were found in the lungs, pleura, heart, liver, peritoneum, and
kid-neys. In Case 9, there were microabscesses in the lungs, as well as purulent arthritis, peritonitis, and an inflammation of the
um-bilical stump. In the infants with gram-negative infections, infectious foci outside the central nervous system occurred in 15 of the 22 cases, but frequently only a single organ system was involved. Pneumonia
occurred in eight infants. In five of these there was a history of aspiration shortly
before death; cultures at autopsy showed mixed flora and the distribution of the
in-flammatory process in the lungs also
sug-gested that aspiration had occurred. Otitis media was present in three infants and in one an infected cephalohematoma overlay
a parietal skull fracture. Spread of the infection to the meninges by way of emis-sary veins could not be demonstrated in these four cases. Postmortem cultures of the urine, ears, peritoneum, and pleura in
the infants with pyelonephritis, otitis, peri-tonitis, and pleural effusions revealed or-ganisms that were identified with those isolated from the cerebrospinal fluid.
Neuropathological Findings
There was no instance of subdural ef-fusion. The subarachnoid inflammatory
exudate was obvious in every case and varied from dull yellow to gray-green in
color. The exudate was predominant at
the base of the brain in 11 patients, over the convexity in 5, and evenly distributed
in 9. In general, the exudate was more
marked over the cerebral hemispheres than around the spinal cord. Over the convexity
of the brain, the infiltrate was prominent within the depths of the fissures and sulci
and tended to hug the pial and subarach-noid vessels. In the acute stage of the
dis-ease the underlying brain was swollen and hyperemic, and the lateral ventricles were often small. However, herniation of
cere-bral or cerebellar tissue was not demon-strated. Hydrocephalus occurred in 14 of
the 25 cases, and, although the degree of
four patients the lateral and third ventri-cles were enlarged, the fourth ventricle
being normal. In each of these cases, the aqueduct was partially or completely oc-cluded by either purulent exudate in the acute instances, or gliosis in the more chronic ones. Obstruction of the foramina
of Lushka accounted for hydrocephalus in a fifth case. The ventricular enlargement in nine other infants was communicating
in type, and presumably due either to in-terference with a flow of the cerebrospinal fluid through the basal cisterns or to failure
of adequate absorption from the
subarach-Fic. 2. A collection of polymorphonuclear cells is adherent to an intact ventricular wall. In the sub-ependymal zone there is a glial reaction within the
nests of developing cells. H and E stain, 200x.
noid space around the brain stem and over
the cerebral hemispheres.
The microscopic findings were similar from case to case. Variation occurred only
in the chronicity and severity of the lesions.
THE INFLAMMATORY RESPONSE: In the
first week of the disease (acute stage) the polymorphonuclear leukocytes were the predominant cells in the subarach-noid and ventricular exudate (Fig. 1 and 2). Histiocytes comprised from 5% to 25% of the cells and were most consnicuous Fic. 1. The meningitis is acute. In layer 1 of cortex, .
the microglia are increased in number. H and E near the pal surface. Strands of fibrin
14 NEONATAL MENINGITIS
the bacteria were prominent in a
perivas-cular distribution. Occasional clusters of bacteria were present within the brain sub-stance adjacent to the pia or ependymal surfaces, but only in areas where there had
been an interruption of the surface lining.
In the second and third week (subacute stage) the proportion of
polymorphonu-clear leukocytes in the exudate decreased gradually from about 75 to 25% of the cell
population. At the same time, mononuclear cells, consisting mainly of histiocytes and macrophages, increased in number.
Lymph-ocytes never comprised more than 5 to 10% of the total exudate. Plasma cells were
only rarely seen. Organization of the exu-date into layers began during the last few
days of the first week (Fig. 5). The poly-morphonuclear leukocytes were
aggre-gated next to the arachnoid membrane. More centrally there were collections of
degenerating polymorphonuclear cells,
ccl-.
F:c. 3. Within the fronds of the choroid plexus, as well as within the ventricular fluid, there is an
acute inflammatory reaction. H and E stain, 250 x.
S
a thin inconspicuous meshwork. A similar
purulent exudate was evident along the ependymal surfaces of the ventricles, and was most prominent in the stroma of the
choroid plexus (Fig. 3). Frequently, the lumen of the aqueduct of Sylvius was
ap-preciably narrowed by the purulent exu-date. The lateral recesses of the fourth
ventricle were similarly involved.
..
..In the majority of patients bacteria
could be seen in the subarachnoid space Fic. 4. Bacterial aggregates are frequently sen
as well as within polymorphonuclear leu- within the subarachnoid space. H and E stain,
ARTICLES
lular debris and dense fibrin strands.
Col-lections of macrophages and histiocytes, as
well as the occasional lymphocytes, were
located near the pia and ependyma (Fig.
6). In the early stages of organization of the
subarachnoid exudate, fibrin, fibroblasts, and collagen emerged as radiating strands
from the adventitia of medium-sized blood
vessels. In the ventricular exudate, fibro-blastic activity was absent. However, in
areas where the ependyma had been
de-nuded, glial tufts frequently projected into
the exudate from the subependymal tissue
and the fragments of interrupted epen-dyma formed rosettes among the glial
fibers (Fig. 7). Intra and extra cellular
bac-teria were still conspicuous. As many as 15 to 30 bacteria could be identified within
a single macrophage.
After 3 weeks (chronic stage), the
exu-Fic. 5. Organization has occurred within the
menin-geal exudate. Mononuclear cells layer next to the
pia and the polvmorphs collect toward the
arach-noid. H and li stain, 200x.
Fic. 6. There is organization within the ventricular
exudate. The mononuclear cells are adjacent to the
ependyma. H and E stain, 400x.
date in both the subarachnoid space and
the ventricles was considerably less pro-nounced. A major portion of the cellular population was now composed of mono-nuclear cells. Polymorphonuclear
leuko-cytes accounted for less than 10% of the cells and many of them were poorl\’ stained and showed varying degrees of karyorrhexis. The number of histiocytes and macrophages were also diminished,
16
NEONATAL MENINGITISof glial tissue projected into the ventricu-lar lumen in areas where the ependyma
had been denuded. Glial bridges narrowed and partitioned the aqueduct of Sylvius (Fig. 8) and in the floor of the fourth
ven-tricle they obliterated the rhomboid fossa. Neither intracellular nor extracellular bac-teria could be identffied at this stage of the
disease.
THE BLOOD VESSEL CHANGES: Character-istically the cerebral blood vessels showed phlebitis and arteritis. In this series every
case but one showed varying degrees of
F:c. 7. Small foci of denuded ependyma have
re-sulted in the herniation of glial tufts into the
aque-duct. H and E stain, 150x.
numerous; this may not have been an
ab-solute increase, but only a reflection of the
decrease in the other cellular elements.
Much of the debris had been cleared away.
In some areas indications of layering of
an earlier phase remained but more
char-acteristically the pia-arachnoid was
thick-ened by an excess of fine fibrous
trabecu-lations with relatively few rather widely
dispersed clusters of inflammatory cells.
Thick collagenous strands radiated from
the thickened adventitia of meningeal
blood vessels. The underlying pial surface
was intact. Remaining patches of the
ven-tricular exudate showed changes in the
character of the cell population similar to
those in the subarachnoid exudate.
How-ever, organization of the ventricular
exu-date was not as prominent, and fibrous Fic. 8. Glial bridges have narrowed and partially
tissue replacement was confined to the occluded the aqueduct. Phosphotungstic acid
these changes (Fig. 9 and 10). Infiltrations of inflammatory cells were most evident in
the medium and small veins that traversed the subarachnoid space, but the
subepen-dymal veins were also affected. Character-istically, the phlebitis, though present in
the early stages of the disease, was most prominent in the second and third weeks.
In the more chronic cases, thickening of
the vessel wall was conspicious.
The arteritis consisted of an infiltration of the adventitia by inflammatory cells; the smooth muscle fibers of the media and
the intima usually were spared. The small arteries within the subarachnoid space
Fic. 10. There are inflammatory cells within the
adventitia of this small artery, as well as within
the intima. H and E stain, 300x.
were predominantly affected. Arteritis was most prominent in the subacute phase of
the disease. An involvement of all three layers of the vessel wall was observed in only two cases, and in these it was focal in nature. In later stages, proliferating
con-nective tissue radiated from the adventitia of both arteries and veins into the inflam-matory exudate.
Thrombophlebitis with occlusion of the
veins occurred in the subependymal zones in five cases. In two others, cortical throm-bophiebitis was associated with gross cere-bral infarction; in both of these infants, a hemiplegia had been noted clincally.
THE PARENCHYMAL CHANGES: These were
of three types: a glial reaction in areas
di-rectly subjacent to the inflammatory
exu-Fic. 9. Inflammatory cells are prominent within the date, a diffuse encephalopathy, and
18 NEONATAL MENINGITIS
changes described. In the molecular layer
of the cerebral and cerebellar hemispheres
and in the marginal white matter of the
brain stem and spinal cord, a diffuse
pro-liferation of pleomorphic microgliacytes had occurred by the middle of the first week and was most intense during the second and third week of illness. No
re-lationship could be discerned between the
severity of the meningeal exudate and the
degree of microglial proliferation. Neither
macrophages nor bacteria were
conspicu-ous in the zones of microglial activation. Astrocytic glial fibers were prominent in these same areas.
In the subependymal zones the intensity of the glial reaction increased with the duration of the illness. As a rule, only a patchy loss of ventricular ependymal lining
was present early in the disease; but, by
the middle of the first week, a diffuse
sub-ependymal astrocytic and microglial
pro-liferation occurred. Tufts of glial tissue
projected into the ventricular lumen and
subependymal rosettes of ependymal cells
appeared in the adjacent tissue. As the disease evolved the gliosis became more intense.
The ependymal lining of the aqueduct and fourth ventricle was similarly affected.
Where ependymal cells were lost, tufts of
glial fibrils herniated through the opening
(Fig. 7). Rosettes of denuded ependyma
were conspicuously embedded in the glial
scars. Bridges of glial fibrils formed across the aqueduct as well as the lateral walls
and ventral sleeves of the fourth ventricle.
These glial bridges resulted in a
narrow-ing of these lumens and, in one case, in a
complete obstruction of the aqueduct
(Fig. 8).
A varying degree of affection of the
cerebral cortex was present in all the cases.
A diffuse encephalopathy, characterized in
the early stages by karyorrhexis and loss of nerve cells, was more evident in the lower layers of the cerebral cortex, in
Sommer’s sector of the hippocampus and
less frequently in the basal ganglia,
thala-mus, and the dentate nuclei. In the more chronic stages, the neuronal loss was ac-companied by a mild proliferation of the protoplasmic astrocytes. Capillary
endo-thelial hyperplasia was prominent in these zones. These diffuse changes probably had a metabolic basis and could not be
at-tributed to the direct effects of inflamma-tory infiltrates within cerebral tissue or to bacterial invasion.
RADICULOPATHY: The roots of cranial and
spinal nerves, as they passed through the
subarachnoid space, were frequently
in-filtrated by inflammatory cells. Focal areas of degeneration were occasionally evident. These changes were most pronounced dur-ing the second and third week of illness. The most severe involvement occurred in the mesencephalic subarachnoid space and
affected the third to eighth cranial nerves.
ARACHNOIDITIS: Fibrosis was conspicuous
in the subarachnoid space in the chronic stage of the disease. Fibroblasts as well as collagen extended from the adventitia
of medium-sized arteries. Bridges of con-nective tissue extended to the arachnoid.
The arachnoid.bs was most marked in Cases 20 and 22 in which dense
collagen-ous connective tissue occluded large areas
of subarachnoid space around the brain stem as well as over the cerebral
hemi-spheres.
DISCUSSION
Obstetrical abnormalities in the third trimester occur frequently in the mothers
of infants who develop meningitis in the first weeks of,life.2’3’161#{176} Premature birth, prolonged labor, premature rupture of the fetal membranes, and maternal infections have been cited as common predisposing factors. However, the importance of pen-natal maternal infections has not been sufficiently emphasized. Ziai and Haggerty2
found maternal infections in 12% of their cases of neonatal meningitis, hut made no
ARTICLES
instances in 45 infants. In our experience, maternal infection was probably the most significant factor in the pathogenesis of
the meningitis. Proven infection occurred in 12 mothers, and, if the 4 mothers with
sustained peninatal fever are added, 57% of mothers had infectious complications. Furthermore, in the mothers in whom a bacteriologic diagnosis was made, the or-ganism was almost invariably the same as that derived from their infant’s spinal fluid.
Similar observations have been made by Keitel, et al.’2 who isolated organisms from the cervix of asymptomatic mothers at term which were identical with those
subse-quently cultured from the spinal fluid of
infants with meningitis. These data clearly
indicate that the mother is an important source of infection for the infant. Support-ing this view is the finding that there is an
increased incidence of infection in infants
who are horn to mothers with infections of the urinary tract at the time of delivery.2i
The discrepancy between our data and others2’ 18 may be explained by the fact that in seven of our cases no mention of
maternal infection appeared in the infant’s
record. It was not until the mother’s record was reviewed that the presence of infec-tion became apparent. Had our clinical data been derived from the infant’s records, the incidence of maternal infection would
have been only 18%. Further studies are
necessary to determine whether cultures
taken routinely from the cervix during la-bor would enhance the determination of the etiology of an infection which may subsequently develop in the infant.
Deter-mination of the sensitivity to antibiotics of organisms recovered in this way may prove to be important in the treatment of such infants.
The fact that 76% of the infants in our
series were boys is consistent with the observations of Washburn, Medearis, and Childs24 who demonstrated an increased incidence of bacterial meningitis in males
of all ages, but mostly among newborn infants. These authors postulate that the
preponderance of cases in males is due to a gene locus on the x chromosome which
is involved with the synthesis of
immuno-globulins.
The most impressive clinical feature of our cases, and one which has been repeat-edly noted by other authors” 2. 4. 1619 was the non-specific nature of the early symp-toms and signs of neonatal meningitis. Hyperirnitability, lethargy, feeding
diffi-culty, respiratory distress, and fever are
frequent manifestations of systemic illness in the young infant and certainly not the
symptoms that one ordinarily associates
with meningitis. Although neurological
signs of meningeal irritation and increased
intracranial pressure occurred in two-thirds of our cases, these signs invariably appeared
late in the course of the illness and fre-quently after the diagnosis of meningitis
had been established from the examination
of the cerebrospinal fluid.
In view of the nonspecific nature of the
early symptoms of neonatal meningitis, the
examination of the spinal fluid is crucial in establishing the diagnosis. It cannot be overemphasized that lumbar puncture
should be performed before any antibiotics
are administered in cases of neonatal
sep-ticemia. This problem was clearly pointed
out by two examples (Cases 15 and 22) in our series. In both of these infants the spinal fluid examinations were normal,
despite the fact that the presence of
men-ingitis was suspected clinically and proved
pathologically. In both, also, antibiotics
had been given for another infection, in
doses that served only to mask and alter the clinical features of the meningitis. In another instance (Case 20), it appears that the injudicious use of antibiotics sup-pressed the meningeal infection, which later flared up and proved fatal.
20 NEONATAL MENINGITIS
are small and difficult to locate. In
addi-lion, the brain of the neonate is extremely
soft and injury to it may leave large zones of destruction.
The predilection of the newborn infant to infection by gram-negative intestinal
organisms has been well 2
16-19, 25-27 In the pre-antibiotic era, coliform organisms were the causative agents in only 30% of the instances of neonatal
septi-cemia;28 but, since the widespread use of antibiotics, the percentage of cases with
gram-negative intestinal septicemia has
in-26 A similar situation exists in
meningitis of the newborn. In 1943
Flems-borg noted that 53% of the bacteriologically proven cases were due to the coliform group.15 More recently, studies by others2’
3,17-19 have reported an incidence as high
as 88%. In the present series coliform
or-ganisms accounted for the meningeal
in-fection in 85% of the infants. Of these, as
in the previously mentioned series, E. coli
was the single most frequent etiologic
agent. The predisposition of the neonate to coliform meningitis is further demon-strated by the fact that 62% of all instances
of E. coli meningitis occur in infants under 3 months of age.27’28 The particular
sus-ceptibility of the neonate to systemic in-fection by usually saprophytic coliform bacteria has yet to be adequately
ex-plained. Although distinct “pathogenic” strains of E. coli have been isolated from newborn infants suffering from diarrhea, organisms found in systemic infection are not of these strains. Flemsborg’5 has sug-gested that the natural isolation of the newborn makes him less prone to infection by the pathogens affecting other age
groups; others have postulated that the in-creased susceptibility is due to the new-horns’ reduced capacity to resist infection. Recent experiments have shown that
ag-glutination antibodies to the coliform bac-teria appear in the 19-S macroglobulin fraction of the serum proteins which are not transmitted across the placental mem-branes.29-3’ However, the capacity to man-ufacture macroglobulins is present in the
first week of life.31 Furthermore, since all
infants acquire a flora of coliform bacteria
within the first few days of life and most tolerate this without incident, some other factor must be responsible for the preva-lence of these organisms as infectious agents in the newborn.
Data collected by Watson indicate that
coliform infections tend to become symp-tomatic within the first 2 weeks of life, whereas a later onset of symptoms is more
frequently found in cases of gram-positive infections.’8 Others have corroborated these
19 However, the observations of Dupont and Thamdrupl7 indicate that an early onset of symptoms occurs more
fre-quently in premature infants, but that the
type of organism has little importance in
this respect. In our cases, the symptoms had their onset during the first week of life in 55% of these infants, and 79% were ill by the end of the second week. The
differences in time of onset could not be
attributed to the infective agent. It must
be clearly understood, however, that the onset of clinical symptoms did not neces-sarily indicate the actual time of infection. This was evident from an analysis of the pathological material. Thus, of the seven cases in which the meningeal cellular exu-date appeared to be 2 to 3 weeks old, five had been symptomatic for 4 days or less.
In general, the duration of illness as de-termined by histopathological criteria cor-related more closely with the age of the infant than with the duration of clinical symptoms, indicating that in most cases
the onset of meningeal infection occurred
near the time of birth.
Once the infection became clinically
ap-parent, its course was characteristically fulminant in 16 cases; death occurred within 4 days frcm the onset of symptoms. The administration of antibiotics did little to influence the course or outcome of the
in-fection, except in the two cases in which the spinal fluid became sterile promptly after
the intraventricular injections of polymyxin B. The mortality from neonatal meningitis
the reported 1619 These studies give no indication of the length of time the
infants were followed and how many suc-cumbed to the sequelae of meningitis, which were present in 63 to 85% of the survivors. In our series, in addition to the
only survivor, four other infants seemed to recover from the acute manifestations of their disease only to succumb later to complications which were a direct
con-sequence of their initial illness.
Previous references to the pathological
features of purulent meningitis in the
neonate consists mainly of infrequent and
brief case 610 The postmortem
investigation of the present series (25 infants who succumbed after illnesses of varying duration) were particularly helpful in understanding the temporal sequence of
the pathological changes. In cases of similar duration, the nature of the lesions differed only in degree, and, in general, different organisms evoked a similar pathological
reaction. From our observations, the histo-pathologic features of purulent meningitis in the neonate are qualitatively similar to those in older age groups. Nevertheless, several points of difference are worth
not-ing. The cerebral swelling did not lead to herniation in any of the cases in this study.
This finding undoubtedly results from the newborn’s ability to relieve intracranial
pressure by widening the cranial sutures. The prompt appearance of a pronounced exudate of polymorphonuclear leukocytes
in the subarachnoid and ventricular spaces supported the contention of Eitzman and Smith that the newborn infant is able to marshal an effective inflammatory re-sponse.32 Although the predominant cell in the acute reaction was the granulocyte, mononuclear cells resembling histiocytes
and occasional macrophages were also seen. Several studies have indicated that phagocytosis is not as effective in the pre-mature and full-term newborn infant as it is later in life.33’34 The invariable
identi-fication of organisms within granulocytes and macrophages whenever extracellular bacteria could be demonstrated indicated
that phagocytosis had occurred. Although the presence of phagocytosis could
con-sistently be demonstrated, we had no way
of measuring its effectiveness. The fact that macrophages contained many times more the number of organisms than the
poly-morphonuclear leukocytes did not neces-sarily mean that they were more efficient in combating the infection.
The changing character of the meningeal
exudate and its ultimate resolution and or-ganization were, in most respects, quite similar to the evolution of the inflammatory process in older age 3637 The
spar-sity of the plasma cell and lymphocyte was,
however, a particular attribute of the me-ningeal reaction in the neonate. This
de-ficiency was most obvious during the second and third week of illness, a time when the plasma cells and lymphocytes are a pro-minent feature of the exudate in older children and adults.37 A similar deficiency
and delay in the change from granulocytes to mononuclear cells occurred in the new-born subjected to minor sterile abrasions of the skin.’ The delay in the appearance of these cells in the meningeal exudate
ap-peared, therefore, to be a consequence of a generalized alteration of the newborn’s inflammatory rcsponses rather than a
pe-culiarity of the blood-spinal fluid barrier. The deficiency of lymphocytes and plasma cells may impair the infant’s ability to com-bat a meningeal infection, since these cells have a significant role in the elaboration of
specific antibody.8’9
Phlebitis and arteritis were the most common vascular lesions associated with the meningeal reaction in the neonate. These changes were quite similar to those
described in purulent meningitis affecting older children and adults.36’37”o Phlebitis
and arteritis represented extensions of the meningeal and subependymal inflammation to walls of blood vessels. The frequent
oc-currence of thrombophlebitis is readily ex-plained by the fact that the entire venous
22 NEONATAL MENINGITIS
neurologic deficits were observed, cortical
infarcts associated with venous occlusions
were usually found.
That a diffuse encephalopathy may
ac-company meningitis and result in severe
cortical changes has been emphasized
pre-vi6742 The earliest descriptions
of the parenchymal lesions, consisting of
nerve cell loss in the deep layers of the cerebral cortex, appeared in the monograph of Thomas.41 Wertham42 attributed the neuronal changes to a disturbance of the local circulation due to inflammatory
in-volvement of the blood vessels and Hassin6 described similar changes which he
at-tributed to the stagnation of metabolic
waste products. Others have considered a
toxic etiology.37 We have been impressed
by the widespread degeneration of cerebral cortical neurones, most evident in the lower layers of the cortex, but have found these lesions difficult to differentiate from those of anoxic encephalopathy. Considering the
high incidence of respiratory difficulties in these infants, some degree of anoxic
dam-age might be expected. Furthermore, sev-eral infants showed the typical lesions of periventricular leukomalacia, indicative of neonatal anoxic encephalopathy. It is
difficult, therefore, to be certain of the role of anoxia or some other metabolic distur-bance associated with meningitis in the pathogenesis of the diffuse encephalopathy.
Hydrocephalus is a frequent sequel of meningitis in the neonatal period and is readily explained by the pathological
changes. The destruction of the ependyma allows glia to project into the lumen and to bridge and obstruct crucial areas such as
the foramina of Luschka and the aqueduct
of Sylvius (non-communicating
hydro-cephalus). Chronic meningeal fibrosis (arachnoiditis) results in the obliteration of the subarachnoid space (communicating hydrocephalus). The loss of cerebral
corti-cal tissue and the secondary white matter degeneration, which characterize the en-cephalopathy of meningitis, results in a distension of the ventricles without
ob-struction to spinal fluid flow (hydrocephalus ex vacuo).
Hydrocephalus, encephalopathy, and
in-farction of cerebral tissue (the common
sequelae of neonatal meningitis) are pre-cisely the complications that were so
fre-quently observed in the preantibiotic era in the survivors of meningitis in older patients. In the neonate, treatment with
antibiotics is usually delayed, and often
the best that can be expected are varying
degrees of arrest of the meningeal infection, allowing the development of the charac-teristic sequelae.
SUMMARY
The case histories of 29 infants in whom purulent meningitis developed during the first month of life were reviewed. There was a high incidence of maternal perinatal in-fections, and identical organisms were fre-quently isolated from both the mother and offspring. Gram-negative intestinal organ-isms were the most frequent etiologic
agents. Because signs suggesting meningeal and nervous system involvement developed only late in the course of the illness, the diagnosis was frequently not made until the spinal fluid was examined. The course
of the illness was usually fulminant; death occurred within 4 days from the onset of symptoms in the majority of infants. Of the five infants who recovered from the menin-gitis, four died from neurologic complica-tions within a few months.
Postmortem examinations were per-formed on 25 infants. Although the inflam-matory reaction was essentially limited to the spinal fluid pathways and their con-tents, a wide-spread, at times devastating, non-infectious encephalopathy occurred in
every case.
those in the more mature individuals, ex-cept for the sparsity of lymphocytes in the subacute stage of the meningeal reaction, the prominence of bacteria in the me-ningeal exudate long after appropriate
anti-biotics have been employed, and the high frequency of sequelae in the survivors. The sparsity and delay in appearance of lym-phocytes and plasma cells in the inflamma-tory response may be an important factor in the inadequate defense of the newborn to
this infection.
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