ENTEROVIRAL
MENINGITIS
IN VERY
YOUNG
INFANTS
Alan G. Nogen, M.D., and Martha L. Lepow, M.D.
From the Department of Pediatrics, Cleveland Metropolitan General Hospital, and
Wertern Reserve University School of Medicine, Cleveland, Ohio
(Submitted March 20; revision accepted May 24, 1967.)
This investigation was supported in part by Public Health Service Research Grant Number 5 RO1
A105770, from the National Institute of Allergy and Infectious Diseases.
ADDRESS FOR REPRINTS: Department of Pediatrics, Cleveland Metropolitan General Hospital, 3395
Scranton Road, Cleveland, Ohio 44109.
PEDIATRICS, Vol. 40, No. 4, Part I, October 1967
T
lIE syn(lrome of enteroviral meningitishas rarely been recognized in infants
less than 6 weeks of age. Most published
reports of enteroviral disease in this age
group have described severe systemic
ill-ness involving multiple organ systems and
frequently culminating in death.
This report describes five cases of
entero-viral meningitis in young infants with
isola-tion of virus from cerebrospinal fluid
(CSF ). Four of the patients were treated at
the Cleveland Metropolitan General
Hos-pital (CMGH) during the period from Au-gust through October 1966. A fifth case
oc-curred iii 196:3 at the Babies and Childrens
Hospital, Cleveland, Ohio, and was studied
by one of the authors (MLL). The
experi-ence with suspected enteroviral meningitis
in infants less than 6 weeks of age at
CMCH during the 10-year period from
1956 to 1966 will be reviewed.
MATERIALS
AND
METHODS
Collection of Specimens
The specimens obtained for viral studies
included throat and rectal swabs
(
whichwere placed in 2 ml of neutral Hank’s solu-tion with 0.5% bovine serum albumin, pen-icillin 1,000 units/ml and streptomycin 10
&g/m1), CSF, and acute and convalescent
sera. All specimens for virus isolation were
processed within 12 to 24 hours and
inocu-lated into tissue cultures.
Viral Studies
Examinations for enterovirus in stool,
throat, and CSF were performed in monkey
kidney and HEP-2 cells, according to the
previously described standard methods
em-plowed by the virus laboratory of CMGH.’
Viruses were identified by neutralization in
tissue culture, using specific hperimmune
monkey antisera produced in this
labora-tory.
Serologic Tests
Neutralizing antibody titers were
deter-mined in sul)jects sera as follows : mixtures
of twofold dilutions of serum and 100 TCD,#{176} of the virus isolated from
pa-tients’ cerebrospinal fluids were inoculated
into stationary cultures of African green
monkey kidney tissue. The highest dilution
of seruii preventing cytopathic effect was
considered to represent the actual titer and results are ex1)ressed as the reciprocal of the serum dilution.
CASE REPORTS
Patient 1
A 3,540 gm, white male vas born at University
Hospitals of Cleveland to a 29-year-old multipara
in August 1963 following an uncomplicated
preg-nancy. A few (lays prior to the mother’s
confine-nient two children at home were noted to have
“flu-like” illnesses with fevers of 39#{176}Cand
respira-tory and gastrointestinal symptoms. The infant
appeared normal at birth, but at 5 days of age
he was noted to be febrile (38.4#{176}C), anorectic,
lethargic, and mildly jaundiced (bilirubin + 7.9
mg/100 ml). Because of the possibility of bacterial
infection the infant was given 80 mg of
strepto-mvcin and 100,000 units of aqueous procaine
peni-cillin intramuscularl and transferred from the
obstetrical division to the pediatric service.
Pulse was 170 and the respiratory rate was 60.
The fontanelle was soft, but otherwise the 1)hySical
examination was normal. CSF examination revealed
#{176}TCD, is that dilution of virus which will
cause cytopathic effect in 50% of the inoculated
618
23 cells, 5 of which were polymorphonuclear
leukocytes, 12 were mononuclear cells, and 6 were
red blood cells. The protein was 71 mg/i#{174} ml
and the glucose was 53 mg/100 ml. Twenty-four
hours later the CSF cell count had risen to 129
cells, of which 25 were red blood cells, 98 were
mononuclear, and 6 were polymorphonuclear
leu-kocytes; the protein content was 71 mg/100 ml,
and glucose was 51 mg/100 ml. Treatment was
begun with 150,000 units of penicillin and 100
mg/kg of chioramphenicol intramuscularly every
12 hours for 4 days. Except for three short apneic
spells on the second day, the infant improved,
became afebrile, and was discharged on the fifth
day. Bacterial cultures of blood, throat, urine, and
CSF were negative.
Urine examination for cytomegalic inclusion
bodies was negative; x-ray films of the skull re-vealed no intracranial calcifications. Viral cultures
of the stool and throat were negative; Coxsackie
virus Group B, Type 3 was isolated from the CSF.
The baby’s development has been entirely normal
since discharge.
Patient 2
This 14-day-old, Negro male, the product of
a normal pregnancy and delivery, was delivered
of a 24-year-old multipara on August 11, 1966.
The infant was in good health until 2 days prior
to admission when a pustule, which drained the
following day, appeared on the left groin. At this
time the infant became increasingly irritable,
trem-ulous, anorectic, and warm. These symptoms
per-sisted and he was admitted to the hospital with
the diagnosis of suspected bacterial meningitis. There was no family illness.
The temperature on admission was 38.2#{176}C
(rectally), pulse was 180, and the respiratory rate
was 34. Examination of the left groin revealed a
2 x 2 cm lesion, which was no longer draining
pus. The infant was alert and tremulous, and he
was found to have bilateral sustained clonus of
both lower extremities and increased muscle tone.
The Moro, tonic neck, walking, and sucking
re-flexes were all normal.
The white blood count was 22,700, of which
40% were polymorphonuclear leukocytes, 1% were
bands, 47% were lymphocytes, and 12% were
mono-cytes; the hematocrit was 43%. Urinalysis and
x-ray films of the chest were negative. Admission
electrolyte values, including calcium and glucose,
were normal. The CSF obtained at time of
admis-sion revealed 20 red blood cells and 2,450 white
blood cells (of which 89% were mononuclear), a
protein content of 112 mg/100 ml, and glucose
of 43 mg!100 ml (blood glucose 72 mg/100 ml).
No organisms were seen on Gram’s stain. Because
of the possibility of bacterial meningitis, the child
was treated with methicilhin (200 mg/kg/day
in-travenously), colistin sulfate (10 mg/kg/day
intra-muscularly), and chloramphenicol (50 mg/kg/day).
Anticonvulsants were added because of the extreme
tremulousness. A repeat lumbar puncture 24 hours
after admission was traumatic, but the CSF was
again cultured for both bacteria and viruses. By
the second day after admission the tremulousness
had decreased. A third cerebrospinal fluid
exam-ination 4 days after admission revealed 240 white
blood cells, of which 99% were mononuclear; the
protein was 1 18 mg/100 ml, and glucose was 40
mg/100 ml. A final lumbar puncture on the
eigh-teenth day of hospitalization revealed 62 cells, of
which 61 were mononuclear. The clinical status of the infant remained stable during hospitalization.
Blood, throat, urine, and CSF cultures were
consistently negative for bacteria. Culture of the
skin lesion yielded proteus and Staphylococcus
aureus.
Coxsackie virus Group B, Type 5 was isolated
from the first and second CSF samples and the
stool specimen.
Patient 3
This Negro male was born at CMCH on July
15, 1966, to a 19-year-old primipara who had not
had any prenatal care. Two minutes prior to
delivery the fetal heart rate was 80, but the infant
was considered to be normal at birth.
He did well until 6 weeks of age when he was
brought to the hospital with a 1-day history of
irritability, fever, and a single, loose, yellow stool.
There was no other illness in the family.
On admission, the temperature was 38.5#{176}C
(rectally), pulse was 140, and respiratory rate was
52. Physical examination was normal except for
otitis media of the right ear and a diaper rash.
White blood count was 9,670 with a normal
dif-ferential; urinalysis and x-ray examination of the
chest were negative. Cerebrospinal fluid findings
revealed 35 white blood cells, of which 27 were
mononuclear and 8 were polymorphonuclear
leu-kocytes. Protein and glucose determinations were
not done. A second lumbar puncture was done 2
hours later; CSF examination revealed 42 cells
with a protein content of 35 mg/100 ml and
glucose of 62 mg/100 ml.
The infant was treated with sulfisoxazole for
the otitis media. Bacterial cultures of blood, stool,
and CSF were negative. He became afebrile on
the third hospital day and was discharged
asymp-tomatic on the fifth day.
ECHO virus Type 9 was isolated from the CSF
and rectal swab of this patient.
Patient 4
This 6-week-old, Negro male was born August
4, 1966, to a 21-year-old multipara following a
full-term, uncomplicated pregnancy; he weighed
the child developed a fine, erythematous, papular
rash over the arms and upper trunk which lasted
5 days. On the day before hospitalization the
in-fant’s temperature rose to 40#{176}C(rectally).
He was admitted to the hospital in September
with a temperature of 39.5#{176}C(rectally). The pulse
was 168, and respiratory rate was 66. Except for
somewhat increased tremulousness, the physical
examination was within normal limits. White blood
cell count was 13,350 with 86% lymphocytes. X-ray
film of the chest, urinalysis, and an intermediate
strength tuberculin skin test were negative. The
initial lumbar puncture at the time of admission
was slightly traumatic and examination of the CSF
revealed 437 white blood cells (all of which were
mononuclear), a protein of 63 mg/100 ml, and a
glucose of 44 mg/100 ml. A repeat lumbar
punc-ture was done 2 days later and the CSF contained
19 mononuclear cells, 15 red blood cells, protein
of 65 mg/100 ml, and a glucose of 54 mg/100 ml.
The child became afebrile within 24 hours after
admission and made an uneventful recovery.
Cul-tures of stool, blood, urine, and CSF were negative
for bacteria.
Coxsackie virus Group B, Type 5 was isolated
from the rectal swab and CSF specimen.
Patient 5
A 3,560 gm Negro, male was born in September
1966. He was the product of a normal pregnancy
and delivery and was well until 4 weeks of age
when he evidenced a non-specific erythematous
papular rash on the face and scalp. A week later he
was brought to the hospital because of fever and
ir-ritability for one day. The temperature was 38.9#{176}C
(rectally), pulse was 140, and respiratory rate was
40. Physical examination was entirely normal
ex-cept for the rash noted about the face and scalp.
White blood cell count was 15,000 with a normal differential; urinalysis and x-ray film of the chest were normal.
CSF examination revealed 440 white blood cells,
of which 96% were mononuclear and 4% were
polymorphonuclear leukocytes. Spinal fluid protein
was 48 mg/100 ml, and the glucose was 70 mg/
100 ml. The child was treated for 2 days with
methicillin (200 mg/kg intravenously) and received
2 doses of kanamycin (30 mg and 15 mg
intra-muscularly).
Bacteriologic cultures of stool, throat, blood, and
cerebrospinal fluid were negative, and
chemother-apy was discontinued. He became afebrile on the
third day of illness and was discharged
asymptom-atic on the fifth day of hospitalization. Coxsackie
virus, Group B, Type 5, was isolated from the
rectal and throat swabs and the CSF.
Three days after discharge a very fine,
papu-lovesicular eruption appeared on the chest and
back. Viral cultures obtained from these lesions
were negative.
CLINICAL FEATURES
During the 10-year period from 1956 to 1966 there have been at least 12 suspected cases of enteroviral meningitis in infants less than 6 weeks of age at CMGH. In eight of these babies the diagnosis has been made by exclusion of bacterial processes,
and recognizable viral lesions, since no
vi-ruses were isolated. In four of the patients
whose case histories are described in this
report, the diagnosis has been firmly estab-lished by the isolation of an enterovirus from the CSF. An additional case has been included of an infant hospitalized at an-other institution in Cleveland from whom Coxsackie, Group B, Type 3 was recovered in the CSF.
Description of the Patients
The age at onset of the syndrome varied
from 5 days to 6 weeks of age, but half of these infants became ill between the fourth to sixth week. As is the case with bacterial infections in the newborn, the male sex pre-dominated
(
10 males to 3 females).
All but one of the patients were Negro, which reflects the major population treated atCMGH. Birth weights varied from 2,340 gm to 3,720 gm. Those infants from whom enterovirus was recovered from the CSF were ill during the months of September or October.
Signs and Symptoms
Unexplained fever and irritability were often the only abnormal findings, as shown
iiiTable I.
Twelve patients were febrile with tem-peratures ranging from 38.2#{176}C to 39.5#{176}C
(rectally) ; 2 of the 12 had temperatures of 39#{176}C
(
rectally)
or greater. Of the 13 casesstudied, 10 were noted to be irritable while
two were lethargic. Irritability in two was accompanied by tremulousness present during sleep.
The most common gastrointestinal symp-toms were anorexia and vomiting. Anorexia
was present in three of the infants while
620
not diarrhea. Five infants manifested skin
lesions. The face and trunk of one infant
had small pustules which were sterile on
bacterial cultures, while another had pe-techiae on the forearms. Three patients
had non-specific, erythematous,
maculo-papular rashes on the face and trunk. Neurologic evaluation performed on
ad-mission to the hospital was described as
within normal limits in eight of the cases.
Five infants were noted to have
exaggerat-ed s’Ioro and deep tendon reflexes, and one
of these
(
Patient 2)
was noted to have in-creased muscle tone in both lowerextremi-ties with tremulousness. No abnormalities
of head circumference were noted. The
an-tenor fontanelle was normal in 12 infants.
Because of the difficulty in assessing
neuro-logical impairment at this age, long-term
follow-up is necessary. The longest follow-up in a child with a virus recovered from the CSF has been 3 years.
Laboratory Data
The white blood cell count was variable, but in most infants it was either normal or
increased. The most important diagnostic
procedure was an examination of the CSF. Lumbar puncturesf were performed on
all patients the day of admission. In some
cases a repeat examination of the CSF was
made several hours after admission
(
TableII
)
. Over half of the infants had from 10 to250 cells/mm in the CSF, and only one
child had more than 1,000 cells/mm’. Gen-erahly, the cell count returned to normal
values before the CSF protein.
The differential cell count of the CSF
re-vealed that none of these infants had less
than 25 mononuclear cells; the majority had over 50% mononuclear cells.
Protein levels in the spinal fluid were
ob-f A standard pediatric text lists up to 10
mono-nuclear cell/mm3 and a protein up to 120 mg/lOO
cc as normal.2 A spinal fluid glucose of 40 mg/100
ml or one-half of the blood glucose was considered
normal. Recognizing the variability of opinions,’
the foregoing criteria were utilized (except in the
premature infant in whom a CSF protein may be
up to 200 mg/100 ml until 1 week of age).’
tamed in 11 patients and 10 of these were within normal limits. In two additional
pa-tients the Pandy testy indicated a 2+ value.
In one of the patients the sPinal tap was traumatic.
None of the spinal fluid glucose
deter-minations performed on 10 patients was
less than 40 mg/100 ml. In six infants the
glucose was between 40 mg/100 ml and 60 mg/100 ml. In four additional neonates a five-tube reduction test, utilizing
Ben-edict’s qualitative solution, was performed.
In three instances there was reduction in four tubes; in one, three tubes showed re-duction.
VIRAL
STUDIES
Virus Isolation
Of the 13 infants studied, the CSF was received for viral culture from 10 and an enterovirus was isolated from 5, as is shown in Table III. Seven stool specimens were examined and an enterovirus was isolated from five. Seven pharyngeal swabs were
tested for virus, but only two positive
cul-hires were obtained. ECHO virus, Type 9 was isolated from the rectal swab and CSF sample of Patient 3, and Coxsackie virus Group B, Type 5 was isolated from both the CSF and stool in Patients 2, 4, and 5. Coxsackie virus Group B, Type 3 was iso-hated only from the CSF of Patient 1, but throat and rectal swabs were negative.
Serologic Studies
In an effort to determine whether any
in-fants with virus in the CSF were infected in
utero, blood specimens were obtained from mother and infant
(
Table III ).Unfortu-nately, all the sera were not obtained early
in the course of illness. Since enteroviral infection is usually followed by an immu-nologic response, previous maternal infec-tion could be documented by the presence of neutralizing antibodies in the sera and
recent infection in mothers or infants by a
TABLE I
Pinsicti. Fisis IN 3 YOUNG INFANTS
. . ?Stnnber of
Findings
I alien/s
Sign
Fever U
38-38.5#{176}C 4
38.6-39#{176}C 6
over 39#{176}C
Irrital)ility 10
Lethargy
Anorexia S
Vomiting
Rash* 3
‘seurolo)gi( Examination
Normal 8
‘Freniulousiiess 3
Nuehal rigidity 1
Increased muscle tone 1
Exaggerated deep tendon reflexes
Exaggerated Moro response 3
* Included is a transient rash 7 days prior to
adniis-sion.
mother had low or absent antibody titers at
tIlC time of onset of illness in the infant, she
might have experienced infection (luring childhood with a decline of antibody below detectable levels, or she might be
undergo-ing concurrent infection. A second serum
sample, obtained from the mother several weeks later, could provide an answer to the
(lue5ti0I of recent infection. If the mother
had a low antibody titer at delivery, then
the infant would be susceptible to infection
at birth and would presumably have
ac-1uirel his infection either from his mother at the time of delivery or from the family contact at home. No serologic studies were performed on Patient 1. Patient 2 and his mother had antibody levels of 64 or greater to Coxsackie virus Group B, Type 5 in all sera tested, so that the time of onset of in-fection could not be determined. No acute serum samples were obtained from either the mother or the baby. Patient 5
demon-strated similar features. Patient 3 showed a
rise from less than 4 to 8 against ECHO
virus Type 9 during that period, indicating
an infant susceptible at birth who probably acquired his disease in the household. Pa-tient 4 and his mother were apparently
both infected simultaneously during a
family outbreak and both developed a
significant antibody titer to Coxsackie virus
Group B, Type 5 within 2 weeks after the
onset of illness. Rectal swabs obtained from
other family members at the time the infant
was admitted to the hospital yielded the same enterovirus.
COMMENT
Five young infants with enteroviral
men-ingitis, proven by virus isolation from the
CSF, and eight additional infants suspected
of having this disease have been described.
It is apparent from the findings in these
pa-tients that signs of meningeal irritation are
frequently lacking and symptoms are
non-specific. More frequently the diagnosis of enteroviral meningitis is made by exclusion of a bacterial etiology. It is quite likely that enteroviral meningitis occurs much more
frequently in infants less than 6 weeks of
age than has been previously appreciated.
A summary of some of the recent reports
of enteroviral disease with central nervous
system involvement in neonatal infants is shown in Table IV. Many Coxsackie and
ECHO viruses have been incriminated, in-chiding Coxsackie Types A-4,5 A-16,
B-i-5,10-22 and ECHO Types 7,23.s 9. and
15.1 1The majority of the reports emphasize
fatal illnesses. It is quite evident that in some fatal cases widespread pathologic changes occur. The findings in the brain include petechial hemorrhage in white matter,12 I)erivascular infiltrate,10 lympho-histiocytic arachnoiditis,hs and focal non-inflammatory necrosis of cerebral white matter.13 Other investigators have de-scribed grey matter lesions.11 Occasional-ly, infants have died showing little histolog-ic evidence of inflammation, but virus has been present in many organs.5’
Patient Age at Onset W1?(’/mm3
%
Mononuclear1 5da 7 70
! 14 (III t,4.5() 89
S 6wk 35 78
4 6wk 437 100
5 4 wk 440 96
(; 18 (lit 13 .55
7 6 uk ‘306 80
S ‘34 wk 99 37
9 6wk 2I 67
11) 4 uk 720
11 10 dii 75 55
U 6wk 60 40
13 6wk 750 85
* Paucly test (lone.
t Benedict’s reducing solution used.
% Poly-morjihonuciear
Protein
(mg/100 iii!) (iiil/ /(1() iii!)
30 71 .53
U IU 43
U 35 6
0 63 44
4 48 70
45 37
0 - 4/St
63 5 43
33 40 61
74 So 4/St
45 +* 3/St
60 4/St
15 172 56
622
and ECHO 9 have previously been
re-covered in the CSF of young infants with only mild illness.’27
The infant may be infected in utero, from his mother during or after birth, or by family contact. Several investigators30’31 have reported in utero enteroviral infections with Group B Coxsackie virus. In these cases the infants became ill between the second and third day of life with fever and succumbed in congestive failure from 3
days to 1 week later. The importance of the
mother as an environmental contact has been emphasized previously.1 Coxsackie Group B, Type 2 was isolated from the CSF of a 1-week-old infant who manifested a meningoencephalitis at postmortem ex-amination and whose mother developed pleurodynia four days postpartum.
In Patients 2 and 5 antibody titers to the infecting virus in all sera tested from both mother and infant were greater than 64,
and it was not possible to establish if in
utero infection occurred. Serologic studies
in Patients 3 and 4 indicated that the moth-ers lacked antibodies at delivery and that their infants probably acquired their infec-tions from members of the household. Fecal samples obtained from other members of
the family of Patient 4 were found to con-tam Coxsackie virus Group B, Type 5, but none of these persons was symptomatic. No sera were available from the first patient or his mother, but it might be speculated that
the baby acquired the virus from the
mother.
The presence of maternally acquired an-tibody in the infant’s serum at birth does not always assure his protection.32 It is quite possible that the titer of antibody, passively acquired, may determine whether or not active infection can take place. It has certainly been well documented with vac-cine strains of pohioviruses that low levels of circulating, neutralizing antibody, pas-sively acquired, will not prevent intestinal infection.’ Although usually maternal and cord blood antibody titers are comparable, in a few cases neutralizing antibodies to Coxsackie viruses have been found in
ma-temal serum without being present in the cord blood.3 It is important to note that the neonatal infants in the present series, as well as those of others,21,2731 demonstrated immunologic competence with the develop-ment of neutralizing antibodies following enteroviral infections.
Previous investigators have stressed the
TABLE II
.1ge at
Sno/eel
Onset
I’iral (‘ul/i,re
Stool Throat (‘SF
Day Sera
Sample Neutralizing
f)btained 1ntibody
(After Titer*
Onset)
Patient I 4 dii
Patient t 14 dii
Mother ‘2
Patient 3 6 uk
Mother 3
Patient 4 6 wk
Mother 4
Sibling 4
Father 4
Patient 5 4 uk
Mother 5
(-)
Coxsaekie Group
B, TypeS
NT
EChO Type 9
Coxsackie Group
B, TypeS
Coxsackie Group
B, Type S
(‘oxsackie Group
B, Type 5
Coxsackie Group
B, Type 5
Coxsackie Group
B, Type 5
NT
(-)
NT
NT
NT
(‘oxsackie Group
B, TypeS
Coxsackie Group
B, Type 5
(-)
(-)
NT
(‘oxsackie Group
B, Type 3
(‘oxsackie Group
B, Type 5
NT
EChO ‘l’ype 9
Coxsackie Group
B, Type 5
Coxsackie Group
B, Type 5
NT
NTt
64 or > 64 or >
64 or >
64 or >
<4 8
<4
<4
<4 64 or>
<4
16
64 or > 64 or >
64 or >
64 or >
38
16 38
4 33
21 33
1 14
1
14
7 39
7
39
* Expressed as reciprocal of the serum dilution.
t Not tested.
TABLE III
Viuocooic AND SEROLOGIC FINDINGS IN FIvE PATIENTS WIT!! ENTEROVIRUSES IN CEREBROSPINAL Fiuin AND SOME FAMILY MEMBERS
ubiquity of enteroviruses and the
impor-tance of family spread.35’3#{176} Seasonal varia-tion is important, since enteroviral infec-tions are most prevalent from August 15 to October 15 in the Northern United States. The five infants whose CSF samples yield-ed an enterovirus were
ill
during these months.The presence of enteroviruses in the feces only in patients with non-bacterial
meningitis must be interpreted cautiously,
since up to 10% of normal infants may har-bor such viruses at various times of the year.37 Isolation of virus directly from the cerebrospinal fluids is far more significant.
TABLE IV
REI’ORTED CASES OF \OUNG INFANT ENTEROVIRUS
1)ISEcSE ASSOCIATED VITI1 CENTRAL NERVOUS
SYSTEM INVOLl’EMENT
Oirotip
A A
B
B
B B
B 624
Serolype 1801(itiOfl Reference1 ReportedYear AgeChildof
(ozoackie
4 Brain 8 1961 18 da
16 Heart.
intestine 9 1963 7 wk
I Brain 13 1963 9 du
(‘SF 11 1960 1 mo
3 Brain l 1936 9do
4 Brain 1961 ?
3 CSF l 1961 tinder I mo
ECho
CSF t)
7 CSF !
9 Brain 5
9 CSF 7
11 Stool 6
15 CSF 11
1960
19&1
1964
1966 1964
1960
1mo
I mo
lOda
6 do
Sda 6 wk
Group B, Type 5 had been isolated from many patients with non-bacterial meningi-tis in the Cleveland area since 1958. It might be postulated that a considerable res-ervoir of susceptible persons to these two enteroviruses existed in the population, in-cluding women of the child-bearing age.
The
association of exanthems withentero-virus infections is well established.35’39 Of
the 13 infants in the present report, five had skin manifestations.
It is interesting to speculate as to the re-cent success of viral isolation from the
spi-nat fluid of the four young infants studied
during 1966. Some investigators have pro-posed that an inverse relationship exists be-tween the number of cells in the CSF and the isolation of virus.40 Perhaps interferon is released by these cells which prevents the virus from propagating in the spinal fluid.41 Other investigators, however, have chal-lenged this idea.42
Viral culture techniques have not changed significantly during this time and are an unlikely explanation for the increased success. Perhaps the metabolic require-ments of the enteroviruses have changed so that they can now exist in the
spi-nal fluid. Possibly the eradication of p-lioviruses has allowed other, less virulent
enteroviruses to infect the human host. It would seem that certain enteroviruses are more readily isolated from the cerebrospi-nal fluid than others, and isolation would be more likely in seasons when these vi-ruses are prevalent.
There have been no reported fatalities in infants from whose spinal fluid virus was isolated in vivo either in the present series or the literature. The paucity of reported
cases, unfortunately, makes this statement
less meaningful. It may be concluded,
how-ever, that the mortality rate of enteroviral meningitis in the neonatal infant is lower than that of bacterial meningitis.
A significant question presently
swered is whether or not there is any iieu-rologic damage associated with enteroviral neonatal meningitis. Infection d tiring preg-nancy with ECHO virus, Type 9 has not been shown to increase the incidence of congenital anomalies, or to lead to an in-creased rate of fetal loss.’ On the other hand, intra-uterine infection with Coxsackie Group B has been associated with wide-spread and frequently fatal infections.
Of the five patients with virus present in the cerebrospinal fluid, only one child is suspect of possible brain damage. Patient 2 was quite tremulous a month after hospital-ization and did not follow a light well. Close follow-up and repeated neurologic examinations will be conducted on all these infants in the future.
Viral studies are expensive and mans’
areas in the country do not have facilities
for them. In addition, it usually takes sever-al days before a virus is isolated from the
CSF, making it an unimportant immediate diagnostic tool. It would seem, however, that in larger communities enough viral laboratories exist which could he used if the
diagnosis is suspected. It remains for the
SUMMARY
Enteroviral meningitis was studied in five
infants less than 6 weeks of age.
Eight additional cases of suspected
en-teroviral meningitis from the Cleveland
Metropolitan General Hospital were
re-ViCWC(l with regard to symptoms, CSF
findings, neurologic examination, prognosis, and epidemiology.
The entity of enteroviral meningitis
should be considered in and viral cultures
obtained from any young infant when
cx-amination of the CSF reveals a pleocytosis,
normal glucose, and absence of organisms
on Cram’s stain and culture.
REFERENCES
1. Lepov, \l. L., Warren, R. J., Gray, N., Ingram,
V. G., and Robbins, F. C. : Effect of Sabin
Tpe I poliomyelitis vaccine administered by
fllOtIth in newborn infants. New. Eng. J.
MC(l., 264:1071, 1961.
2. Nelson, W. E., ed. : Textbook of Pediatrics,
1. 8. Philadelphia: W. B. Saunders Co.,
I). 1588, 1964.
3. Samson, K. : Der normale liquor
cerebrospi-nalis im ersten lebenstrimenon. Z. Ges.
Neu-rol. Psvchiat., 128:494, 1930.
4. \Videll, S. : On the cerebrospinal fluid in
nor-mal children and in patients with acute
abacterial meningo-encephalitis. Acta
Pae-(hat. Scand. (Suppl.), 115:1, 1958.
5. Silver, H. K., Kempe, C. H., and Bruyn, H. B.:
Handbook of Pediatrics, ed. 5. Los Altos,
California : Lange Medical Publishers, p.
493, 1963.
6. Gyllenswiird, A., and Malmstr#{246}m, S. : The
cere-brospinal fluid in immature infants. Acta
Paediat. Scand. (Suppl.), 135:54, 1962.
7. Davidsohn, I., and Wells, B., ed. :
Todd-San-ford Clinical Diagnosis by Laboratory
Meth-ods, ed. 13. Philadelphia: \V. B. Saunders
Co., p. 922, 1962.
8. Gold, E., Carver, D. H., Heineberg, H.,
Mel-son, L., and Robbins, F. C.: Viral infection:
A possible cause of sudden, unexpected
death in infants. New Eng. J. Med., 264:
5:3, 1961.
9. \Vright, H. T., Jr., Landing, B. H., Lennette,
E. FL., and McAllister, H. M.: Fatal
infec-lion in an infant associated with coxsackie
virus group A, type 16. New Eng. J. Med.,
268:1041, 1963.
10. Sussman, \l. L., Strauss, L., and Hodes, H. L.:
Fatal coxsackie group B virus infection in
the newborn: Report of a case with necropsy
findings and brief review of the literature.
J. Dis. Child., 97:483, 1959.
11. Montgomery, J., Gear, J., Prinsloo, F. H., Kahn,
M., and Kirsch, Z. G. : Mvocar(litis of the
newborn: An outbreak in a maternity home
in Southern Rhodesia associated with
cox-sackie group B virus infection. South Afr.
Med. J., 29:608, 1955.
12. Javett, S. N., Heymann, S., Mundel, B., Pepler,
W. J., Lurie, H. I., Gear, J., Measroch, V.,
and Kirsch, Z. C. : Myocarditis in the
new-born infant: A study of an outbreak
as-sociated with coxsackie group B virus
infec-tion in a maternity home in Johannesburg.
J. Pediat., 48:1, 1956.
13. Wright, H. T., Jr., Okuyama, K., and
Mc-Ahlister, R. M. : An infant fatality associated
with coxsackie B1 virus. J. Pediat., 63:428,
1963.
14. Johnson, H. T., Shuey, H. E., and Buescher,
E. L. : Epidemic central nervous system
disease of mixed enterovirus etiology. I.
Clin-ical and epidemiologic description. Amer.
j. Hyg., 71:321, 1960.
15. Rohino, C., Perlman, A., Togo, Y., and Reback,
J.: Fatal neonatal infection due to coxsackie
B2 virus. J. Pediat., 61:911, 1962.
16. Kibrick, S., and Benirschke, K. : Acute aseptic
myocarditis and meningoencephalitis in the
newborn child infected with coxsackie virus
group B, type 3. Nest! Eng. J. Med., 255:
883, 1956.
17. Hosier, D. M.. and Newton, W. A., Jr. : Serious
coxsackie infection in infants and children. J.
Dis. Child., 96:251, 1958.
18. Fechner, R. E., Smith, M. C., and
Middel-kamp, J. N. : Coxsackie B virus infection of
the newborn. Amer. J. Path., 42:493, 1963.
10. Moossv, j., and Geer, J. C. : Encephalomvelitis,
myocarditis and adrenal cortical necrosis in
coxsackie B3 virus infection: Distribution of
the central nervous system lesions. Arch.
Path., 70:614, 1960.
20. Kibrick, S., and Benirschke, K. : Severe
gen-eralized disease
(encephalohepatomyocardi-tis) occurring in the newborn period and due
to infection with coxsackie virus, group B:
Evidence of intra-uterine infection with this
agent. PEDIATRICS, 22:857, 1958.
21. Brightman, V. J., Scott, T. F., \Vestphal, M.,
and Boggs, T. R. : An outbreak of coxsackie
B5 virus infection in a newborn nursery.
J.
Pediat., 69:179, 1966.
22. van Creveld, S., and de Jager, H. :
\Ivocardi-tis in newborns, caused b coxsackie virus:
Clinical and pathological data. Ann.
Pae-diat. (Basel), 187: 100, 1956.
23. Moore, M. L., Hooser, L. E., Davis, E. V.,
and Siem, R. A.: Sudden unexpected death
ENTEROVIRAL MENINGITIS
Proc. Soc. Exp. Biol. Med., 116:231, 1964.
24. Kleinman, H., Ramras, D. C., Cooney, M. K.,
and Boyd, L. : Aseptic meningitis due to
ECHO virus type 7. New Eng. J. Med.,
267:1116, 1962.
25. Rawls, W. E., Shorter, R. C., and Herrmann,
E. C. : Fatal neonatal illness associated with
ECHO 9 (coxsackie A-23) virus. PEDIATRICS,
33:278, 1964.
26. Berkovich, S., and Kibrick, S. : ECHO II
out-break in newborn infants and mothers.
PEDIATRICS, 33:534, 1964.
27. Jahn, C. L., and Cherry,
J.
D. : Mild neonatalillness associated with heavy enterovirus
infection. New Eng.
J.
Med., 274:394, 1966.28. Lukacs, V. F., and Romhanyi,
J.
: On ameningo-encephalo-myocarditis epidemic in
newborn infants during the epidemic of
Bornholm’s disease in Hungary in 1958. I.
Clinical and pathological findings. Ann.
Paediat. (Basel), 194:89, 1960.
29. Domok, I., and Molnar, E. : An outbreak of
meningo-encephalo-myocarditis among
new-born infants during the epidemic of
Born-holm’s disease of 1958 in Hungary. II.
Aetiological findings. Ann. Paediat. (Basel),
194:102, 1960.
30. Delaney, T. B., and Fukunaga, F. H. :
Myo-carditis in a newborn infant with
encephalo-meningitis due to coxsackie virus group B,
type 5. New Eng.
J.
Med., 259:234, 1958.31. Rapmund, C., Gauld, J. R., Rogers, N. C.,
and Holmes, C. E.: Neonatal myocarditis
and meningoencephalitis due to coxsackie
virus group B, type 4. Virologic study of a
fatal case with simultaneous aseptic
menin-gitis in the mother. New Eng.
J.
Med.,260:819, 1959.
32. Eichenwald, H. F., and Kotsevalov, 0. :
Im-munologic responses of premature and
full-term infants to infection with certain viruses.
PEDIATRIcS, 25:829, 1960.
33. Lepow, M. L., Warren, R. J., Ingram, V. C.,
Daugherty, S. C., and Robbins, F. C.:
Sabin type I (LS2ab) oral poliomyelitis
vaccine. Effect of dose upon response of
newborn infants. Amer.
J.
Dis. Child., 104:67, 1962.
34. Cramblett, H. G., Wilken, F. D., Langmack,
M., and Porter, J.: Patterns of transpiacental
transfer of neutralizing antibodies against
ECHO virus types 1, 2, 8, 11. and 20. Amer.
J. Hyg., 73:90, 1961.
35. Lepow, M. L.. Carver, D. H.. Wright, H. T.,
Jr., Woods, W. A., and Robbins, F. C. : A
clinical, epidemiologic and laboratory
in-vestigation of aseptic meningitis during the four-year period 1955-1958. 1. Observations
concerning etiology and epidemiology. New
Eng. J. Med., 266:1181, 1962.
36. Lerner, A. M., and Finland, M. : Coxsackie
viral infections. Arch. Intern. Med., 108:
329, 1961.
37. Karzon, D. T. : The enteroviruses and the
aseptic meningitis syndrome. Quart. Rev. Pediat., 14:78, 1959.
38. Lerner, A. M., Klein, J. 0., Cherry, J. D.,
and Finland, M. : New viral exanthems
(concluded). New Eng. J. Med., 269:736,
1963.
39. Cherry,
J.
D., Lerner, A. M., Klein, j. 0.,and Finland, M. : Coxsackie W infections
with exanthems. PEDIATRICS, 31 :455, 1963.
40. Chang, T. W., and Weinstein, L. : Relationship
of cerebrospinal fluid pleocytosis to recovery
of ECHO 9 virus. J.A.M.A., 182:1040, 1962.
41. Cresser, I., and Naficy, K.: Recovery of an interferon-like substance from cerebrospinal fluid. Proc. Soc. Exp. Biol. Med., 117:285, 1964.
42. Portnoy, B., Leedom, J. M., Hanes, B., and
Wehrle, P. F.: Factors affecting ECHO 9
virus recovery from cerebrospinal fluid.
Amer. J. Med. Sci., 248:521, 1964.
43. Kleinman, H., Prince, j. T., Mathey, W. E.,
Rosenfield, A. B., Bearman, J. E., and
Syverton, J. T. : ECHO 9 virus infection
and congenital abnormalities : A negative
report. PEDIATRICS, 29:261, 1962.
44. Peterson, J. C., and Glicklich, L. : The effect
of ECHO 9 infection on the fetus. Amer. J.
Dis. Child., 100:779, 1960.
Acknowledgment
The authors wish to thank Drs. Alfred D. Heggie
and Russell