Cerebrospinal Fluid Lactic Acid Dehydrogenase Activity Levels in Untreated and
Partially Antibiotic-Treated Meningitis
William E. Feldman, MD, MS
High levels of cerebrospinal fluid (CSF) lactic acid dehydrogenase (LDH) activity were found in 23 cases of bacterial meningitis, but significantly lower levels of CSF LDH activity were observed in 11 patients with viral meningitis and in 13 patients with no central nervous system infection. No correlation was found between levels of CSF LDH activity and specific agents or the amounts of CSF white blood cells, protein, and glucose. The number of meningitis cases of unknown cause that could be classified as probably bacterial or viral was increased by determination of the level of CSF LDH activity. The level of CSF LDH activity is useful in differentiating bacterial from viral meningitis and, along with determination of the CSF blood cell counts and protein and glucose levels, aids in classification of meningitis before culture results are available. fluid (CSF) Totallacticcerebrospinal dehydrogenase (LDH) much
acid is activity greater in patients with bacterial meningitis than in pa¬ tients with aseptic meningitis.13 Thus, determination of the level of CSF LDH activity has been proposed for use in situations where clinical and laboratory differentiation be¬ tween bacterial and viral meningitis is difficult. However, no studies have systematically compared the levels of CSF LDH activity with commonly used CSF measurements to deter¬ mine the relative usefulness of these values in the diagnosis of meningitis. The present study compares the value of determination of the level of CSF LDH activity with CSF white blood cell (WBC) count and concentrations of CSF protein and glucose in differ¬ entiating bacterial and viral men¬
SUBJECTS AND METHODS A prospective study of 70 consecutive pediatrie patients admitted to the Medical College of Virginia Hospitals with a pre¬ sumptive diagnosis of meningitis was con¬
ducted between June 1972 and December 1973. Fifty-seven patients received no anti¬ microbial therapy before admission; of these, 22 had bacterial meningitis, ten had viral meningitis, and 25 had meningitis of unknown cause. Lumbar punctures were done on 12 patients who had received oral doses of ampieillin sodium (50 to 100 mg/kg/day) for one to three days before admission (partially antibiotic treated). Bacteria were isolated from the CSF of four patients, and one patient had Grampositive diplococci observed on Gram stain of the CSF. A coxsackievirus B5 was iso¬ lated from the CSF of one patient, and six cases were of unknown cause. Thirteen control patients with no central nervous system (CNS) infection had CSF WBC counts of three lymphocytes or less, values of CSF protein and glucose concen¬ trations within the normal range, and no growth in CSF bacterial and viral cultures. The diagnosis of meningitis was made when there were more than ten WBCs per cubic millimeter of CSF. Generally, high WBC counts in addition to abnormalities of the CSF glucose concentration or pro¬ tein concentration or both were present. The etiologic diagnosis of meningitis was established by recovery of a bacterium or virus from the CSF. Organisms were isolated and identified by standard tech¬
niques.4·5
Received for 1.
publication
March 11, 1974;
ac-
From the Department of Pediatrics, Medical College of Virginia, Richmond. Reprint requests to Department of Pediatrics, Medical College of Virginia, Health Sciences Division, Virginia Commonwealth University, Richmond, VA 23298 (Dr. Feldman).
RESULTS
Table 1 compares the age and sex of untreated patients with meningi¬ tis of bacterial, viral, and unknown causes with control patients. The average age of patients with bacte¬ rial meningitis (10.5 months) was less than that of patients with viral men¬ ingitis (71 months), meningitis of un¬ known cause (38.7 months), or of con¬ trol patients (33 months). However, considerable overlap of the respective ranges was observed. A majority of each group was male, presumably re¬ flecting both the clinic population and the relatively small numbers of pa¬ tients in each group. The age and sex of partially antibiotic-treated pa¬ tients were similar to those of un¬ treated patients. Values of CSF WBC count, per-
Table 1.—Characteristics of Patients With No CNS Infection and Untreated Patients With Meningitis of Bacterial, Viral, and Unknown Causes
ingitis.
cepted July
The level of total CSF LDH activity was determined by the method of Wacker et al." No cases had to be excluded from the study due to bloody CSF. Specimens were refrigerated at 4 C (39 F) and enzyme ac¬ tivity was determined within 24 hours of the lumbar puncture. Total WBC and differential cell counts and glucose and protein concentrations were routinely determined on CSF speci¬ mens. All CSF glucose concentrations greater than 50 mg/100 ml were consid¬ ered normal. The normal range of CSF to¬ tal protein concentrations was 15 to 45 mg/100 ml.
Cases Sex M
No CNS Infection 13
7
Meningitis
,-v--, Bacterial Unknown Viral 22 25 10 7
13
18
F_(5_3_9_7
Age (mo) Mean
33
71
10.5
38.7
Range_1.5-120_1-168_0.25-84_0.25-144
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Table 2.—CSF Protein and Glucose Concentrations, Levels of LDH Activity, WBC Counts, and Isolates From Partially Antibiotic-Treated Patients With Meningitis
No.
10 11 12
Protein,
Glucose,
ml 480 400 103 60 100 40 80 90 38 32 38 110
ml 11 10 22 34
mg/100
mg/100
WBCs/ cu mm
%
Isolate
435
29,590 4,425
96 98 86 79 57 10 43 26 20 80 76 99
Gram-positive diplococci* D/p/ococcus pneumoniae
178 130 74 230 21 215 47 20 13 13 60
63
74 41 70 70
Gram-positive diplococci
*
LHD, Units/ml
were
356 794 135 389 760
1,126 101 285 640
1,640
observed
on a
PMNs,
CSF Gram
D pneumoniae
Haemophilus
influenzae
H influenzae Coxsackievirus B5 None None None None None None
stain, but cultures had
no
growth.
Table 3.—CSF Bacterial and Viral Isolates and Levels of LDH Activity From Untreated Patients With Meningitis LDH
Isolate
Haemophi/us influenzae Streptococcus pyogenest D/p/ococcus pneumoniae
No. of No. of Cases Cases Bacteria 11
Value 424*
Range 70-1,300 531- 875
92-1,000
Escher/ch/a coli Listeria monocytogenes
Staphylococcus epidermidist Mycobacterium tuberculosis
Activity, Units/ml
394 175 305 145
1
Viruses Coxsackievirus B5 Echovirus 4 Echovirus 11 Echovirus 14 *
Mean value.
t
/3-hemolytic, Infected
21* 20* 18 12
10-29 16-26
not Lancefield typed. ventriculoperitoneal shunt.
centage of polymorphonuclear leu¬ kocytes (PMNs), and total protein
concentrations from patients with bacterial and viral meningitis are shown in Fig 1. The WBC count of two patients with bacterial men¬ ingitis was clotted. Percentage of PMNs was not determined for four patients with viral meningitis whose WBC counts were 14, 32, 39, and 75 per cu mm of CSF. When mean values from untreated patients with bacte¬ rial and viral meningitis were com¬ pared, significant differences were observed. For example, the average CSF WBC count from patients with bacterial meningitis was 8,000/cu mm
compared to 300/cu mm from pa¬ tients with viral meningitis. Sim¬ ilarly, the mean total protein concen¬ trations in the CSF were 347 and 52 as
mg/100 ml, respectively. However, values observed from patients with
viral meningitis were overlapped by those from patients with bacterial
meningitis.
Values of CSF glucose concentra¬ tion and LDH activity from un¬ treated patients with bacterial and viral meningitis are shown in Fig 2. The mean CSF glucose concentration from patients with bacterial men¬
ingitis (21 mg/100 ml) was signifi¬ cantly different from that of patients
with viral
meningitis (58 mg/100 ml), although overlap of the ranges was
observed. In contrast to the other CSF measurements, both the mean value (444 units/ml) and the range of values (70 to 1,300 units/ml) of the CSF LDH activity from patients with bacterial meningitis differed from those of patients with viral men¬ ingitis (mean, 19 units/ml; range, 10 to 20 units/ml). The mean level of CSF LDH activity of 13 control pa¬ tients was 20 units/ml (range, 5 to 30 units/ml). The level of CSF LDH ac¬ tivity and, to a lesser degree, the CSF glucose concentration more accurate¬ ly reflected the viral or bacterial cause of the meningitis than did the CSF total WBC and differential cell counts and total protein concentra¬ tion (Fig 1 and 2). The majority of untreated cases of meningitis of unknown cause had rel¬ atively low CSF WBC counts, total protein concentrations, percentage of PMNs (Fig 1), and levels of CSF LDH activity (Fig 2). The CSF glucose con¬ centrations were relatively high (Fig 2). These values were similar to those from patients with viral meningitis. Four cases had values of CSF LDH activity within the bacterial range (greater than 70 units/ml) associated with low CSF glucose concentrations. Four cases had levels of CSF LDH ac¬ tivity between those observed from proved bacterial and viral cases of meningitis (42 to 45 units/ml). One of the latter cases had a low CSF glucose concentration of 45 mg/100 ml, which indicated that this case was possibly of bacterial cause. The CSF WBC counts, percentage of PMNs, and to¬ tal protein concentrations were not helpful in the classification of these cases.
The CSF WBC count, percentage of
PMNs, concentrations of CSF protein and glucose, and level of LDH activ¬ ity from patients with partially anti¬ biotic-treated meningitis are shown
in Table 2. Bacteria were isolated from four patients and a coxsackie¬ virus B5 from one patient. Case 1 was diagnosed as bacterial on the basis of Gram-positive diplococci observed on Gram stain of the CSF and typical values of other CSF measurements, although bacterial cultures showed no
Downloaded From: http://archpedi.jamanetwork.com/ by a University of California - San Diego User on 06/11/2015
=300
O)
E
150 • #
CD
•
t.
·······
O — Q-
·········
0
100
• · · • ·· ·
·· · · ·· ·
50
»·· · · ·· ·
o.
• · · ·
=2,000
>· · ·
1,000 m
Bacterial
Viral
Unknown
Fig l.-The CSF total WBC count, percentage of PMNs, and total protein concentrations in 55 cases of untreated meningitis of bacte¬ rial, viral, and unknown
causes.
Unknown Viral Bacterial LDH activity and levels of concentrations 2.—The CSF Fig glucose in 55 cases of untreated meningitis of bacterial, viral, and unknown causes.
growth. Cases 9 and 11 were classi¬ fied as aseptic on the basis of typical findings, including levels of CSF LDH activity within the viral range. The CSF glucose concentration and level of LDH activity were not af¬ fected by partial antibiotic treatment
cases from which an agent isolated from the CSF (cases 1 through 6). Cases 7 and 12 were clas¬ sified as probably of bacterial origin on the basis of high CSF WBC counts, levels of LDH activity, and total pro¬ tein concentrations. Cases of men¬ ingitis of unknown cause could not all be classified on the basis of these measurements (cases 8 and 10). For example, case 10 had a low CSF glu¬ cose concentration (41 mg/100 ml), but also a low level of CSF LDH ac¬
in those was
tivity (13 units/ml). However,
as
noted in the group of untreated pa¬ tients, the level of CSF LDH activity and glucose concentration most accu¬ rately reflected the cause of the men¬
ingitis (cases
1
through 6) in this
small series of partially treated cases. A presumptive diagnosis of bacte¬ rial or viral meningitis was made on the basis of the initial CSF measure¬ ments, including level of CSF LDH activity, although all patients were treated intravenously with high-dose, broad-spectrum antibiotics. Patients with bacterial meningitis who had levels of CSF LDH activity that were uniformly greater than 70 units/ml were treated intravenously with ap¬ propriate high-dose antibiotics for at least 14 days. Both the clinical course and CSF measurements of cases of presumed viral cause in which initial levels of CSF LDH activity were less than 30 units/ml were reevaluated af¬ ter three to five days of antibiotic therapy, and treatment was stopped if a typically viral picture, including a second CSF LDH activity level of less than 30 units/ml and no growth in bacterial cultures, was observed. Cases with levels of CSF LDH activ¬ ity between 30 and 70 units/ml were
considered bacterial. The level of CSF LDH activity was found to be useful both as a guide to therapy of sus¬ pected cases of viral meningitis and as an indication of response of proved bacterial cases to treatment. Further¬ more, the level of CSF LDH activity was the most sensitive CSF measure¬ ment in this regard, as compared to CSF total WBC and differential cell counts and total protein and glucose concentrations. The bacterial and viral isolates from the CSF of untreated patients are shown in Table 3. Eleven of 22 of the bacterial isolates were Haemo¬ philus influenzae. Listeria monocytogenes and Escherichia coli were iso¬ lated from patients 2 weeks and 1 month old, respectively. Streptococcus pyogenes (/3-hemolytic, not Lancefield typed) was isolated from four infants who were 1 week, 2 weeks, 2 months, and 3 months old. The levels of CSF LDH activity of the latter two pa¬ tients were 531 and 875 units/ml, re-
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A CSF LDH activity level of 68 units/ml was found in one pa¬ tient who had probable tuberculous meningitis (positive tine test, a low CSF glucose concentration of 28 mg/100 ml, a CSF protein concentra¬ tion of 100 mg/100 ml, and a CSF WBC count of 80 lymphocytes per cu¬ bic millimeter of CSF), and Mycobac¬ terium tuberculosis was isolated from the CSF of another patient. Staphylo¬
spectively.
epidermidis (coagulase-negative) was repeatedly isolated from the CSF of one patient with an infected ventriculoperitoneal shunt. Among the untreated cases, cox¬
coccus
sackievirus B5 and echovirus 4 ac¬ counted for five and three of the viral isolates, respectively (Table 3). Echoviruses 11 and 14 comprised the re¬ mainder. Only one virus was isolated in December. The rest were recovered from June through September (five viruses were isolated during August 1972). In contrast, bacteria were re¬ covered predominantly from Decem¬ ber through March (14 cases). No quantitative relationship was found between the level of CSF LDH activ¬ ity and causative bacterial and viral
agents.
Organisms were recovered from the CSF in six of 13 cases of partially an¬ tibiotic-treated meningitis (Table 2). Haemophilus influenzae was isolated from two patients, and Diplococcus pneumoniae was isolated from two patients. Coxsackievirus B5 was the only viral isolate. COMMENT
Converse and co-workers7 showed that determination of the CSF total WBC and differential cell counts and total protein and glucose concentra¬ tions may not identify all cases of bacterial meningitis. The present study shows that addition of the de¬ termination of the level of CSF LDH activity to these measurements in¬ creases the likelihood of correct classi¬ fication of cases of meningitis before culture results are available. Previous studies suggested that de¬ termination of the level of CSF LDH activity would be useful in the differ¬ entiation between early or partially antibiotic-treated bacterial menin¬ gitis and aseptic meningitis.13·8 The
data in this study indicate that de¬ termination of the level of CSF LDH activity is useful, although further studies are necessary to compare the levels of CSF LDH activity with other measurements used in the diag¬ nosis of partially treated meningitis. These results confirm the preliminary data of Neches and Platt2 who showed that the level of CSF LDH activity was high or low in 13 cases of men¬ ingitis due to various bacteria or mumps virus, respectively, despite prior antibiotic therapy. Although the range of levels of CSF LDH activity from patients with viral meningitis was not overlapped by that of patients with bacterial meningitis is this series, Beaty and Oppenheimer1 and Neches and Platt2 reported a small number of cases of bacterial meningitis that had values of CSF LDH activity in the aseptic range. This overlap of values is com¬ parable to that observed with concen¬ trations of CSF protein and glucose and WBC count. Thus, cases that have levels of CSF LDH activity above the normal range should be treated as bacterial until proved oth¬ erwise. Furthermore, other conditions such as metastatic tumor to the CNS, intrameningeal leukemia, and cerebrovascular accident can elevate the level of total CSF LDH activity.3-8 The level of CSF LDH activity must be interpreted only in conjunction with other laboratory values and clin¬ ical observations. Beaty and Oppenheimer1 reported a relationship between a high level of CSF LDH activity and recovery of pneumococci, while a relatively low level of CSF LDH activity was associ¬ ated with the recovery of meningococci. Neches and Platt2 reported low levels of CSF LDH activity in three cases of probable mumps meningitis. No relationship between specific agents and the level of CSF LDH ac¬ tivity was found in the present study. The origin of the CSF LDH activity in patients with bacterial and viral meningitis is not clear. Several inves¬ tigators reported no relationship be¬ tween the level of CSF LDH activity and CSF total WBC and differential cell counts and protein and glucose concentrations.11 However, patterns
of CSF LDH isozymes from pa¬ tients with bacterial meningitis showed a preponderance of isozymes 4 and 5, which suggested that the enzyme was derived from granulocytes.19 The CSF LDH isozyme patterns from patients with aseptic meningitis showed elevated levels of isozymes 1 and 2, which suggested that the enzyme was derived from brain tissue.1 An interpretation con¬ sistent with available data is that the level of CSF LDH activity reflects the type and number of WBCs and the kinetics of WBC turnover involved in the host response to infection. S. Bakerman, MD, and M. Escobar, PhD, pro¬ vided support and encouragement; William Laupus, MD, and Harold Maurer, MD, reviewed the manuscript.
Nonproprietary Name and Trademarks of Drug Ampieillin sodium—Alpen-N, Amcill-S, Omnipen-N. References 1. Beaty HN, Oppenheimer S: Cerebrospinal fluid lactic dehydrogenase and its isoenzymes in infections of the central nervous system. N Engl J Med 279:1197-1202, 1968. 2. Neches W, Platt M: Cerebrospinal fluid LDH in 287 children, including 53 cases of meningitis of bacterial and nonbacterial etiology. Pediatrics 41:1097-1103, 1968. 3. Lending M, Slobody LB, Mestern J: Cerebrospinal fluid glutamic oxaloacetic transaminase and lactic dehydrogenase activities in children with neurologic disorders. J Pediatr 65:415-421, 1964. 4. Bailey WR, Scott EG: Diagnostic Microbiology: A Textbook for the Isolation and Identification of Pathogenic Microorganisms, ed 3. St. Louis, CV Mosby Co, 1970,
pp 115-225. 5. Melnick JL, Wenner HA: Enteroviruses, in Lennette EH, Schmidt NJ (eds): Procedures for Viral and RickDiagnostic ettsial Infections, ed 4. New York, American Public Health Assoc Inc, 1969, pp 529\x=req-\ 602. 6. Wacker WEC, Ulmer DD, Vallee BL: infarcMetalloenzymes and action: II. Malic and lactic tivities and zinc concentrations in serum. N Engl J Med 255:449-453, 1956. 7. Converse GM, Gwaltney JM Jr, Strassburg DA, et al: Alteration of cerebrospinal fluid findings by partial treatment of bacterial meningitis. J Pediatr 83:220-225, 1973. 8. Wroblewski F, Decker B, Wroblewski R: The clinical implications of spinal-fluid lactic dehydrogenase activity. N Engl J Med 258:635-639, 1958. 9. Van der Helm HJ, Zondag HA, Klein F: On the source of lactic dehydrogenase in cerebrospinal fluid. Clin Chim Acta 8:193\x=req-\ 196, 1963.
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myocardial dehydrogenase
Partially Antibiotic-Treated Meningitis
William E. Feldman, MD, MS
High levels of cerebrospinal fluid (CSF) lactic acid dehydrogenase (LDH) activity were found in 23 cases of bacterial meningitis, but significantly lower levels of CSF LDH activity were observed in 11 patients with viral meningitis and in 13 patients with no central nervous system infection. No correlation was found between levels of CSF LDH activity and specific agents or the amounts of CSF white blood cells, protein, and glucose. The number of meningitis cases of unknown cause that could be classified as probably bacterial or viral was increased by determination of the level of CSF LDH activity. The level of CSF LDH activity is useful in differentiating bacterial from viral meningitis and, along with determination of the CSF blood cell counts and protein and glucose levels, aids in classification of meningitis before culture results are available. fluid (CSF) Totallacticcerebrospinal dehydrogenase (LDH) much
acid is activity greater in patients with bacterial meningitis than in pa¬ tients with aseptic meningitis.13 Thus, determination of the level of CSF LDH activity has been proposed for use in situations where clinical and laboratory differentiation be¬ tween bacterial and viral meningitis is difficult. However, no studies have systematically compared the levels of CSF LDH activity with commonly used CSF measurements to deter¬ mine the relative usefulness of these values in the diagnosis of meningitis. The present study compares the value of determination of the level of CSF LDH activity with CSF white blood cell (WBC) count and concentrations of CSF protein and glucose in differ¬ entiating bacterial and viral men¬
SUBJECTS AND METHODS A prospective study of 70 consecutive pediatrie patients admitted to the Medical College of Virginia Hospitals with a pre¬ sumptive diagnosis of meningitis was con¬
ducted between June 1972 and December 1973. Fifty-seven patients received no anti¬ microbial therapy before admission; of these, 22 had bacterial meningitis, ten had viral meningitis, and 25 had meningitis of unknown cause. Lumbar punctures were done on 12 patients who had received oral doses of ampieillin sodium (50 to 100 mg/kg/day) for one to three days before admission (partially antibiotic treated). Bacteria were isolated from the CSF of four patients, and one patient had Grampositive diplococci observed on Gram stain of the CSF. A coxsackievirus B5 was iso¬ lated from the CSF of one patient, and six cases were of unknown cause. Thirteen control patients with no central nervous system (CNS) infection had CSF WBC counts of three lymphocytes or less, values of CSF protein and glucose concen¬ trations within the normal range, and no growth in CSF bacterial and viral cultures. The diagnosis of meningitis was made when there were more than ten WBCs per cubic millimeter of CSF. Generally, high WBC counts in addition to abnormalities of the CSF glucose concentration or pro¬ tein concentration or both were present. The etiologic diagnosis of meningitis was established by recovery of a bacterium or virus from the CSF. Organisms were isolated and identified by standard tech¬
niques.4·5
Received for 1.
publication
March 11, 1974;
ac-
From the Department of Pediatrics, Medical College of Virginia, Richmond. Reprint requests to Department of Pediatrics, Medical College of Virginia, Health Sciences Division, Virginia Commonwealth University, Richmond, VA 23298 (Dr. Feldman).
RESULTS
Table 1 compares the age and sex of untreated patients with meningi¬ tis of bacterial, viral, and unknown causes with control patients. The average age of patients with bacte¬ rial meningitis (10.5 months) was less than that of patients with viral men¬ ingitis (71 months), meningitis of un¬ known cause (38.7 months), or of con¬ trol patients (33 months). However, considerable overlap of the respective ranges was observed. A majority of each group was male, presumably re¬ flecting both the clinic population and the relatively small numbers of pa¬ tients in each group. The age and sex of partially antibiotic-treated pa¬ tients were similar to those of un¬ treated patients. Values of CSF WBC count, per-
Table 1.—Characteristics of Patients With No CNS Infection and Untreated Patients With Meningitis of Bacterial, Viral, and Unknown Causes
ingitis.
cepted July
The level of total CSF LDH activity was determined by the method of Wacker et al." No cases had to be excluded from the study due to bloody CSF. Specimens were refrigerated at 4 C (39 F) and enzyme ac¬ tivity was determined within 24 hours of the lumbar puncture. Total WBC and differential cell counts and glucose and protein concentrations were routinely determined on CSF speci¬ mens. All CSF glucose concentrations greater than 50 mg/100 ml were consid¬ ered normal. The normal range of CSF to¬ tal protein concentrations was 15 to 45 mg/100 ml.
Cases Sex M
No CNS Infection 13
7
Meningitis
,-v--, Bacterial Unknown Viral 22 25 10 7
13
18
F_(5_3_9_7
Age (mo) Mean
33
71
10.5
38.7
Range_1.5-120_1-168_0.25-84_0.25-144
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Table 2.—CSF Protein and Glucose Concentrations, Levels of LDH Activity, WBC Counts, and Isolates From Partially Antibiotic-Treated Patients With Meningitis
No.
10 11 12
Protein,
Glucose,
ml 480 400 103 60 100 40 80 90 38 32 38 110
ml 11 10 22 34
mg/100
mg/100
WBCs/ cu mm
%
Isolate
435
29,590 4,425
96 98 86 79 57 10 43 26 20 80 76 99
Gram-positive diplococci* D/p/ococcus pneumoniae
178 130 74 230 21 215 47 20 13 13 60
63
74 41 70 70
Gram-positive diplococci
*
LHD, Units/ml
were
356 794 135 389 760
1,126 101 285 640
1,640
observed
on a
PMNs,
CSF Gram
D pneumoniae
Haemophilus
influenzae
H influenzae Coxsackievirus B5 None None None None None None
stain, but cultures had
no
growth.
Table 3.—CSF Bacterial and Viral Isolates and Levels of LDH Activity From Untreated Patients With Meningitis LDH
Isolate
Haemophi/us influenzae Streptococcus pyogenest D/p/ococcus pneumoniae
No. of No. of Cases Cases Bacteria 11
Value 424*
Range 70-1,300 531- 875
92-1,000
Escher/ch/a coli Listeria monocytogenes
Staphylococcus epidermidist Mycobacterium tuberculosis
Activity, Units/ml
394 175 305 145
1
Viruses Coxsackievirus B5 Echovirus 4 Echovirus 11 Echovirus 14 *
Mean value.
t
/3-hemolytic, Infected
21* 20* 18 12
10-29 16-26
not Lancefield typed. ventriculoperitoneal shunt.
centage of polymorphonuclear leu¬ kocytes (PMNs), and total protein
concentrations from patients with bacterial and viral meningitis are shown in Fig 1. The WBC count of two patients with bacterial men¬ ingitis was clotted. Percentage of PMNs was not determined for four patients with viral meningitis whose WBC counts were 14, 32, 39, and 75 per cu mm of CSF. When mean values from untreated patients with bacte¬ rial and viral meningitis were com¬ pared, significant differences were observed. For example, the average CSF WBC count from patients with bacterial meningitis was 8,000/cu mm
compared to 300/cu mm from pa¬ tients with viral meningitis. Sim¬ ilarly, the mean total protein concen¬ trations in the CSF were 347 and 52 as
mg/100 ml, respectively. However, values observed from patients with
viral meningitis were overlapped by those from patients with bacterial
meningitis.
Values of CSF glucose concentra¬ tion and LDH activity from un¬ treated patients with bacterial and viral meningitis are shown in Fig 2. The mean CSF glucose concentration from patients with bacterial men¬
ingitis (21 mg/100 ml) was signifi¬ cantly different from that of patients
with viral
meningitis (58 mg/100 ml), although overlap of the ranges was
observed. In contrast to the other CSF measurements, both the mean value (444 units/ml) and the range of values (70 to 1,300 units/ml) of the CSF LDH activity from patients with bacterial meningitis differed from those of patients with viral men¬ ingitis (mean, 19 units/ml; range, 10 to 20 units/ml). The mean level of CSF LDH activity of 13 control pa¬ tients was 20 units/ml (range, 5 to 30 units/ml). The level of CSF LDH ac¬ tivity and, to a lesser degree, the CSF glucose concentration more accurate¬ ly reflected the viral or bacterial cause of the meningitis than did the CSF total WBC and differential cell counts and total protein concentra¬ tion (Fig 1 and 2). The majority of untreated cases of meningitis of unknown cause had rel¬ atively low CSF WBC counts, total protein concentrations, percentage of PMNs (Fig 1), and levels of CSF LDH activity (Fig 2). The CSF glucose con¬ centrations were relatively high (Fig 2). These values were similar to those from patients with viral meningitis. Four cases had values of CSF LDH activity within the bacterial range (greater than 70 units/ml) associated with low CSF glucose concentrations. Four cases had levels of CSF LDH ac¬ tivity between those observed from proved bacterial and viral cases of meningitis (42 to 45 units/ml). One of the latter cases had a low CSF glucose concentration of 45 mg/100 ml, which indicated that this case was possibly of bacterial cause. The CSF WBC counts, percentage of PMNs, and to¬ tal protein concentrations were not helpful in the classification of these cases.
The CSF WBC count, percentage of
PMNs, concentrations of CSF protein and glucose, and level of LDH activ¬ ity from patients with partially anti¬ biotic-treated meningitis are shown
in Table 2. Bacteria were isolated from four patients and a coxsackie¬ virus B5 from one patient. Case 1 was diagnosed as bacterial on the basis of Gram-positive diplococci observed on Gram stain of the CSF and typical values of other CSF measurements, although bacterial cultures showed no
Downloaded From: http://archpedi.jamanetwork.com/ by a University of California - San Diego User on 06/11/2015
=300
O)
E
150 • #
CD
•
t.
·······
O — Q-
·········
0
100
• · · • ·· ·
·· · · ·· ·
50
»·· · · ·· ·
o.
• · · ·
=2,000
>· · ·
1,000 m
Bacterial
Viral
Unknown
Fig l.-The CSF total WBC count, percentage of PMNs, and total protein concentrations in 55 cases of untreated meningitis of bacte¬ rial, viral, and unknown
causes.
Unknown Viral Bacterial LDH activity and levels of concentrations 2.—The CSF Fig glucose in 55 cases of untreated meningitis of bacterial, viral, and unknown causes.
growth. Cases 9 and 11 were classi¬ fied as aseptic on the basis of typical findings, including levels of CSF LDH activity within the viral range. The CSF glucose concentration and level of LDH activity were not af¬ fected by partial antibiotic treatment
cases from which an agent isolated from the CSF (cases 1 through 6). Cases 7 and 12 were clas¬ sified as probably of bacterial origin on the basis of high CSF WBC counts, levels of LDH activity, and total pro¬ tein concentrations. Cases of men¬ ingitis of unknown cause could not all be classified on the basis of these measurements (cases 8 and 10). For example, case 10 had a low CSF glu¬ cose concentration (41 mg/100 ml), but also a low level of CSF LDH ac¬
in those was
tivity (13 units/ml). However,
as
noted in the group of untreated pa¬ tients, the level of CSF LDH activity and glucose concentration most accu¬ rately reflected the cause of the men¬
ingitis (cases
1
through 6) in this
small series of partially treated cases. A presumptive diagnosis of bacte¬ rial or viral meningitis was made on the basis of the initial CSF measure¬ ments, including level of CSF LDH activity, although all patients were treated intravenously with high-dose, broad-spectrum antibiotics. Patients with bacterial meningitis who had levels of CSF LDH activity that were uniformly greater than 70 units/ml were treated intravenously with ap¬ propriate high-dose antibiotics for at least 14 days. Both the clinical course and CSF measurements of cases of presumed viral cause in which initial levels of CSF LDH activity were less than 30 units/ml were reevaluated af¬ ter three to five days of antibiotic therapy, and treatment was stopped if a typically viral picture, including a second CSF LDH activity level of less than 30 units/ml and no growth in bacterial cultures, was observed. Cases with levels of CSF LDH activ¬ ity between 30 and 70 units/ml were
considered bacterial. The level of CSF LDH activity was found to be useful both as a guide to therapy of sus¬ pected cases of viral meningitis and as an indication of response of proved bacterial cases to treatment. Further¬ more, the level of CSF LDH activity was the most sensitive CSF measure¬ ment in this regard, as compared to CSF total WBC and differential cell counts and total protein and glucose concentrations. The bacterial and viral isolates from the CSF of untreated patients are shown in Table 3. Eleven of 22 of the bacterial isolates were Haemo¬ philus influenzae. Listeria monocytogenes and Escherichia coli were iso¬ lated from patients 2 weeks and 1 month old, respectively. Streptococcus pyogenes (/3-hemolytic, not Lancefield typed) was isolated from four infants who were 1 week, 2 weeks, 2 months, and 3 months old. The levels of CSF LDH activity of the latter two pa¬ tients were 531 and 875 units/ml, re-
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A CSF LDH activity level of 68 units/ml was found in one pa¬ tient who had probable tuberculous meningitis (positive tine test, a low CSF glucose concentration of 28 mg/100 ml, a CSF protein concentra¬ tion of 100 mg/100 ml, and a CSF WBC count of 80 lymphocytes per cu¬ bic millimeter of CSF), and Mycobac¬ terium tuberculosis was isolated from the CSF of another patient. Staphylo¬
spectively.
epidermidis (coagulase-negative) was repeatedly isolated from the CSF of one patient with an infected ventriculoperitoneal shunt. Among the untreated cases, cox¬
coccus
sackievirus B5 and echovirus 4 ac¬ counted for five and three of the viral isolates, respectively (Table 3). Echoviruses 11 and 14 comprised the re¬ mainder. Only one virus was isolated in December. The rest were recovered from June through September (five viruses were isolated during August 1972). In contrast, bacteria were re¬ covered predominantly from Decem¬ ber through March (14 cases). No quantitative relationship was found between the level of CSF LDH activ¬ ity and causative bacterial and viral
agents.
Organisms were recovered from the CSF in six of 13 cases of partially an¬ tibiotic-treated meningitis (Table 2). Haemophilus influenzae was isolated from two patients, and Diplococcus pneumoniae was isolated from two patients. Coxsackievirus B5 was the only viral isolate. COMMENT
Converse and co-workers7 showed that determination of the CSF total WBC and differential cell counts and total protein and glucose concentra¬ tions may not identify all cases of bacterial meningitis. The present study shows that addition of the de¬ termination of the level of CSF LDH activity to these measurements in¬ creases the likelihood of correct classi¬ fication of cases of meningitis before culture results are available. Previous studies suggested that de¬ termination of the level of CSF LDH activity would be useful in the differ¬ entiation between early or partially antibiotic-treated bacterial menin¬ gitis and aseptic meningitis.13·8 The
data in this study indicate that de¬ termination of the level of CSF LDH activity is useful, although further studies are necessary to compare the levels of CSF LDH activity with other measurements used in the diag¬ nosis of partially treated meningitis. These results confirm the preliminary data of Neches and Platt2 who showed that the level of CSF LDH activity was high or low in 13 cases of men¬ ingitis due to various bacteria or mumps virus, respectively, despite prior antibiotic therapy. Although the range of levels of CSF LDH activity from patients with viral meningitis was not overlapped by that of patients with bacterial meningitis is this series, Beaty and Oppenheimer1 and Neches and Platt2 reported a small number of cases of bacterial meningitis that had values of CSF LDH activity in the aseptic range. This overlap of values is com¬ parable to that observed with concen¬ trations of CSF protein and glucose and WBC count. Thus, cases that have levels of CSF LDH activity above the normal range should be treated as bacterial until proved oth¬ erwise. Furthermore, other conditions such as metastatic tumor to the CNS, intrameningeal leukemia, and cerebrovascular accident can elevate the level of total CSF LDH activity.3-8 The level of CSF LDH activity must be interpreted only in conjunction with other laboratory values and clin¬ ical observations. Beaty and Oppenheimer1 reported a relationship between a high level of CSF LDH activity and recovery of pneumococci, while a relatively low level of CSF LDH activity was associ¬ ated with the recovery of meningococci. Neches and Platt2 reported low levels of CSF LDH activity in three cases of probable mumps meningitis. No relationship between specific agents and the level of CSF LDH ac¬ tivity was found in the present study. The origin of the CSF LDH activity in patients with bacterial and viral meningitis is not clear. Several inves¬ tigators reported no relationship be¬ tween the level of CSF LDH activity and CSF total WBC and differential cell counts and protein and glucose concentrations.11 However, patterns
of CSF LDH isozymes from pa¬ tients with bacterial meningitis showed a preponderance of isozymes 4 and 5, which suggested that the enzyme was derived from granulocytes.19 The CSF LDH isozyme patterns from patients with aseptic meningitis showed elevated levels of isozymes 1 and 2, which suggested that the enzyme was derived from brain tissue.1 An interpretation con¬ sistent with available data is that the level of CSF LDH activity reflects the type and number of WBCs and the kinetics of WBC turnover involved in the host response to infection. S. Bakerman, MD, and M. Escobar, PhD, pro¬ vided support and encouragement; William Laupus, MD, and Harold Maurer, MD, reviewed the manuscript.
Nonproprietary Name and Trademarks of Drug Ampieillin sodium—Alpen-N, Amcill-S, Omnipen-N. References 1. Beaty HN, Oppenheimer S: Cerebrospinal fluid lactic dehydrogenase and its isoenzymes in infections of the central nervous system. N Engl J Med 279:1197-1202, 1968. 2. Neches W, Platt M: Cerebrospinal fluid LDH in 287 children, including 53 cases of meningitis of bacterial and nonbacterial etiology. Pediatrics 41:1097-1103, 1968. 3. Lending M, Slobody LB, Mestern J: Cerebrospinal fluid glutamic oxaloacetic transaminase and lactic dehydrogenase activities in children with neurologic disorders. J Pediatr 65:415-421, 1964. 4. Bailey WR, Scott EG: Diagnostic Microbiology: A Textbook for the Isolation and Identification of Pathogenic Microorganisms, ed 3. St. Louis, CV Mosby Co, 1970,
pp 115-225. 5. Melnick JL, Wenner HA: Enteroviruses, in Lennette EH, Schmidt NJ (eds): Procedures for Viral and RickDiagnostic ettsial Infections, ed 4. New York, American Public Health Assoc Inc, 1969, pp 529\x=req-\ 602. 6. Wacker WEC, Ulmer DD, Vallee BL: infarcMetalloenzymes and action: II. Malic and lactic tivities and zinc concentrations in serum. N Engl J Med 255:449-453, 1956. 7. Converse GM, Gwaltney JM Jr, Strassburg DA, et al: Alteration of cerebrospinal fluid findings by partial treatment of bacterial meningitis. J Pediatr 83:220-225, 1973. 8. Wroblewski F, Decker B, Wroblewski R: The clinical implications of spinal-fluid lactic dehydrogenase activity. N Engl J Med 258:635-639, 1958. 9. Van der Helm HJ, Zondag HA, Klein F: On the source of lactic dehydrogenase in cerebrospinal fluid. Clin Chim Acta 8:193\x=req-\ 196, 1963.
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myocardial dehydrogenase
