March 1976 The Journal o f P E D I A T R I C S
473
Cerebrospinal fluid evaluation in neonates: Comparison of high-risk infants with and without meningitis Results of CSF examinations from 117 high-risk neonates were reviewed The mean CSF cell count was 8.4 cells~ram 3 and the range was 0 to 32 cells~ram. 3 Approximately 60% o f the C S F WBC were polymorphonuclear leukocytes. Average CSF protein concentrations were 90 mg/dl (range, 20-170 mg/dl) in term and 115 mg/dl (range, 65 - 150 mg/dl) in preterm infants. The average CSF glucose was 81% of the blood glucose value in term and 74% in preterm infants. Comparison o f these CSF findings with those from 119 infants with bacterial meningitis revealed that there was considerable overlapping o f values, but only one o f the 119 infants with meningitis had a completely normal initial CSF examination. The decision to,initiate antimicrobial therapy in neonates with suspected meningitis must be based on total evaluation of the patient.
Larrie D. Sarff, M.D., Lynn H. Platt, M.D., and George H. MeCraeken, Jr., M.D.,* Dallas, T e x a s
A RECURRING CLINICAL DILEMMA is evaluation of cerebrospinal fluid findings in high-risk neonates who appear septic. In these babies we are repeatedly urged to examine and culture CSF for the possibility of meningitis before initiating antibiotic therapy. Although normal values are well established for CSF cell counts and protein and sugar contents in children and adults, this is not the case for neonates. Pediatricians are frequently confronted by the problem of a sick neonate whose CSF has ten to 20 white blood cells and must decide whether" this is within the range of normal values or might represent the early stages o f bacterial meningitis. A review of literature ( T a b l e I) shows that there is general agreement among seven different studies spanning a period from 1925 to 1968 that the average CSF white blood cell count is 6 to 7 cells/mm ~ in neonates. 1-~ With the exception of Naidoo's article, 7 data are not available for the acceptable variability in CSF white blood ceU counts in neonates. All of these studies evaluFrom the Department of Pediatrics, The University of Texas Health Science Center at Dallas, Southwestern Medical School. *Reprint address: Department of Pediatrics, 5323 Harry Hines Blvd., Dallas, Texas 75235.
ated healthy neonates and were performed before the availability of modem obstetrical and neonatal intensive care facilities which have resulted in survival of a large number of infants who are at high-risk of developing systemic bacterial diseases because of obstetrical complications, prematurity, and invasive procedures utilized in their management. The CSF cell counts and sugar and protein values in these high-risk babies are unknown. The purpose of this paper is to present the CSF findings of 117 high-risk neonates who had no evidence of bacterial or viral diseases of the central nervous system and to compare these values with those obtained from the initial CSF examination of infants with bacterial meningitis. STUDY POPULATION CHARACTERISTICS
From July 1, 1972, through June 30, 1973, 132 neonates born at Parkland Memorial Hospital, Dallas, had lumbar punctures performed. These infants had clinical findings suggesting infection and constituted a high-risk group because of such problems as unexplained jaundice, prematurity, prolonged rupture of membranes, chorioamionities, abruptio placenta, maternal fever, or toxemia. Fifteen of the 132 neonates were excluded for the
VoL 88, No. 3, pp. 473-477
474
Sarff, Platt, and McCracken
The Journal of Pediatrics March 1976
34
Table II. Cerebrospinal fluid examination in high-risk neonates without meningitis
52
30
Term
A 28
J o,,~,,,,,,,,4b FULL-TERM, r =-.11 ~----~. LOW BIRTH WEIGHT, r =.36 9
26
/x
24 E 22 E
A
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9
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WBC count (cells/mm ~) No. of infants Mean Median SD Range +_ 2 SD Percentage PMN* Protein (mg/dl) No. of infants Mean Range Glucose (mg/dl) No, of infants Mean Range CSF/blood glucose (%) No. of infants Mean Range
[
Preterm
87 8.2 5 7.1 0-32 0-22.4 61.3%
30 9.0 6 8.2 0-29 0-25.4 57.2%
35 90 20-170
17 115 65 - 150
51 52 34-119
23 50 24-63
51 81 44-248
23 74 55-105
2 * P M N = Po ly mo r p h o n u c le a r cells. 0
0
I
2
'
4I
t
;
I
t0
NEONATES' AGE IN DAYS
Fig. 1. WBC count in CSF by postnatal age in high-risk neonates. Pearson r correlation coefficients were used for analysis.
T a b l e I, Previous studies of cerebrospinal fluid white blood cell counts in neonates
_ ~ ells/mm3 No,
Reference
infants
Roberts (1925) 1 Waitz (1928)-' Samson (1931) 5
423 50 NR
Otila (1948)"
Wyers and Bakker (1954) ~ Widell (1958) 6 Naidoo (1968) 7
N R = riot recorded. *(P) = P r e t e r m b a b i e s . t(T) =Termbabies,
21 (P)* 15 (e) 30 (P) 20 (T)t NR
NR 135 (T) 20 (T)
Age
~
Range
1 day 6.3 0-2 wk NR 0-2 wk 4 3-4 wk 3 1/3 2 wks-3 mo 3 3-6 mo 1 1/3 0-1 wk 9 1-2 wk 13 2-4 wk 9 2 wks-3 mo 1 day 8.3
0-1 wk 0-2 wk 1 day 1 wk
8.1 7.5 5 3
2-17 5-20 1-6 2/3 0-5 0-3 1/3 NR NR NR 1-4 0-29
0-15 NR NR
following r e a s o n s : four infants had traumatic taps resulting in grossly bloody CSF; seven had positive serologic tests for syphilis, and four babies had bacterial or viral meningitis. Blood, urine, and cerebrospinal fluid cultures from the remaining 117 neonates were sterile, and there was no clinical e v i d e n c e o f viral or bacterial disease in these infants. Twenty-eight infants were preterm with appropriate weights for their gestational ages (birth weights: 970-2,500 gm; gestational ages: 28-38 weeks) and two infants were small for gestational age (2,190 gm at 40 weeks and 1,195 g m at 31 weeks). Eightyseven infants were term babies with appropriate birth weights. One hundred eleven of the 117 infants were seven days of age or less; two infants were ten days o f age, and four preterm babies were two to four weeks o f age. There were 75 boys and 42 girls. F o r comparative purposes, the initial data o f CSF examination from 135 neonates with bacterial diseases were reviewed. These included 98 patients with gramnegative bacillary meningitis who were part o f the Cooperative Neonatal Meningitis Study Group (19711975), 8 21 neonates with group B beta-hemolytic streptococcal meningitis treated at Parkland M e m o r i a l Hospital and Children's Medical Center o f Dallas from 1969 to 1975, and 16 neonates with septicemia without meningitis treated at Parkland Memorial Hospital during 1974. Examination of the cerebrospinal fluid was performed in the hospital laboratories by routine procedures.
Volume 88 Number 3
Cerebrospinal fluid evaluation in neonates
fp
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GROUP B
# - HEMOLYTIC
STREPTOCOCCUS M E N I N G I T I S o----o
s,~
0....o ..... I 10
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9 8 N E O N A T E S WITH GRAM-NEGATIVE MENINGITIS
"0"~ I 100
CEREBROSPINAL
'
'
FLUID
.....
'1 1,000
WBC
'
'
' ..... I 10,000
.
....... I 100,000
'
COUNT/cmm
Fig. 2. Comparison of WBC counts in CSF in neonates with or without meningitis.
RESULTS In Table II the results of cerebrospinal fluid analysis in the high-risk neonates who did not have meningitis are summarized. The mean CSF WBC count from 87 term babies was 8.2 cells/mm 3 (range, 0-32 cells/mm 3) with a standard deviation of 7.1 cells/mm ~. The mean CSF count for the 30 preterm babies was 9.0 W B C / m m ~ (range, 0-29 cells/mm ~) with a standard deviation of 8.2 cells/mm ~. Polymorphonuclear leukocytes accounted for approximately 60% of the CSF WBCs. No correlation was found between CSF white blood cell counts and postnatal age for term infants (correlation coefficient, --0.11), whereas the correlation for preterm infants (correlation coefficient, 0.357) was at the 0.05 < p < 0.1 level (Fig. 1). The cell count decreased in term infants and increased in preterm infants "during the first week of life. The CSF red blood cell counts varied considerably. Term neonates had a median of 180 R B C / m m ~ of CSF with a range of 0 to 45,000 cells/mm~; preterm babies had a median of 112 RBC/mm ~ of CSF with a range of 0 to 39,000 cells/mm 3. In both groups the most frequently occurring RBC count (the mode) was 0. There was no discernable association between RBC and WBC counts in these neonates. CSF protein and glucose concentrations are summarized in Table II. Average CSF protein contents of 90 mg/dl (range: 20 to 170 mg/dl) and 115 m g / d l (range: 65 to 150 mg/dl) were observed in term and preterm babies, respectively. The average glucose content was approxi-
mately 50 mg/dl for both infant groups with the average percentage of CSF to blood glucose being 81% for term and 74% for preterm infants. The cerebrospinal fluid values from the initial lumbar taps of 119 neonates with proved bacterial meningitis were reviewed (Fig. 2). Twenty-nine percent of infants with group B streptococcal meningitis and 4% of those with gram-negative bacillary meningitis were within the range (0 to 32 W B C / m m 3) detected in our high-risk, uninfected babies. The percentages of polymorphonuclear cells varied considerably in infected and uninfected infants. CSF protein concentrations were within the 20 to 170 mg/dl range found in our high-risk group in 47% of infants with streptococcal meningitis and in 23% of the infants with gram-negative disease. The percentages of CSF glucose to blood glucose were greater than 44% (the lower limit in the high-risk group) in 45% and 15% of infants with streptococcal and gram-negative bacillary meningitis, respectively. Bacteria were seen in Gram and methylene blue-stained smears of the initial CSF specimens from 83% of patients with streptococcal meningitis and from 78% of those with gram-negative disease. The results of CSF analysis from 16 infants with septicemia without meningitis were reviewed. The CSF cell counts ranged from 0 to 112 W B C / m m ~ (mean, 20 cells/mm 3, median, 8 cells/mm ~) and three infants had counts greater than 32 W B C / m m ~. CSF protein concentration and the CSF glucose to blood glucose ratio was
476
Sarff, Platt, and McCracken
abnormal in one patient each. Bacteria were not observed in stained smears of CSF from these patients. Thus, four (25%) infants had at least one abnormal CSF test. COMMENT
The average CSF white blood cell count for all 117 high-risk neonates was 8.4 cells/mm ~which is comparable to the values observed previously in healthy babies. ~-7 Two standard deviations above the mean was 23 cells/ nun ~ and 3 SD, which includes 99% of values, was 31 ceUs/mm3. The observation of a decreasing CSF cell count during the first week of life in term babies and an increasing cell count in preterm infants confirms the earlier study by Otila. 4 In that study, 4 the CSF protein content in preterm infants also increased during the first seven days after birth; there was an inverse correlation between the degree of prematurity and the duration of elevated CSF cell and protein values. There is general agreement among all studies that the CSF protein content is higher in neonates than that observed in older infants and children. CSF glucose content is proportionally higher in relation to blood glucose in neonates than in older patients. Approximately 75% to 80% of blood glucose values was detected in the CSF of our infants. This corresponds to data of previous investigators,",~ and is higher than the stated normal range of 40% to 60% in children and adults) . . . . o The reasons for the higher CSF cell, protein, and glucose values of neonates compared with older infants and children are unknown. Several observations favor altered permeability of the "blood-brain" barrier rather than cerebral hemorrhage or occult viral or protozoan infections. (1) The CSF cell counts, protein content, and ratio of CSF to blood glucose are increased in the majority of healthy and high-risk neonates and tend to be higher in the more Premature infants. (2) Passive antibody, 1~ dyes 4 and a-fetoprotein1~ can be detected in the CSF of neonates, suggesting increased permeability to these substances. Further investigations are necessary before this theory can be considered proved. Comparison of CSF values from the high-risk group and those from infants with meningitis revealed that no single test of the CSF was reliable for differentiation of uninfected from infected infants. However, only one of the 119 infants with culture-proved bacterial meningitis had a completely normal CSF examination. The culture from this ten-day-old infant's initial CSF yielded Escherichia coli KI and contained no WBC; the glucose content was 111 mg/dl; protein, 140 mg/dl. Subsequent CSF examinations showed the characteristic cellular, glucose-, and protein findings of purulent meningitis and cultures
The dournal of Pediatrics March 1976
and stained smears were positive for nine days. Thus, with rare exception, the initial CSF examination from infants with bacterial meningitis is usually abnormal in at least one of the tests routinely performed. The CSF findings in neonates with congenitally or postnatally acquired viral meningitis, congenital syphilis, or toxoplasmosisx3-18 may at times be difficult to distinguish from those observed in high-risk infants or in neonates with septicemia and/or meningitis. It is important to identify those infants with a treatable infection because early diagnosis and prompt treatment may improve the outcome from these diseases. The decision to initiate antimicrobial therapy must be based on total evaluation of the patient which includes the epidemiologic setting of the disease, the clinical manifestations and severity of the illness, the results of serologic and immunologic studies, a n d routine laboratory data, including CSF examination. If a definitive diagnosis cannot be established from this evaluation and any one of the CSF tests is abnormal, antimicrobial therapy should be started using a penicillin and an aminoglycoside in dosages suitable for meningitis. The need to continue or alter therapy should be re-evaluated 48 to 72 hours later when results of the blood and CSF cultures are available and the clinical features of the illness have been defined. Joan S. Reisch performed the statistical analysis of the data. REFERENCES
I. RobertsMH: The spinal fluid in the newborn with especial references to intracranial hemorrhage, JAMA 85:500, 1925. 2. Waitz R: Le liquide cephalorachidien du Nouveau-nt, Rev Franc Pediatr 4:1, 1928, 3. SamsonK: Die liquordiagnostik im kindesaltor, Ergeb inn Med Kinderheilkd 41:553, 1931. 4. Otila E: Studies on the cerebrospinal fluid in premature infants. Acta Paediatr 35(Suppl) :8, 1948. 5. Wyers HJG, and Bakker JCW: De liquor cerebrospinalis van normale, a terme geboren neonat, Maandschrift Kindergenceskunde 22:253~ 1954. 6. Widell S: On the cerebrospinal fluid in normal children and in patients with acute abacterial meningoencephalitis, Acta Paediatr 47(SuppI) 115, 1958. 7. Naidoo BT: The cerebrospinal fluid in the healthy newborn infant, S Aft Med J 42:933, 1968. 8. McCrackenGH, and Sarff LD: Current status and therapy of neonatal E, coli meningitis, Hospital Pract, October, 1974. 9. Liebe S: Zur disgnose und prognose geburtsti-aumatisher intrakranieller blutunger, Monatsschr Kinderheilkd 83:1, 1940. 10. Steward D: The normal cerebrospinal fluid in children, Arch Dis Child 3:96, 1928. 11. Thorley JD, Holmes RK, Kaplan JM, McCracken GH Jr, and Sanford JP: Passive transfer of antibiodies of maternal
Volume 88 Number 3
12. 13.
14. 15.
origin from blood to cerebrospinal fluid in infants, Lancet 1:651, 1975. Seller MJ, and Adinolfi M: Blood-brain barrier in the human fetus, Lancet 1:1030, 1975. Marier R, Rodriquez W, Choloupek RJ, Brandt CD, Kim HW, Baltimore RS, Parker CL, and Artenstein MS: Coxsachievirus B5 infection and aseptic meningitis in neonates and children, Am J Dis Child 129:321, 1975. Nogen AG, and Lepow ML: Enteroviral meningitis in very young infants, Pediatrics 40:617, 1967. Desmond M, Wilson GS, Melnick JL, Singer DB, Zion TE, Rudolph AJ, Pineda RG, Ziai M, and Blattner RJ: Congenital rubella syndrome, J P~DIATR71:311, 1967.
Cerebrospinal fluid evaluation in neonates
477
16. Reynolds DW., Stagno S, Stubbs G, Dahle AJ, Livingston MM, Saxon SS, and Afford CA: Inapparent congenital cytomegalovirus infection with elevated cord Igm levels, N Engl J Med 290:291, 1974. 17. Alford CA, Foft JW, Blankenship WJ, Cassady G, and Benton JW: Subclinical central nervous system disease of neonates: A prospective study of infants born with increased levels of IgM, J PED1AXR75:1167, 1969. 18. Nabaroo D: Congenital syphilis, London, t954, Edward Arnold (Publishers) Ltd.
473
Cerebrospinal fluid evaluation in neonates: Comparison of high-risk infants with and without meningitis Results of CSF examinations from 117 high-risk neonates were reviewed The mean CSF cell count was 8.4 cells~ram 3 and the range was 0 to 32 cells~ram. 3 Approximately 60% o f the C S F WBC were polymorphonuclear leukocytes. Average CSF protein concentrations were 90 mg/dl (range, 20-170 mg/dl) in term and 115 mg/dl (range, 65 - 150 mg/dl) in preterm infants. The average CSF glucose was 81% of the blood glucose value in term and 74% in preterm infants. Comparison o f these CSF findings with those from 119 infants with bacterial meningitis revealed that there was considerable overlapping o f values, but only one o f the 119 infants with meningitis had a completely normal initial CSF examination. The decision to,initiate antimicrobial therapy in neonates with suspected meningitis must be based on total evaluation of the patient.
Larrie D. Sarff, M.D., Lynn H. Platt, M.D., and George H. MeCraeken, Jr., M.D.,* Dallas, T e x a s
A RECURRING CLINICAL DILEMMA is evaluation of cerebrospinal fluid findings in high-risk neonates who appear septic. In these babies we are repeatedly urged to examine and culture CSF for the possibility of meningitis before initiating antibiotic therapy. Although normal values are well established for CSF cell counts and protein and sugar contents in children and adults, this is not the case for neonates. Pediatricians are frequently confronted by the problem of a sick neonate whose CSF has ten to 20 white blood cells and must decide whether" this is within the range of normal values or might represent the early stages o f bacterial meningitis. A review of literature ( T a b l e I) shows that there is general agreement among seven different studies spanning a period from 1925 to 1968 that the average CSF white blood cell count is 6 to 7 cells/mm ~ in neonates. 1-~ With the exception of Naidoo's article, 7 data are not available for the acceptable variability in CSF white blood ceU counts in neonates. All of these studies evaluFrom the Department of Pediatrics, The University of Texas Health Science Center at Dallas, Southwestern Medical School. *Reprint address: Department of Pediatrics, 5323 Harry Hines Blvd., Dallas, Texas 75235.
ated healthy neonates and were performed before the availability of modem obstetrical and neonatal intensive care facilities which have resulted in survival of a large number of infants who are at high-risk of developing systemic bacterial diseases because of obstetrical complications, prematurity, and invasive procedures utilized in their management. The CSF cell counts and sugar and protein values in these high-risk babies are unknown. The purpose of this paper is to present the CSF findings of 117 high-risk neonates who had no evidence of bacterial or viral diseases of the central nervous system and to compare these values with those obtained from the initial CSF examination of infants with bacterial meningitis. STUDY POPULATION CHARACTERISTICS
From July 1, 1972, through June 30, 1973, 132 neonates born at Parkland Memorial Hospital, Dallas, had lumbar punctures performed. These infants had clinical findings suggesting infection and constituted a high-risk group because of such problems as unexplained jaundice, prematurity, prolonged rupture of membranes, chorioamionities, abruptio placenta, maternal fever, or toxemia. Fifteen of the 132 neonates were excluded for the
VoL 88, No. 3, pp. 473-477
474
Sarff, Platt, and McCracken
The Journal of Pediatrics March 1976
34
Table II. Cerebrospinal fluid examination in high-risk neonates without meningitis
52
30
Term
A 28
J o,,~,,,,,,,,4b FULL-TERM, r =-.11 ~----~. LOW BIRTH WEIGHT, r =.36 9
26
/x
24 E 22 E
A
-2 2C z 9
o o
9
oo
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r
~ m
9 oo
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9
9
12 10 8 6
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WBC count (cells/mm ~) No. of infants Mean Median SD Range +_ 2 SD Percentage PMN* Protein (mg/dl) No. of infants Mean Range Glucose (mg/dl) No, of infants Mean Range CSF/blood glucose (%) No. of infants Mean Range
[
Preterm
87 8.2 5 7.1 0-32 0-22.4 61.3%
30 9.0 6 8.2 0-29 0-25.4 57.2%
35 90 20-170
17 115 65 - 150
51 52 34-119
23 50 24-63
51 81 44-248
23 74 55-105
2 * P M N = Po ly mo r p h o n u c le a r cells. 0
0
I
2
'
4I
t
;
I
t0
NEONATES' AGE IN DAYS
Fig. 1. WBC count in CSF by postnatal age in high-risk neonates. Pearson r correlation coefficients were used for analysis.
T a b l e I, Previous studies of cerebrospinal fluid white blood cell counts in neonates
_ ~ ells/mm3 No,
Reference
infants
Roberts (1925) 1 Waitz (1928)-' Samson (1931) 5
423 50 NR
Otila (1948)"
Wyers and Bakker (1954) ~ Widell (1958) 6 Naidoo (1968) 7
N R = riot recorded. *(P) = P r e t e r m b a b i e s . t(T) =Termbabies,
21 (P)* 15 (e) 30 (P) 20 (T)t NR
NR 135 (T) 20 (T)
Age
~
Range
1 day 6.3 0-2 wk NR 0-2 wk 4 3-4 wk 3 1/3 2 wks-3 mo 3 3-6 mo 1 1/3 0-1 wk 9 1-2 wk 13 2-4 wk 9 2 wks-3 mo 1 day 8.3
0-1 wk 0-2 wk 1 day 1 wk
8.1 7.5 5 3
2-17 5-20 1-6 2/3 0-5 0-3 1/3 NR NR NR 1-4 0-29
0-15 NR NR
following r e a s o n s : four infants had traumatic taps resulting in grossly bloody CSF; seven had positive serologic tests for syphilis, and four babies had bacterial or viral meningitis. Blood, urine, and cerebrospinal fluid cultures from the remaining 117 neonates were sterile, and there was no clinical e v i d e n c e o f viral or bacterial disease in these infants. Twenty-eight infants were preterm with appropriate weights for their gestational ages (birth weights: 970-2,500 gm; gestational ages: 28-38 weeks) and two infants were small for gestational age (2,190 gm at 40 weeks and 1,195 g m at 31 weeks). Eightyseven infants were term babies with appropriate birth weights. One hundred eleven of the 117 infants were seven days of age or less; two infants were ten days o f age, and four preterm babies were two to four weeks o f age. There were 75 boys and 42 girls. F o r comparative purposes, the initial data o f CSF examination from 135 neonates with bacterial diseases were reviewed. These included 98 patients with gramnegative bacillary meningitis who were part o f the Cooperative Neonatal Meningitis Study Group (19711975), 8 21 neonates with group B beta-hemolytic streptococcal meningitis treated at Parkland M e m o r i a l Hospital and Children's Medical Center o f Dallas from 1969 to 1975, and 16 neonates with septicemia without meningitis treated at Parkland Memorial Hospital during 1974. Examination of the cerebrospinal fluid was performed in the hospital laboratories by routine procedures.
Volume 88 Number 3
Cerebrospinal fluid evaluation in neonates
fp
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i
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21 N E O N A T E S WITH
GROUP B
# - HEMOLYTIC
STREPTOCOCCUS M E N I N G I T I S o----o
s,~
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475
9 8 N E O N A T E S WITH GRAM-NEGATIVE MENINGITIS
"0"~ I 100
CEREBROSPINAL
'
'
FLUID
.....
'1 1,000
WBC
'
'
' ..... I 10,000
.
....... I 100,000
'
COUNT/cmm
Fig. 2. Comparison of WBC counts in CSF in neonates with or without meningitis.
RESULTS In Table II the results of cerebrospinal fluid analysis in the high-risk neonates who did not have meningitis are summarized. The mean CSF WBC count from 87 term babies was 8.2 cells/mm 3 (range, 0-32 cells/mm 3) with a standard deviation of 7.1 cells/mm ~. The mean CSF count for the 30 preterm babies was 9.0 W B C / m m ~ (range, 0-29 cells/mm ~) with a standard deviation of 8.2 cells/mm ~. Polymorphonuclear leukocytes accounted for approximately 60% of the CSF WBCs. No correlation was found between CSF white blood cell counts and postnatal age for term infants (correlation coefficient, --0.11), whereas the correlation for preterm infants (correlation coefficient, 0.357) was at the 0.05 < p < 0.1 level (Fig. 1). The cell count decreased in term infants and increased in preterm infants "during the first week of life. The CSF red blood cell counts varied considerably. Term neonates had a median of 180 R B C / m m ~ of CSF with a range of 0 to 45,000 cells/mm~; preterm babies had a median of 112 RBC/mm ~ of CSF with a range of 0 to 39,000 cells/mm 3. In both groups the most frequently occurring RBC count (the mode) was 0. There was no discernable association between RBC and WBC counts in these neonates. CSF protein and glucose concentrations are summarized in Table II. Average CSF protein contents of 90 mg/dl (range: 20 to 170 mg/dl) and 115 m g / d l (range: 65 to 150 mg/dl) were observed in term and preterm babies, respectively. The average glucose content was approxi-
mately 50 mg/dl for both infant groups with the average percentage of CSF to blood glucose being 81% for term and 74% for preterm infants. The cerebrospinal fluid values from the initial lumbar taps of 119 neonates with proved bacterial meningitis were reviewed (Fig. 2). Twenty-nine percent of infants with group B streptococcal meningitis and 4% of those with gram-negative bacillary meningitis were within the range (0 to 32 W B C / m m 3) detected in our high-risk, uninfected babies. The percentages of polymorphonuclear cells varied considerably in infected and uninfected infants. CSF protein concentrations were within the 20 to 170 mg/dl range found in our high-risk group in 47% of infants with streptococcal meningitis and in 23% of the infants with gram-negative disease. The percentages of CSF glucose to blood glucose were greater than 44% (the lower limit in the high-risk group) in 45% and 15% of infants with streptococcal and gram-negative bacillary meningitis, respectively. Bacteria were seen in Gram and methylene blue-stained smears of the initial CSF specimens from 83% of patients with streptococcal meningitis and from 78% of those with gram-negative disease. The results of CSF analysis from 16 infants with septicemia without meningitis were reviewed. The CSF cell counts ranged from 0 to 112 W B C / m m ~ (mean, 20 cells/mm 3, median, 8 cells/mm ~) and three infants had counts greater than 32 W B C / m m ~. CSF protein concentration and the CSF glucose to blood glucose ratio was
476
Sarff, Platt, and McCracken
abnormal in one patient each. Bacteria were not observed in stained smears of CSF from these patients. Thus, four (25%) infants had at least one abnormal CSF test. COMMENT
The average CSF white blood cell count for all 117 high-risk neonates was 8.4 cells/mm ~which is comparable to the values observed previously in healthy babies. ~-7 Two standard deviations above the mean was 23 cells/ nun ~ and 3 SD, which includes 99% of values, was 31 ceUs/mm3. The observation of a decreasing CSF cell count during the first week of life in term babies and an increasing cell count in preterm infants confirms the earlier study by Otila. 4 In that study, 4 the CSF protein content in preterm infants also increased during the first seven days after birth; there was an inverse correlation between the degree of prematurity and the duration of elevated CSF cell and protein values. There is general agreement among all studies that the CSF protein content is higher in neonates than that observed in older infants and children. CSF glucose content is proportionally higher in relation to blood glucose in neonates than in older patients. Approximately 75% to 80% of blood glucose values was detected in the CSF of our infants. This corresponds to data of previous investigators,",~ and is higher than the stated normal range of 40% to 60% in children and adults) . . . . o The reasons for the higher CSF cell, protein, and glucose values of neonates compared with older infants and children are unknown. Several observations favor altered permeability of the "blood-brain" barrier rather than cerebral hemorrhage or occult viral or protozoan infections. (1) The CSF cell counts, protein content, and ratio of CSF to blood glucose are increased in the majority of healthy and high-risk neonates and tend to be higher in the more Premature infants. (2) Passive antibody, 1~ dyes 4 and a-fetoprotein1~ can be detected in the CSF of neonates, suggesting increased permeability to these substances. Further investigations are necessary before this theory can be considered proved. Comparison of CSF values from the high-risk group and those from infants with meningitis revealed that no single test of the CSF was reliable for differentiation of uninfected from infected infants. However, only one of the 119 infants with culture-proved bacterial meningitis had a completely normal CSF examination. The culture from this ten-day-old infant's initial CSF yielded Escherichia coli KI and contained no WBC; the glucose content was 111 mg/dl; protein, 140 mg/dl. Subsequent CSF examinations showed the characteristic cellular, glucose-, and protein findings of purulent meningitis and cultures
The dournal of Pediatrics March 1976
and stained smears were positive for nine days. Thus, with rare exception, the initial CSF examination from infants with bacterial meningitis is usually abnormal in at least one of the tests routinely performed. The CSF findings in neonates with congenitally or postnatally acquired viral meningitis, congenital syphilis, or toxoplasmosisx3-18 may at times be difficult to distinguish from those observed in high-risk infants or in neonates with septicemia and/or meningitis. It is important to identify those infants with a treatable infection because early diagnosis and prompt treatment may improve the outcome from these diseases. The decision to initiate antimicrobial therapy must be based on total evaluation of the patient which includes the epidemiologic setting of the disease, the clinical manifestations and severity of the illness, the results of serologic and immunologic studies, a n d routine laboratory data, including CSF examination. If a definitive diagnosis cannot be established from this evaluation and any one of the CSF tests is abnormal, antimicrobial therapy should be started using a penicillin and an aminoglycoside in dosages suitable for meningitis. The need to continue or alter therapy should be re-evaluated 48 to 72 hours later when results of the blood and CSF cultures are available and the clinical features of the illness have been defined. Joan S. Reisch performed the statistical analysis of the data. REFERENCES
I. RobertsMH: The spinal fluid in the newborn with especial references to intracranial hemorrhage, JAMA 85:500, 1925. 2. Waitz R: Le liquide cephalorachidien du Nouveau-nt, Rev Franc Pediatr 4:1, 1928, 3. SamsonK: Die liquordiagnostik im kindesaltor, Ergeb inn Med Kinderheilkd 41:553, 1931. 4. Otila E: Studies on the cerebrospinal fluid in premature infants. Acta Paediatr 35(Suppl) :8, 1948. 5. Wyers HJG, and Bakker JCW: De liquor cerebrospinalis van normale, a terme geboren neonat, Maandschrift Kindergenceskunde 22:253~ 1954. 6. Widell S: On the cerebrospinal fluid in normal children and in patients with acute abacterial meningoencephalitis, Acta Paediatr 47(SuppI) 115, 1958. 7. Naidoo BT: The cerebrospinal fluid in the healthy newborn infant, S Aft Med J 42:933, 1968. 8. McCrackenGH, and Sarff LD: Current status and therapy of neonatal E, coli meningitis, Hospital Pract, October, 1974. 9. Liebe S: Zur disgnose und prognose geburtsti-aumatisher intrakranieller blutunger, Monatsschr Kinderheilkd 83:1, 1940. 10. Steward D: The normal cerebrospinal fluid in children, Arch Dis Child 3:96, 1928. 11. Thorley JD, Holmes RK, Kaplan JM, McCracken GH Jr, and Sanford JP: Passive transfer of antibiodies of maternal
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12. 13.
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origin from blood to cerebrospinal fluid in infants, Lancet 1:651, 1975. Seller MJ, and Adinolfi M: Blood-brain barrier in the human fetus, Lancet 1:1030, 1975. Marier R, Rodriquez W, Choloupek RJ, Brandt CD, Kim HW, Baltimore RS, Parker CL, and Artenstein MS: Coxsachievirus B5 infection and aseptic meningitis in neonates and children, Am J Dis Child 129:321, 1975. Nogen AG, and Lepow ML: Enteroviral meningitis in very young infants, Pediatrics 40:617, 1967. Desmond M, Wilson GS, Melnick JL, Singer DB, Zion TE, Rudolph AJ, Pineda RG, Ziai M, and Blattner RJ: Congenital rubella syndrome, J P~DIATR71:311, 1967.
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16. Reynolds DW., Stagno S, Stubbs G, Dahle AJ, Livingston MM, Saxon SS, and Afford CA: Inapparent congenital cytomegalovirus infection with elevated cord Igm levels, N Engl J Med 290:291, 1974. 17. Alford CA, Foft JW, Blankenship WJ, Cassady G, and Benton JW: Subclinical central nervous system disease of neonates: A prospective study of infants born with increased levels of IgM, J PED1AXR75:1167, 1969. 18. Nabaroo D: Congenital syphilis, London, t954, Edward Arnold (Publishers) Ltd.
