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CLIN. CHEM. 41/3, 343-360 (1995)

CLINICALCHEMISTRY,Vol. 41, No. 3, 1995 343

Clinical Utility of Biochemical Analysis of Cerebrospinal FluidMark A. Watson and Mitchell G. Scott’

In addition to microbial culture, cytology, and immuno-logical studies, physicians rely on the clinical chemistrylaboratory for biochemical analysis of patients’ cerebro-spinal fluid (CSF). However, apart from routine glucoseand protein determinations, the clinical value of otherCSF analytes is often unclear. Here, we review theliterature pertaining to the use of CSF biochemical mea-surements in managing patients with infectious disease,neoplasia, stroke and trauma, and dementia. Although asmall number of studies demonstrate potential useful-ness of some markers, we conclude that, without furtherstudy, the data are insufficient to support the routineclinical use of most of the analytes examined.

Indexing Terms: glucose/protein/lactate dehydrogenase/lactate/gne/p2-mrogIobuIk/iaoo’w,mes/crealine knase/cytoknes/C-re-active protein/AIDS dementia complex/Alzheimer disease/multiplesclerosis/cerebral ischemia/subaiachnoid hemontia ge/meningitis!eicepha’opamy/ca’,cer/centra’ ne.vta system/Ieukemia/t,qnpMoma/tumor rnai*ers/hypoxia/pediatric chemistty/monitonng therapy/car-diac resuscitation/ace 4dcholinesterase/(3-amyloid protein/neuronalthread protein/enolase

There are many clinical settings in which laboratoryanalysis of cerebrospinal fluid (CSF) may be requestedto aid in patient management: e.g., infectious diseases,neoplastic processes, infarction, trauma, autoimmu-nity, and degeneration of the central nervous system(CNS).2 While not covered in this review, CSF analysishas also been evaluated in the diagnosis and assess-ment of psychiatric illness (1-3).

Microbiological cultures and immunological studiesare often very useful in evaluating CNS disease andare regularly used in conjunction with biochemicalanalyses. The cytology, microbiology, and immunologyof the CSF have been reviewed elsewhere (4-8) andwill not be considered here. The clinical chemistrylaboratory also has a major role in evaluating patients’

Washington University School of Medicine, Departments ofPathology and Medicine, Division of Laboratory Medicine, Box8118, 660 South Euclid Ave., St. Louis, MO 63110.

‘Author for correspondence. Fax 314-362-1461.2Nonsd abbreviations: CSF, cerebrospinal fluid; CNS,

central nervous system; LDH, lactate dehydrogenase; ADA, aden-osine deaminase; CRP, C-reactive protein; TNFa, tumor necrosisfactor a; IL, interleukin; AIDS, acquired unmunodeficiency syn-drome; H1V, human immunodeficiency virus; 32-M, -micro-globulin; ADC, AIDS dementia complex; NSE, neuron-specificenolase; CK-BB, creatine kinase brain isoenzyme; CEA, carcino-embryonic antigen; CT, computerized tomography; AChE, acetyl-cholinesterase; BuChE, butyryicholinesterase; APP, amyloida-protein precursor; and MS, multiple sclerosis.

Received June 7, 1994; accepted December 9, 1994.

CSF; however, apart from protein and glucose determi-nations in patients with suspected meningitis, theclinical utility of other biochemical analytes in CSF isoften not clear. Most “nontraditional” CSF diseasemarkers have been evaluated in small, poorly con-trolled, or poorly selected study groups and often withlittle analytical standardization. Furthermore, CSFsamples from healthy individuals are difficult to obtainso that reference ranges for well-controlled studies areoften unavailable. Assays for many of the analytesdiscussed here are not yet commercially available. Allthings considered, it is not surprising that requests foradditional (i.e., besides glucose and protein) CSF anal-yses are met with uncertainty regarding their useful-ness.

Several recent requests for nontraditional CSFchemistries prompted us to review the available liter-ature to ascertain how valuable these might be forpatient care. Here we summarize the available dataregarding the proposed use and clinical utility of CSFanalytes in a variety of clinical scenarios. Our hope isthat this review will familiarize the clinical laborato-nan with the proposed utffity of numerous nontradi-tional CSF analytes, and that the laboratorian willthus be better able to help the clinician in makinginformed use of CSF biochemical analysis.

Biochemistry and Physiology of CSF

In examining the utility of various CSF markers, it ishelpful to first understand CSF synthesis and turn-

over. Several excellent reviews (4, 9-13) cover thistopic in much more detail than the following summary.

The physiological functions of CSF include buoyantphysical support of the brain, intracerebral transportof biomolecules, removal of CNS metabolites such aslactate and C02, maintenance of constant intracranialpressure, and defense against pathogen invasion.About 70% of CSF is produced in the choroid plexus, anintricate network of capillaries, epithelial cells, andinterstitial connective tissue found in the lateral, third,and fourth ventricles. CSF circulatesfrom the lateralcerebral ventricles into the third and fourth ventricles,and then travels into the subarachnoid space. In thesubarachnoid space, flow is primarily back toward thecerebral hemispheres to the parasagittal region wherereabsorption occurs. A small amount of flow is alsodirected down the brain stem and spinal cord, ulti-mately returning to the cerebral subarachnoid space(Fig. 1). In CNS trauma, severe meningeal inflamma-tion, tumor obstruction, or tissue displacement by

VENTRICULARSAMPLING(VIA SHUNT)

Arachnoid -

Granulations

SubarachnoidSpace

TO VENOUS

,,,0CIRCULA TION

Chroid Plexus of:Lateral Ventricle

Third Ventricle

Fourth Ventricle

LUMBAR PUNCTURE

Fig. 1. Flow of cerebrospinal fluid (CSF) in relation to relevantanatomical structures in the central nervous system is depicted bysolid arrows; ventricular and lumbar puncture sites for obtainingCSF are shown.

“u”e Concentration Gradient Active Pump

Channel Counter-transporter

344 CLINICALCHEMISTRY, Vol. 41, No. 3, 1995

intracranial hemorrhage, the flow of CSF may besignificantly obstructed and affect the concentrationsof biomolecules at different sampling sites. Normally,the lumbar to cranial transit of CSF requires -1 h; flowfrom the head to the lower back is considerably morerapid. The total volume of CSF in adults is -- 140 mL.Generated at an average rate of 0.35 mLmin (500mllday), the CSF is thus replaced every 5-7 h (9).

CSF is generated in the choroid plexus throughprocesses similar to those found in renal tubular epi-thelial cells. A NaVK-ATPase in the choroid plexusactively transports Na into the CSF, causing freewater to follow. Choroid epithelial cells contain car-bomc anhydrase, and the countertransport of C1 andbicarbonate are integral to CSF formation. Vitaminsand other nutrients are secreted into the CSF byspecific transporters whereas lipophilic compoundsand physiological metabolites such as W, C02, andammonia may pass by simple diffusion (Fig. 2). Pro-teins are transported from serum to CSF by pinocytosisor specific carriers. Four properties govern the concen-tration of serum proteins in the CSF: molecular radiusof the protein, charge of the protein, plasma concentra-tion of the protein, and functional state of the blood-CSF barrier.

CSF is normally a crystal-clear fluid. Cloudy, puru-lent, bloody, or pigmented CSF is associated with manydisease states. Viscous CSF usually indicates meta-static spread of mucinous tumors into the CNS orsevere meningeal infection; frank clots or pellicles inCSF do not occur unless protein concentration exceeds

.“ Passive Diffusion 00 Carrier

©i Pinocytosis X Enzyme Catalysis

Fig. 2. Representative transport mechanisms employed by choroi-dal epithelial cells to move ions and macromolecules betweenserum and CSF; individual cells depict (left to right): water andelectrolyte transport; protein, vitamin, and micronutrient carriers;and bicarbonate metabolism and transport.

15 g/L. Xanthochromia, or pigmentation, of CSF maybe seen in several disease states. A pink or orangepigmentation is associated with oxyhemoglobin, whichmay have been generated from recent (within 2-36 h)cerebral hemorrhage. Yellow pigmentation is associ-ated with the presence of bilirubin, formed as thehemoglobin from patients with cerebral hemorrhage ismetabolized (10-48 h and up to 4 weeks after theevent); it will also be observed when serum bilirubinexceeds 100 mg/L. Xanthochromia may also occur invitro if uncentrifuged samples from a traumatic tap(i.e., erythrocyte-contaminated CSF) are allowed tostand for longer than 2 h.

The composition of CSF is 99% water (vs 93% inplasma). The osmolalities of serum and CSF are verysimilar, but each contains a slightly different comple-ment of common solutes (Table 1). More detailed tablesof reference values may be found elsewhere (9). About80% of CSF protein is serum-derived and 20% isproduced intrathecally. CNS-specific proteins, includ-ing myelin basic protein, glial fibrillary acidic protein,and T protein (desialated transferrin),constitute only1-2% of the total protein in normal CSF. Other CNS-specific proteins may be released into the CSF invarious disease states. Most CSF analytes, includingtotal protein (9), (32-microglobulin (2-M) (14), neuron-specific enolase (NSE), S-100 protein, and myelin basicprotein (15), have a wide range of reported “normal

Table 1. Common solutes in CSF and serum.Mean conc

Solute

Sodium, mmoVLPotassium, mmoVLCalcium, mmoVLChloride, mmoVLBicarbonate, mmoVLGlucose, mg/LLactate, mmovLTotal protein, mg/LCreatinine, mg/L-Microglobulin, mg/LNeuron-specific enolase, g/LS-i 00 protein, pmoVLMyelin basic protein, mg/L

Serum

1404.04.8

10326

900

1.070

101.9

CSF

1382.82.1

119

22600

1.6350

121.1 (14)6.5 (15)

406<4

Anae

Glucose

Protein

Lactate

Lactatedehydrogenase

References

6, 13, 17-19

6,9, 13

16, 20, 21, 24-28

16, 29-31

32-34

26, 35-38

39-44

a Tables 2-5: M, indicator of metabolic changes; C, indicator of specific cellular product; I, indicator of immuneactivity; D, indicatorof cell death; and P.indicatorof altered cell physiology.

CLINICAL CHEMISTRY, Vol. 41, No. 3, 1995 345

Lactate dehydrogenase, U/L 10.5 (16)a As reported in ref. 9, except as noted in parentheses.

values”. Part of this variability may be due to disparateassay techniques, but the concentrations of CSF ana-lyte are dependent on the patient’s age (9, 14, 15) andthe sampling site (9, 12). Any value obtained must beinterpreted in light of these variables.

Changes in the biochemical composition of CSF are

almost always a result of altered metabolic activity, celldeath, or immune and inflammatory activity. With fewexceptions, the substances that can be measured inCSF reflect these biological changes as sequelae to theactual pathological process rather than the processitself. Here we will review the biochemical basis and

clinical performance of various substances that can bemeasured in CSF with respect to several categories ofCNS pathologies.

Infectious Disease (Table 2)

In evaluating a patient with suspected meningitis,the clinician must obtain a careful clinical history inaddition to CSF cytology (leukocyte count and differen-tial) and cultures (5, 6, 13). Traditionally, biochemicalmeasurements of CSF protein and glucose are alsoused to distinguish bacterial, flingal, or tuberculous(i.e., septic) meningitis from viral (i.e., aseptic) menin-gitis.

CSF glucose. CSF glucose concentrations <450mg/L or <50-66% of serum values are suggestive of

150 bacterial meningitis (13). Decreased CSF glucose re-suits from changes in the physiological functioning ofthe choroid epithelium as well as from consumption bybacterial pathogens and leukocytes (9). Thus, alteredCSF glucose may reflect the sequelae of disease ratherthan the specific pathology (microbial invasion) andmay also be seen in numerous other disease states suchas meningeal neoplasia, chemical meningitis (afterintrathecal chemotherapy), and subarachnoid hemor-rhage (9). CSF glucose concentrations depend on theserum concentration, and measurement of the formerwithout the latter can be uninterpretable (17). In ahypoglycemic patient, a low CSF glucose may in fact benormal, whereas hyperglycemia may mask an other-wise apparent decrease in CSF glucose. Furthermore,in cases of uncontrolled diabetes, blood glucose as great

Table 2. Analytes measured in CNS infectious disease.

Adenosinedeaminase

C-reactive

protein

Cytokines

Basis’ Characteristics

P, M, I Derived from serumglucose; equilibrateswith serum glucose in-4 h.

C, I 80% derived from serum;blood:CSF barnerdependent.

M, I, D Independent of serumconcentrations.

Origin unclear; possiblyfrom leukocyte release.

Nonspecific leukocytecellular enzyme; used todiagnose tuberculosis inbody fluids.

Acute-phase reactant;serum-derived.

Mediators of immuneactivity.

Advantages

Familiar; simple assay;normalizes rapidly inresponse to therapy.

Familiar; simple assay.

Simple assay; moresensitive than glucose(?); remains increasedin partially treatedmeningitis patients.

Earlier detection;equivalent to glucose insome studies; remainsincreased in partiallytreated patients.

Simple, inexpensiveassay.

“Bedside” assayavailable.

Present earlier in diseasethan pleocytosis.

Disadvantages

Influenced by serumconcns.; insensitive(80%).

Insensitive and verynonspecific.

Redundant to glucose.

Redundant to glucose;unfamiliar to clinicians;falsely increased inhemolytic samples.

No more sensitive thanglucose or lactate; fewstudies.

Insensitive; depends onhost inflammatoryresponse.

Depends on hostinflammatory response;slow/expensive assays.

346 CLINICAL CHEMISTRY, Vol. 41, No. 3, 1995

as 7000 mg/L may saturate the glucose transportmechanism and result in a CSF:blood glucose ratioapproaching 0.4 in an otherwise healthy individual (9).Equilibration between serum and CSF glucose may bedelayed by as much as 4 h; hence, the timing of bothserum and CSF sample acquisition is critical, espe-cially in the febrile patient who is in a state of meta-bolic flux (17, 19). We often receive requests for CSFglucose determinations without accompanying serumsamples. This implies that, in clinical practice, serum:CSF glucose ratios are seldom used or, when they aredetermined, their values are calculated from inappro-priately timed collections. In infants, a CSF:bbood glu-cose ratio of <0.8 should be considered significant(6, 13). However, this ratio is known to vary during thefirst few months of life, making interpretation difficultin neonates (18).

Despite these theoretical limitations, reported sensi-tivities and specificities for distinguishing septic andaseptic meningitis are favorable. Using a CSF:serumratio cutoff of <0.4, Donald et al. (19) reported an 80%sensitivity and 98% specificity for distinguishing bac-terial (n = 119) and aseptic (n = 97) meningitis. Usingthe same cutoff value in a smaller population (23bacterial and 27 aseptic cases), Genton and Berger (20)determined a sensitivity of 91% and specificity of 96%.Other studies report similar values, but caution thatresults may depend on the patient’s age and the infec-tious organism (13, 16). In general, CSF glucose mea-surement is adequately sensitive and specific in pa-tients already clinically suspected of having septic oraseptic meningitis. Another advantage of CSF glucose(compared with CSF protein or lactate; see below) isthat values often return to normal soon after effectivetherapy, suggesting that serial determinations may beuseful for monitoring treatment efficacy (13).

CSF proteir&. Measurement of CSF protein is alsoused to distinguish septic from aseptic meningitis.Protein concentrations >1 g/L are often viewed asdiagnostic for bacterial, fungal, or tuberculous menin-gitis, reflecting the presence of the pathologic organism(13). Unfortunately, the increase of CSF protein is asequela in many CNS disease processes, usually inassociation with increased permeability of the blood-brain barrier, vasogenic brain edema, hypercellularity,and release of brain-specific proteins during cell death(9, 12). Furthermore, contamination by erythrocytes

from a traumatic lumbar puncture or intracerebralhemorrhage will increase CSF protein concentrationsby -10 mgfL for every 1000 erythrocytes (6). Never-theless, like glucose measurements, reported diagnos-tic performance is quite good in preselected patientpopulations having a high suspicion of infectious men-ingitis. Using a cutoff value of 2 g/L, Genton andBerger (20) calculated a sensitivity of 86% and aspecificity of 100% for distinguishing bacterial andaseptic meningitis. At a 1 gIL cutoff, Donald and Malan(21) calculated sensitivities and specificities of 82%and 98% in their meningitis patient population. Thesereports demonstrate that, although an isolated deter-

mination of CSF protein is a poor tool for differentialdiagnosis of unknown CNS disease, in conjunction withother clinical and laboratory data it may provide usefulinformation to support or refute a diagnosis.

CSF lactate. Although the combined findings fromCSF cytology, culture, and glucose and protein deter-mination are often sufficient to establish or refute adiagnosis of septic meningitis, several other adjuvantbiochemical markers have been investigated. The beststudied of these is lactate. The concentration of CSFlactate depends largely on production from CNS glycol-ysis and is independent of serum lactate [at physiolog-ical pH, lactate is ionized and crosses the blood-CSFbarrier at a very slow rate (22 )]. Although increases inCSF lactate may be due to diverse processes such ashypoxia of inflamed tissues, reduced blood flow fromcerebral edema, and granulocyte and bacterial metab-olism, in most cases of infectious meningitis the CSFproduction of lactate is apparently a sequela of (and isproportional to) increased numbers of leukocytes (23).

Many authors have suggested that CSF lactate is amore sensitive indicator of bacterial meningitis than isglucose or protein. For example, Genton and Berger(20), studying 53 cases of diagnosed meningitis, dem-onstrated that 24 of 25 patients with bacterial menin-gitis (culture or gram-stain positive) initially presentedwith a CSF lactate >4.2 mmol/L. At the same time,none of the 28 patients with presumed viral meningitis(as evidenced by negative cultures and spontaneouscure without antibiotics) demonstrated values exceed-ing the 4.2 mmol/L cutoff. However, use of a CSF:bloodglucose ratio of 0.4 allowed the categorization of pa-tients into bacterial and aseptic cases with almostequal sensitivity (96% by lactate vs 91% by glucoseratio). In another investigation, use of a lower cutoff of3.0 mmol/L identified 30 of 32 septic meningitis pa-tients, with only 2 false-positive cases (24). Theseauthors also observed several patients in whom CSFlactate concentrations were increased before any indi-cation of CSF pleocytosis. Additional studies haveshown similar sensitivities in discriminating betweenseptic and aseptic meningitis patients by use of CSFlactate concentrations (16, 21, 25-27). These studies,however, were performed on small patient populations,with cutoff values optimized from the test population,and often without reference to other measures such asthe CSF:serum glucose ratio. Lactate does have theadvantage of being independent of serum concentra-tions. Unlike glucose, CSF lactate may remain in-creased for longer periods after the initiation of suc-cessful treatment (13); this makes lactate lessdesirable as a measure of patient response but perhapsit is a more appropriate measure in patients treatedwith antibiotics before lumbar puncture (28).

Lactate dehydrogenase (LDH). Several authors havecited LDH, a 135-kDa intracellular enzyme that cata-lyzes the final step of anaerobic glycolysis, as a usefulCSF analyte for detecting bacterial meningitis (29).For example, Knight et al. (16) calculated a referenceinterval for CSF LDH activity (0-23.5 UIL) and then


demonstrated that mean concentrations were higher inpatients with bacterial meningitis (805 U/L; n = 73)

than in aseptic patients (10.5 UIL; n = 20). Theyconcluded that LDH is a more sensitive and earlierindicator of bacterial meningitis than glucose is. In apopulation of 70 pediatric patients, Feldman (30) foundthat CSF LDH determinations not only demonstratedlittle overlap between diagnosed viral and bacterialcases, but could also help the clinician classifSr casesthat were indeterminate according to protein and glu-cose measurements. However, other investigators dem-onstrated considerable overlap in LDH values betweenpatients with diagnosed viral and bacterial meningitisand did not advocate its use (31). The discrepancybetween these findings is undoubtedly attributable todifferences in patient populations (both the patientages and the nature of the infectious organisms), timeof sampling with respect to clinical course, and degreeof prior treatment with antibiotics. Unfortunately, be-cause individual patient’s data are not given, it isimpossible to reach a consensus between these studies.Most studies agree that false increases in LDH can beseen in erythrocyte-contaminated samples (29, 31).LDH reference values are also higher in neonates (31).Finally, CSF LDH is increased in several noninfectiousCNS diseases (discussed later). Although we seldomreceive requests for CSF LDH values for diagnosinginfectious meningitis, this assay appears as useful asglucose and lactate assays (albeit less noted) for thispurpose.

Adenosine deaminase (ADA). Originally suggestedas a marker to distinguish tuberculous meningitis fromother forms of septic and aseptic meningitis, CSF ADAactivity has been evaluated in several studies as amarker of septic meningitis. An enzyme abundant inleukocytes, increased concentrations of ADA indicateincreased inflammatory activity as a sequela to septicCNS infection. An early report (32) demonstrated thatCSF ADA was increased in 64% of tuberculous andbacterial meningitis cases-a sensitivity that offers noadvantage over protein or glucose determinations. Fur-thermore, septic patients demonstrated a wide range ofvalues. Several other studies (33, 34) have demon-strated similar findings, and most investigators agreethat CSF ADA does not provide diagnostic informationbeyond that of CSF glucose or protein.

C-reactive protein (CRP). Another analyte used in anattempt to differentiate bacterial and viral meningitisis CRP, an acute-phase reactant protein synthesized bythe liver in response to several disease states, includ-ing trauma, infections, neoplasms, and collagen-vascu-lar diseases. Some reports suggest that CRP may besynthesized in the CNS; however, intrathecal synthesisappears to be minimal and the majority of CSF CRP isindeed derived from serum (9). Thus, measurements ininfants are often unreliable because they display ahigher and unpredictable blood-CSF permeability.Nevertheless, because a qualitative slide test is com-mercially available, the ability to assay CSF CRP “atbedside” has made this an intriguing alternative to

lactate measurements. In a study of 24 patients withculture-proven bacterial meningitis, Corrall et al. (35)demonstrated that all 24 cases were CRP-positive,whereas only 18 of 23 patients had CSF glucose <400mgfL. Furthermore, only 17 of 23 cases were correctlyidentified by gram stain. However, no comparisonswere made with results for CSF lactate or the CSF:serum glucose ratio. At the same time, only 2 of 32documented cases of nonbacterial meningitis exhibiteda positive CRP slide test result. The authors concludedthat its higher sensitivity, good specificity, and ease ofuse make the CRP slide test a helpful diagnostic toolfor distinguishing bacterial and nonbacterial meningi-tis. Other studies of the CRP slide assay have reachedsimilar conclusions (36, 37).

In a contrasting study, Komorowski et a!. (26) mea-sured CSF CRP by both nephelometric and latex ag-glutination assays in 560 patients having a wide vari-ety of neurological disorders, including bacterialmeningitis. CRP >8 mgfL (the value at which aggluti-nation occurs in the slide test) was seen in only 1 of 97“neurology” patients, 5 of 128 cancer and trauma pa-tients, and 7 of 290 “controls.” However, concentrations>8 mgfL were found in only 12 of 37 patients withbacterial meningitis. Thus, the authors concluded thatCRP provided no further diagnostic information be-yond CSF glucose, protein, lactate, or cell counts. Oneexplanation for the discrepant results between this andthe previous study may originate from differences inpatients’ ages, liver function, and the infecting organ-isms in the two study groups. Other investigators havepointed out similar shortcomings of CSF CRP. Using amore sensitive RIA and a cutoff of 100 gfL, Gray et al.(38) detected 42 of 49 culture-proven cases of bacterialmeningitis; however, false negatives were still seen inneonates and in patients with Group B streptococcalinfections, partial antibiotic treatment, early stage ofdisease, immunosuppression, and liver dysfunction.Some false negatives were explained by the fact that, inthe absence of an appropriate inflammatory response,CRP synthesis is attenuated and CSF concentrationsdo not demonstrate the anticipated increase. Finally,they observed a large overlap in CRP values between100 and 1000 g/L in patients with bacterial meningi-tis and patients with other conditions such as non-CNSbacterial infection, seizure disorders, metabolic distur-bances, and peripheral neuropathies (38). Althoughamenable to rapid bedside measurement, apparentlyCSF CRP is often insensitive, nonspecific, and toodependent on a functioning host inflammatory re-sponse to make it diagnostically useful for distinguish-ing septic from aseptic meningitis.

Cytokines in CSF. Inflammatory mediator cytokinessuch as tumor necrosis factor a (TNFa) and the inter-leukins (IL-2, IL-6) have also been examined for clini-cal utility in CNS infections. One retrospective study(39) observed that 33 of 38 cases of bacterial meningitisdemonstrated detectable amounts of TNFa in CSF,whereas 0 of 18 patients with viral meningitis hadmeasurable amounts. Although this study demon-


strated that the concentrations of TNFa in the septicgroup correlated with CSF protein content and diseaseseverity, no data suggested that TNFa measurementsaided in diagnosis or therapeutic management betterthan CSF protein and glucose concentrations.Glim#{225}keret al. (40) compared the sensitivity andspecificity of a TNFa IRMA with the correspondingvalues for routine CSF protein and glucose measure-ments. In their test population of 139 patients (51 withculture-proven bacterial meningitis and 78 with de-fined aseptic meningitis), they calculated an 82% sen-sitivity and 94% specificity for distinguishing bacterialmeningitis with use of a cutoff value of 67 ngIL. Thiscutoff value was optimized within their patient popu-lation, and the sensitivity and specificity values werenot significantly better than those for CSF protein ortotal CSF glucose. In a similar study, a CSF TNFacutoff value of >200 ng/L achieved 80% sensitivity(similar to that for the serum:CSF glucose ratio) and100% specificity (0 of 63 cases of nonbacterial menin-gitis displayed TNFa >200 ng/L) (41).

In another study, 101 of 106 infants and childrenwith documented bacterial meningitis demonstrateddetectable IL-i (>20 ngfL) in CSF from their initiallumbar puncture (42). However, the variability wastremendous (mean ± SD, 994 ± 1293 ngfL), and nodata were presented comparing IL-i with CSF glucoseor with other analytes sampled at the same time. Thesesame investigators reported that among 42 neonateswith gram-negative meningitis, the 11 who died hadsignificantly higher peak values of IL-i and main-tained CSF concentrations of IL-i above 200 ngfL

longer (3.3 ± 0.5 days) than did the 3i infants whosurvived infection (1.3 ± 0.3 days) (43). In a smallerstudy involving a commercially available ELISA forIL-6 (44), the concentrations of IL-6 were significantlyhigher in patients with bacterial meningitis (975.5 ±617.8 ngfL; n = 9) than in patients with documentedaseptic disease (5.8 ± 8.5 ng/L; n = ii). Although thenumbers of patients in these and other studies aresmall, they often demonstrate that, like CRP, theconcentrations of cytokines present may be highlydependent on the ability and rapidity of the host tomount a proper immune response. Therefore, the tim-ing of sample acquisition and the selection of thepatient population will largely determine the sensitiv-ity of these assays.

By either IRMA or ELISA, interferons have also beenfound to be increased in CSF in response to variousviral and bacterial CNS pathogens (45). For example,one study (46) found detectable amounts of interferon(>1000 lU/L) in 21 of 21 patients with viral meningitis,5 of 7 patients with bacterial meningitis, and only 5 of71 control patients (including those with multiple scle-rosis, migraine headache, or cervical spondylosis).Once again, however, values ranged considerably, from1000 to 60 000 lU/L. Given the lack of specificity indistinguishing septic from aseptic infections, and thewide range of values observed in a given population, it

is unlikely that this marker will be useful for patientcare (47).

Other markers. Finally, some other markers, mostlymediators or indicators of inflammatory processes,have been evaluated for discriminating between bacte-rial and aseptic meningitis; these include ferritin (48),

fibronectin (49), neopterin (50), and a1-antitrypsin(51). Studies evaluating their use are few or singular,and the paucity of available data makes it difficult toevaluate their potential utility. Clinical history, CSFcytology, culture, and measurements of CSF glucoseand protein are usually sufficient to diagnose septicmeningitis. We found no data to suggest that measure-ment of any other biochemical analyte could further orbetter assist the clinician in diagnosing or monitoringCNS infection, except for lactate, which may be appli-cable to patients who have been partially treated withantibiotics. On the basis of their theoretical role asearly and sensitive indicators of host immune responseto microbial invasion, the use of some cytokines such asIL-6 may deserve further clinical investigation as di-agnostic markers, particularly as more standardizedassays become available. At this time, however, their

use should be considered purely experimental.

Hepatic Encephalopathy and HIV-1 -Associated

Dementia (Table 3)

In the absence of infectious disease, the clinician isoften forced to search for other pathologies in thepatient with changes in mental status (e.g., coma,delirium, lethargy). Hepatic encephalopathy may beone cause of such a state and consequently, althoughwe receive very few requests for its measurement, CSFglutamine has been suggested as a simple diagnosticassay. For example, Hourani et al. (52) demonstratedthat CSF glutamine concentrations are higher in coma-tose patients with hepatic encephalopathy (403 ± 140mg/L) than in noncomatose patients with liver disease(216 ± 62 mg/L) or “controls” (126 ± 51 mgfL). Theyalso demonstrated a correlation between grade of en-cephalopathy and the absolute value of CSF glutamine.Other investigators, however, have demonstratedequally high concentrations of CSF glutamine in otherCNS diseases, particularly meningitis with extensivepleocytosis and cerebral hemorrhage (53, 54). Overall,measurement of CSF glutamine is a simple and effec-tive diagnostic assay for evaluating hepatic encepha-lopathy (9), but the clinician should be aware of itspotentially limited specificity.

A newly emerging diagnostic dilemma for dementedpatients involves those who are human immunodefi-ciency virus (HW) positive and present with alteredneurological status. In this population, the clinicianmust distinguish between acquired immunodeficiency

syndrome (AIDS) dementia complex (ADC) and otherneurological processes, e.g., substance abuse, psychiat-ric disorders, opportunistic CNS infections, and CNSlymphoma. We have recently received a number ofrequests for measurement of /32-M in the CSF inresponse to reports that this molecule is a marker of

Analyte Basis Disease Characteristics Advantages Disadvantages References

Glutamine M Hepaticencephalopathy.

Product of CNSammoniametabolism.

Concns. related toclinical grade ofencephalopathy.

May be increased inother nonhepaticCNS disease.

52-54

132-Microglobulin I HIV-dementia(ADC).

HLA-associated cell-surface molecule;derived from bothserum and CNSsources.

Sensitive and specificin discrete patientpopulations.

Generally nonspecific. 55-58

Neopterin I Monitoring ADC orMS.

Pteridine marker ofimmune cellactivity,

None cited. Nonspecific marker;assay not readilyavailable.

57, 59, 132

Cytokines I Monitoring MS. Mediators of immuneactivity,

None cited. Depends oninflammatoryresponse; slow!expensive assays.

134-142

Myelin basicprotein

D Monitoring ADC. Brain-specific protein;release into CSFassociated withwhite matterdestruction.

CNS-specific protein;more specific forCNS destructionthan forinflammatoryprocesses.

Not specific foretiology of CNSdamage; assay notreadily available;less sensitive thanenzyme markers;few studies.

64

Amyloidprecursor

C Marker forAlzheimerdisease.

Brain-specific protein; Specific for disease Role in 125-127

abnormal process. pathophysiologyprocessing unclear; fewassociated with studies; assay notsenile plaques. readily available.

Table 3. Analytes measured in dementias and multiple sclerosis.


neurological involvement in HIV infection (55-57) and

another suggesting that CSF 2-M may be specificallyused to diagnose HW-i dementia (58).

2-M is an ii.7-kDa cell-surface protein associatedwith class I HLA antigens on all nucleated cells; it ispresent in highest concentrations on activated T lym-phocytes and thus can indicate altered immune systemactivity. In a study sponsored by the Multicenter AIDSCohort Study (58), CSF 2-M concentrations weremeasured in 110 HIV-positive, nondemented patientsand 34 HW-demented patients [defined as progressiveneurological deterioration in the absence of computer-ized tomography (CT), culture, or psychiatric findings].An index of intrathecal f32-M synthesis, based on CSFand serum contents of albumin and j32-M, was calcu-lated to correct for anomalous bbood-CSF barrier per-meabiities. The 2-M index was significantly greaterin the 34 demented patients than in their nondementedcounterparts (P <0.001). With use of a cutoff value of2.2 mg/L for total CSF f32-M, abnormal concentrationswere found in 29 of 34 demented patients (4.23 ± 2.33mgfL) vs 27 of 109 nondemented patients (1.65 ± 0.75

mgfL). While suggesting that determination of CSF

132-M may be useful to evaluate cognitive symptoms inH1V patients, the authors emphasized two importantcaveats. First, the patient population was preselectedfor the absence of opportunistic infections and CNSlymphoma, both common diseases in HW patients withsequelae that result in increased immune activity andincreased CSF 132-M (see below). Thus, the specificity ofCSF $32M will clearly be lower among a group ofunselected HW patients. Second, a modest increase ofCSF j32-M in nondemented patients was correlated

with the duration of HIV infection and the degree ofimmunosuppression, resulting in a large overlap of

CSF 132-M values from demented and nondementedpatients with CD4 T cell counts <200. Thus, (32-Mmay be of use in diagnosing HIV dementia only whenpatients present early in the course of HIV infectionand when other known HW-associated CNS patholo-gies are ruled out.

Neopterin, a pteridine compound that also indicatescell-mediated immune activity, has been used to mon-itor ADC (59, 60). Brew et al. (59) found that 70patients with ADC had higher concentrations of CSFneopterin (36.8 ± 3.6 nmoIJL) than did HIV patientswithout neurological involvement (8.2 ± 1.0 nmol/L).However, CSF neopterin was also increased in HWpatients with “headache” (26.5 ± 5.1 nmolfL; n 12),CNS lymphoma (34.8 ± 11.5 nmol/L; n = 6), and otheropportunistic CNS infections (58.2 ± 11.7 nmol/L; n =

14). Whether these increases were nonspecific or rep-resented undiagnosed ADC coincident with these otherneuropathic processes is unclear. The neopterin con-centrations were correlated with severity/stage of ADC

in 7 of 8 patients treated with zidovudine (AZT), anddecreased concentrations were related to clinical im-provement, thus suggesting utility for monitoringtreatment. However, given that “improvement” isstrictly a clinical assessment in ADC, it seems unlikely

that clinicians would use any laboratory value to de-termine the effectiveness of therapy.

Other investigators have examined cytokines such asTNFa, IL-6, and IL-i as potential markers of ADC(61, 62). Although these few studies show that cytokineconcentrations might be related to the severity of ADC,

Analyte

-Microglobulin


Creatine kinase

Neuron-specificenolase

Table 4. Analytes measured In CNS neoplasia.Basis Characteristics Advantages

C, I HLA-associated cell- Sensitive and specific insurface molecule; discrete populations.derived from serumand CNS.

D Well-characterized Familiar assay.intracellular enzyme;sources are CNScells, infiltrating cells,and organisms.

D Brain-specific isoform Familiar assay; CNScomposes 95% of specific.CNS CK activity.

0 CNS-specific enolase CNS specific.dimer.

References

69-78

79-82

84,85

86

350 CUNICAL CHEMISTRY, Vol. 41, No. 3, 1995

the control subjects used in these studies were non-HIV patients with noninflammatory neurological dis-ease (e.g., headache, disc herniation). Therefore, thetrue specificity and diagnostic usefulness of thesemarkers in AIDS patients was probably overrated.Depressed values of CSF fibronectin are also unable todifferentiate ADC from HIV patients with secondaryinfection (63). Myelin basic protein, although nonspe-cific for the etiology of CNS damage, may be morespecific in differentiating CNS destruction in ADCfrom the nonspecific inflammatory changes of opportu-nistic infections (64). Overall, no biochemical marker issufficiently specific to discriminate between ADC andother HIV-related CNS pathology because the biologi-cal sequelae and clinical presentations of ADC, oppor-tunistic CNS infections, and CNS lymphoma are oftenindistinguishable. Because the diagnosis of ADC isoften made by excluding other CNS disease in the HIVpatient, clinicians essentially make the diagnosis with-out the aid of biochemical markers, obviating any needfor a potentially nonspecific test.

CNS Neoplasia (Table 4)

Chemical analysis of CSF has been suggested as anaid for detecting CNS neoplasms that are undetectableby imaging studies, monitoring the efficacy of short-term therapy, monitoring long-term growth of tumors,monitoring relapse in treated patients, and differenti-ating neoplastic from infectious or psychiatric CNSpathologies. Types of CNS neoplasms include primarylesions such as glioma, metastatic lesions from solidtumors, and meningeal infiltration of hematologicalmalignancies. In general, studies investigating theutility of various CSF analytes in CNS neoplasia ex-amine more than one type of tumor. Additional reviewson this subject have been published (65-68).

/32-M. Many studies have shown increased concen-trations of CSF f32-M to be an earlier indicator for CNSrelapse of leukemia and lymphoma than cytologicalfindings (4). In these settings, 132-M represents a cellu-lar product (shedding of -M by hematologic tumorcells) of the actual pathologic process rather than asequela. Mavlight et al. (69) demonstrated that pa-

tients with CNS leukemia had higher concentrations ofCSF 132-M (6.1 ± 2.3 mg/L; n = 5) than those with noCNS involvement (2.0 ± 0.2 mgfL; n = 36). Similarfindings were seen with CNS involvement of lym-phoma. Furthermore, the authors demonstrated thatCSF 132-M decreased and correlated with clinical remis-sion in patients treated with intrathecal chemother-apy.

Another study demonstrated that an increase in CSFcan precede cytological diagnosis by 4 to 8 weeks

(70). In a population of 74 patients receiving intrathe-cal chemotherapy, CSF concentrations of 132-M in pa-tients without CNS relapse (1.30 ± 0.69 mgfL, n = 54)were indistinguishable from disk herniation patientcontrols (1.51 ± 0.72 mgfL, n = 15). In all patients withCNS relapse (n = 20), 132-M was significantly greaterthan in the first two groups (4.97 ± 2.01 mgfL). Nofalse-positive results were obtained, although the au-thors were careful to document that no patient in anygroup had CNS infection (in which case increased CSF

132-M could occur as a sequela to increased immuneactivity). More importantly, this study demonstratedthat the concentrations of CSF p2-M were not increasedby intrathecal chemotherapy.

Despite these promising results, several caveatsmust be noted. Because CSF 132-M is a nonspecificmarker that is increased in several clinical conditionsincluding CNS infection (71, 72), it should be used onlywhen there is a high clinical suspicion of relapsewithout the possibility of other neuropathologic pro-cesses. Several authors have suggested poor correla-tions between CNS relapse of hematological malig-nancy and CSF j32-M values (73-76). In a smallpopulation that included patients with non-Hodgkinlymphoma, Hodgkin lymphoma, and acute lymphocyticand myelocytic leukemias, Hansen et a!. (75) found awide overlap of CSF 2-M concentrations betweenthose patients without relapse (68 -220 nmoLfL; n = 12)and those who experienced relapse (109-576 nmolJL; n= 6). Others have noted that the class and stage oftumor cell differentiation can largely influence theamount of (32-M surface expression, and hence theconcentration in CSF and the resulting sensitivity of

Disadvantages

Generally nonspecific;insensitive for diagnosingnonhematological CNSneoplasia.

Nonspecific; sensitive markerof CNS neoplasia only withleptomeningeal involvement;isoenzymes nonspecific.

Sensitive marker of CNSneoplasia only withleptomeningeal involvement.

Not specific for type of CNSpathology; assay not readilyavailable.


the measurement (76). Also, because of the smallradius of the molecule, nonspecific increases of CSF

132-M may be seen in conditions with disruption of theblood-CSF barrier [e.g., multiple sclerosis (MS), en-cephalomeningitis, or tumor invasion]. Thus, somehave recommended simultaneous measurement of se-rum and CSF concentrations of f32-M (69). Finally,because CSF 132-M contents vary with the patient’s age(14, 77), measurements may need to be normalizedaccordingly and (or) limited to following serial values(78). In summary, $32-M is probably useful only as a“one-way” test, in which an increase of CSF 32-Mvalues is clinically significant only if other CNS pathol-ogies are ruled out. However, normal CSF 2-M valuesdo not rule out CNS metastasis.

LDH and other enzymes. Although release of LDHinto the CSF as a result of cell death occurs in anumber of neuropathic conditions (79), one of the mostcommon clinical uses we observe is to detect CNSmetastasis. Twijnstra et a!. (80) demonstrated thatCSF LDH may be increased in primary CNS neo-plasms, hematological metastases, and solid tumormetastases, but only when metastatic spread involvesthe meningeal membranes. Furthermore, LDH in-crease is common in bacterial meningitis and CNSinjury (see below) so that, once again, other causes ofneurological deterioration must be ruled out. Otherauthors have attempted to increase the specificity ofLDH by measuring LDH isoenzymes (81, 82). For ex-ample, LDH1 and 2 are predominant in CSF of controlpatients, whereas increased LDH4 and LDH5 are as-sociated with neoplastic disease (82). These studies,however, demonstrated a wide overlap in isoenzymepatterns between disease groups and were limited tosmall, selected patient populations, the findings forwhich have not been confirmed in larger studies. Theprevailing conclusion is that measurement of LDHisoenzymes in the CSF is of little utility.

-Glucuronidase, creatine kinase, NSE, and glu-cose-6-phosphate isomerase are other intracellularenzymes (and thus markers of cell death) that havebeen examined for utility as markers of CNS neopla-sia. Unfortunately, none demonstrates sufficientsensitivity or specificity when used alone. For exam-ple, Tallman et a!. (83) demonstrated increased CSFfl-glucuronidase only in 13 of 26 patients with cytol-ogy-documented CNS metastasis. Clinical sensitivityof the measurement depended on the primary lesion,with adenocarcinoma and acute myelogenous leuke-mic metastases showing the best results. A study(78) of solid or hematologic tumors with and withoutCNS involvement found that nonmeningeal meta-static disease resulted in an unimpressive increase of

13-glucuronidase [20 mUfL (n = 26); controls 16 mU/L(n = 73)] and that only patients with leptomeningealmetastases demonstrated appreciable CSF enzymeactivity (mean = 89 mU/L; n = 25). Studies with thecreatine kinase brain isoenzyme (CK-BB) yieldedsimilar results: Among 30 patients with documentedCNS metastasis of breast adenocarcinoma, 10 of 12

patients with leptomeningeal metastasis demon-strated increases in CK-BB, but only 20 of the 30patients with any type of CNS metastasis demon-strated amounts greater than those of control pa-tients (84). In a study of 300 neurology patients,Pfeiffer et al. (85) also detected greater concentra-tions of CK-BB in patients with CNS neoplasms (5.5± 12.2 gfL) than in controls (0.79 ± 0.25 g/L) butfound that the isoenzyme was equally increasedamong patients with cerebral ischemic events andmeningoencephalitis, hence limiting specificity. NSEwas also quite insensitive to CNS neoplasia in bothmetastatic (1 of 44 patients with >11 g/L cutoff)and primary expression (1 of 9 patients above thecutoff) (86). Fewer studies have examined alkalinephosphatase (87) or glucose-6-phosphate isomerase(88), but these markers also have poor sensitivity(<50% detection rate) when the metastasis is tobrain parenchyma rather than leptomeningeal sites.

Tumor cell products/markers. Secreted or shedproducts of tumor cells such as chorionic gonado-tropin, a-fetoprotein, and carcinoembryonic antigen(CEA) are commonly used as non-CNS tumor mark-ers (89). Many investigators have assayed for thesemarkers in CSF, but their utility is limited to smallsubclasses of metastatic disease. For instance, CEAis an insensitive marker for CNS tumor detection(78), except in cases of metastasis where the primarytumor is previously known to shed large amounts ofCEA (e.g., some adenocarcinomas of the lung andbreast) (67). Because CEA, a-fetoprotein, and chori-onic gonadotropin are not expressed in neuronaltissue, they may indeed be very sensitive and usefulmarkers for detecting metastasis in patients withtumors that produce these substances when there isno disruption of the CNS-blood barrier (67, 68).

However, few data are available regarding theirsensitivity in large patient populations.

Perhaps the most promising CSF tumor markers arethose specific to CNS cell types. For example, monoclo-nal antibodies directed against glioma-specific anti-gens have been used to diagnose and monitor theclinical course of a small number of patients withpreviously diagnosed glioblastoma (90). Althoughthese reagents may react with other tumor cell typessuch as malignant melanoma and small-cell lung can-cer cells, development of a sensitive ELISA for use withCSF may allow for early detection of tumors that areundetectable by imaging. Among the other cell type-specific antigens detected in CSF of cancer patientsand used to diagnose metastatic spread of specifictumor types into the CNS are corticotropin (91), vaso-pressin (92), and tissue polypeptide antigen (93). Re-ported studies of these antigens, however, are verypreliminary and would likely be applicable to only asmall subset of neurooncology patients. Again, on thebasis of the available studies, CSF tumor markers areuseful as “one-way” tests; they are not sufficientlysensitive to diagnose CNS neoplasia. However, in pa-tients who present with tumors and increased CSF

Analyte Basis

Lactate M Independent of serum concn.;CNS/CSF sources disputed.

Table 5. Analytes assayed In CNS trauma/stroke.Characteristics Advantages

Creatine kinase

Neuron-specificenolase

References

96, 102, 103

97, 104, 105

98-101, 104

106-111

109, 111-114

115-117

352 CUNICAL CHEMISTRY, Vol. 41, No. 3, 1995

concentrations of a particular biochemical marker, itmay be useful to monitor serial values for remissionand relapse. Unfortunately, many markers (except forsome CNS-specific antigens) may be increased in manynonneoplastic CNS diseases, making it essential torule out these other pathologies as well.

CNS Damage (Table 5)

Chemical analysis of CSF after CNS insult may berequested for a number of reasons, e.g., monitoringclinical course after perinatal CNS damage or hypoxia,predicting outcome in postcardiac-resuscitation pa-tients, managing subarachnoid hemorrhage or CNStrauma, and predicting recovery in patients with cere-bra! ischemia. Diagnosis in these settings is seldom indoubt, so the main function of laboratory testing is tomonitor the patient’s progress and predict outcome.Such tests would have two potential advantages overcurrent tools. First, clinical prediction of patient recov-ery is very subjective and often unreliable. For exam-ple, the Glasgow Coma Scale (94), a rating of neuro-logical function based on clinical assessment, may beuseful in predicting outcome in fewer than 60% ofassessed patients (95). Second, although CT and nu-clear magnetic resonance imaging techniques allowdetection of increasingly smaller CNS lesions, thesemethods cannot distinguish between lesions that pro-duce reversible loss of function and those that areirreversible (95).

Pen natal hypoxia. CSF lactate, which reflectsanaerobic metabolism, has been suggested as an indi-cator of clinical outcome after perinatal hypoxia. Fer-nandez et a!. (96) examined 23 neonates with favorableoutcomes (no neurological impairment) and 6 neonateswith unfavorable outcomes (death or permanent neu-rological impairment); the latter group demonstratedhigher mean concentrations of CSF lactate than the

favorable-outcome group or control patients (4.5 vs 2.5mmoL’L). Unfortunately, there was a large overlapbetween groups. The usefulness of CSF lactate mea-surements after CNS hypoxia is also limited by aninability to distinguish between reversible and irre-versible damage. Furthermore, the difficulty of per-forming well-controlled studies that account for thecritical importance in timing of CSF acquisition inrelation to the hypoxic period made interpretation ofthis study difficult (96). On the other hand, measure-ment of CSF LDH, an indicator of cell death, hasdemonstrated greater clinical utility. CSF LDH wasmeasured in 25 hypoxic infants and 20 “control” new-borns (patients with clinical, but no laboratory, find-ings of sepsis) within 24 h after birth (97). After a

15-month follow-up, the hypoxic patients were classi-fied as normal (n = 0), without deficit (n = 19), orneurologically impaired (n = 6). In the impaired group,initial CSF LDH measurements were considerablyhigher (118 ± 39 kUfL) than in patients without deficit(42 ± 10 kU/L) or in the “normal” controls (38 ± 4kU/L).

CK-BB has also been used to stratify clinical out-come in neonates with other neurological disorders,including posthypoxic encephalopathy. Among 99 in-fants with CSF CK-BB values less than the definednormal upper limit (7 p,g/L), only 6% experienced pooroutcome (death or permanent neurological impair-ment). For infants with CK-BB three to seven times thenormal cutoff limit, 45% had poor outcome, and 6 of 7patients with CSF CK-BB >70 pgfL died or had neu-rological damage (98). Furthermore, in all 150 neo-nates there was a significant relationship between

CK-BB concentration and clinical outcome. The assayhad a calculated sensitivity of 76% and specificity of97% for distinguishing “good” and “poor” outcomes.Little mention was made of the timing of samples, soit


S-i 00 protein

Myelln basicprotein

D Well-characterized intracellularenzyme.

0 Brain-specific isoformcomposes 95% of CNSactivity.

0 CNS-enolase dimer.

D CNS abundant calcium-binding protein.

D Brain specific; associated withwhite matter destruction.

Simple assay.

Familiar assay; sensitivefor ischemic damage;appears later thanother markers afterCNS insult; correlateswith CNS infarct size.

Familiar assay; CNSspecific.

CNS-specific protein;CSF concns related toinfarct size andlocation.

CNS specific; CSFconcns related toinfarct size.

CNS specific; morespecific fordestruction thaninflammation.

Disadvantages

Does not distinguish reversiblefrom irreversible tissuedamage.

Nonspecific; isoenzyme patternsnonspecific; does not correlatewith functional outcome afterinfarct.

CK-BB activity rapidly decays invivo and in vitro; nonspecificfor type of CNS insult.

Not specific for type of CNSpathology; assay not readilyavailable; CSF concns notrelated to functional outcome.

Not specific for type ofpathology; assay not readilyavailable.

Not specific for etiology ofdamage; assay not readilyavailable; less sensitive thanenzymes; few studies.


is difficult to directly relate these results to othermarkers. Nevertheless, the initially promising resultsof these studies suggest that measurement of both CSFLDH and CK-BB for predicting outcome in neonatalhypoxia warrants further clinical investigation.

Cardiac resuscitation. For predicting neurologicaloutcome in patients after cardiac resuscitation, serialdeterminations of CSF total CK activity in a populationof 82 postresuscitative patients demonstrated that in-creases to >11 U/L within 48-72 h after resuscitation(n = 59) were always associated with a persistentcomatose state (99). In contrast, the 12 patients withCSF CK activity <5 UIL during the same perioddemonstrated no residual CNS impairment. The au-thors of this study maintained that their CK determi-nations represented the BB isoenzyme, based on unre-ported isoelectric focusing studies. Roine et al. (100)measured CSF CK-BB mass in 75 postcardiac-resusci-tation patients who remained unconscious (n = 25) orregained consciousness (n = 42). In the former group,CK-BB averaged 96.8 ± 34.4 g/L for samples obtainedwithin 24 h of the event; the latter group averaged 6.7± 1.2 gfL. At an arbitrary cutoff value of 17 p.g/L, thepositive predictive value of this assay was 93%, and thenegative predictive value was 77%. On the other hand,timing of sample acquisition from patient to patientwas not well controlled, and the single measurementsreported may not be as useful as serial determinations[e.g., those made in the earlier study (99)]. Measure-ments of CK-BB mass correlated with Glasgow indicesof function at 7 days and at 3 months after resuscita-tion (Spearman rank correlations range 0.61-0.73).However, it was not possible to determine whether thebiochemical determinations or the clinical assessmentshad greater diagnostic accuracy. Karkela et al. (101)also demonstrated a moderate relation (P = 0.046)between CK-BB activity at 28 and 76 h postresuscita-tion and clinical recovery. Taken together, these stud-ies suggest that the amounts of CK-BB mass or activityin CSF may be a useful predictor of neurologicaloutcome after cardiac resuscitation. However, thesmall number of studies published to date are insuffi-cient to support the use of this assay in a routineclinical setting.

Subarachnoid hemorrhage. Predicting the clinicalcourse of patients who have suffered subarachnoidhemorrhage, CNS trauma, or stroke is another areathat has been investigated by chemical analysis ofCSF. In a small group of head injury patients, DeSalleset a!. (102) demonstrated that the concentrations oflactate in CSF obtained from ventricular samplingcorrelated with patient outcome. In patients with per-manent CNS impairment (n = 11), lactate concentra-tions remained persistently increased from 18 to >48 hafter injury, whereas lactate concentrations that nor-malized within 48 h were associated with good recovery(n = 8). Shimoda et al. (103) followed 38 patients withsubarachnoid hemorrhage and retrospectively exam-ined serial measurements of cisternal and ventricularlactate. In patients with no residual neurological defi-

cit, the mean cisternal lactate concentration was 251 ±55 mgfL (n = 125); those with poor outcome (GlascowComa Scale score <13) had mean lactate contents of326 ± 74 mgfL (n = 72). Differences between ventric-ular samples were also unimpressive, and no samplesfrom lumbar CSF were obtained. Although the authorsmaintain that “sampling of CSF lactate concentration,especially from the cisterna magna, is useful as anindicator of prognosis,” the overlap of data presentedfor these groups suggests that lactate concentrationsare far from reliable as predictors of outcome in thesesettings.

Cerebral ischemia. Vaagenes et al. (104) comparedthe cell death marker CK-BB with LDH, NSE, andaspartate aminotransferase in 35 patients recoveringfrom cerebral ischemic events. Eight patients diedwithout regaining consciousness (group A), 20 had amajor neurological deficit (group B), and the remaining7 showed no deficit (group C). Serial determinations ofenzyme activity within 2-6 h after the insult and at24-h intervals thereafter in most patients demon-strated significant differences between patients ingroup C and group B for peak values of CK-BB, LDH,and aspartate aminotransferase; the differences be-tween group A and group B patients were less pro-nounced. Measurement of CK-BB best discriminatedbetween all three groups, although values frequentlyoverlapped between patients in groups A and B. Theauthors also noted considerable variation in the time topeak enzyme activity after insult, again suggestingthat multiple determinations may be necessary.

Compared with CK-BB, measurements of LDH areprobably a more sensitive indicator of ischemic dam-age, although CSF contents of the latter do not peakuntil much later (>24 h) after insult. This increasedsensitivity reflects a much longer half-life in the CSFand a higher intracellular concentration. Lampl et al.(105) demonstrated that LDH measured <8 h after

insult was significantly higher in patients who experi-enced consequent neurological impairment than inthose whose ischemia was transient and did not resultin impairment. No CSF measurements were performedafter 8 h and no other enzyme markers were comparedin this study. However, the authors did show that LDHconcentrations correlated with infarct location and size(105).

Because of its neurospecificity, NSE has been anattractive marker for postischemic brain damage. Sev-eral rat models have shown that CSF concentrations ofNSE are also proportional to the size of the infarct

(106, 107). However, depending on the site of injury,

clinical outcomes in humans can be independent ofinfarct size or CSF NSE content (108, 109) becauseNSE, like most intracellular CNS enzymes, is uni-formly distributed in CNS tissue rather than concen-trated in regions of functional importance. Althoughbrain-specific, NSE may also be increased in severalother neuropathological processes (e.g., epilepsy andsubarachnoid hemorrhage) that may present with aclinical picture similar to stroke (110, 111). Accord-


ingly, neurospecificity is a helpful but not sufficientcharacteristic of an ideal CSF disease marker.

S-100 protein is an acidic, calcium-binding proteinabundant in brain tissue. It consists of heterodimersand homodimers of two subunits, a (10.4 kDa) and 13(10.5 kDa), and is released into the CSF after CNS celldeath (9). Several studies have investigated its use in

monitoring the clinical course of stroke and head injurypatients. Persson et al. (109) found that the concentra-tions of S-100 protein in CSF were increased between 8h and 4 days after stroke and showed some relation tosize of infarct (i.e., CT-visible vs CT-nonvisible in-farcts). However, S-100 content varied widely amongall 43 patients and overlapped considerably with thecontrol range (<1 to 6.8 g/L by RIA). This same groupalso reported that CSF concentrations of S-100 could beused to predict clinical outcome in patients after sub-arachnoid hemorrhage (112). Patients with S-100>100 g/L had a universally poor outcome (death orneurological impairment); those with <20 g.&gfL sur-vived without complications. Many patients, however,demonstrated intermediate values throughout theirclinical course, suggesting that serial determinationsmay be more useful than single measures. AlthoughCSF S-100 concentrations were sometimes better thanthe Glasgow Coma Scale in predicting outcome, inother patients the assay was unreliable. Again, thelimitations of S-100 and other markers are probablyattributable to nonspecificity (113) and to the fact thatthe size of a lesion or the number of cells destroyed doesnot necessarily correspond to clinical outcome (114).

Among other analytes investigated for assessingCNS damage are glial fibrillary acid protein (114),myelin basic protein (115-117), and calbindin-D (118).Strand et a!. (117) examined 40 patients with an acutecerebral ischemic event and made serial determina-tions of myelin basic protein. Like the previously men-tioned markers, the peak values for this protein at 4-5days postinsultcorrelated with lesion size and short-

term clinical outcome. For example, in 11 of 19 patientswith peak myelin basic protein <5.0 gfL, no neurolog-ical deficits were identified, but 14 of 15 patients withconcentrations >10 gfL died or were disabled.

Summary. Some generalizations may be made withregard to CSF analytes in predicting clinical outcomeafter CNS insult. To date, few studies have directlycompared the utility of imaging studies, clinical assess-ment, and CSF analysis of these markers. There arealso no data to indicate that a single determination ofany analyte in CSF is of clinical utility. As with assaysof cardiac enzymes in myocardial infarction (119),timing of sample acquisition is critical to interpretationand, depending on the type of injury (e.g., stroke vstrauma), the kinetics of analyte appearance in CSF candiffer greatly between analytes (120). Furthermore,analogous to cell death markers in cardiac studies, aCNS marker should be: (a) relatively brain-specific,such as CK-BB; (b) higher in intracellular abundancethan in CSF; and (c) long lived, such as LDH. Each ofthe markers discussed in this section has limitations

for one or more of these criteria, which makes theirless-than-optimal clinical performance unsurprising.Finally, unlike analysis of cardiac enzymes, the re-gional specificity of the brain often prohibits a concor-dance between lesion size (as indicated by CSF valuesof “cell death” analytes) and functional morbidity.

These and other limitations have been discussed atlength elsewhere (95). In clinical practice, data areinsufficient to recommend the routine use of any bio-chemical marker as a prognostic tool in CNS injury.However, this survey of preliminary studies suggeststhat use of both CK-BB and LDH in predicting clinicaloutcome after CNS ischemic injury warrants furtherclinical investigation.

Neurodegenerative Disease (Table 3)

Many studies have examined CSF analytes in Alz-heimer disease, the most common cause of dementia inthe elderly. This subject has been extensively reviewed(121) and will be only briefly discussed here. Fewer

studies have examined CSF from patients with Parkin-son disease or other forms of neurodegeneration anddementia (122, 123).

Early studies of Alzheimer patients detected alter-ations in CSF concentrations of acetylcholine, acetyl-cholinesterase (AChE), and butyrylcholinesterase(BuChE). Because acetylcholine is rapidly degraded inthe CSF (9, 121), measurements in patients are oftenat the limit of assay detection, exhibit large interindi-vidual variations, and are probably unsuitable forclinical use. BuChE accounts for -30% of the cholines-terase activity in CSF and originates from serum andthe CNS. As such, it is a very nonspecific CNS marker,and reports have described decreased, increased, andunaltered BuChE activity in CSF from demented pa-tients (121). Other studies have examined the utility ofAChE, alone or in conjunction with BuChE, in diagnos-ing patients with dementia.

AChE composes the majority of cholinesterase activ-ity in the CSF and is thought to be exclusively derivedfrom neuronal sources. Many authors report consistentreductions in CSF AChE activity in demented patients,but van Gool and Boihuis (121) concluded in theirliterature survey that the number of conflicting reportssuggested that “CSF measures related to the cholin-ergic system are of an altogether limited value.” Otherstudies have identffied qualitative changes in AChEenzyme in patients with Alzheimer disease. Navarat-nam et al. (124) used isoelectric focusing to identify ananomalous form of AChE in 19 of 23 patients with ahistological diagnosis of Alzheimer disease at time ofautopsy. At the same time, none of 19 patients withouthistological evidence of disease displayed the anoma-lous enzyme in their CSF. The significance of thisfinding and its potential use in antemortem diagnosisremains to be determined.

The discovery of 13-amyloid protein deposition insenile plaques and cerebral vasculature of Alzheimerpatients prompted investigations of this molecule as aCSF marker for disease. The amyloid 13-protein is a 4.2


kDa peptide derived from abnormal proteolytic pro-cessing of a larger molecule, amyloid 13-protein precur-sor (APP). Early studies reported both increased anddecreased secretion of APP in CSF of Alzheimer pa-tients; more recent reports seem to confirm decreasedconcentrations. For example, using a highly specfficELISA, Van Nostrand et al. (125) found lower concen-trations of APP in tentatively diagnosed Alzheimerpatients (0.8 ± 0.4 g/L; n = 13) than in non-Alzheimer-type demented patients (2.9 ± 1.0 g/L; n = 18) ornondemented controls (2.7 ± 0.7 g/L; n = 16). Otherstudies have confirmed depressed values of CSF APP

in patients with a hereditary form of early-onset AJz-heimer disease (126) or with a related disorder, hered-itary cerebral hemorrhage with amyloidosis-Dutchtype (127).

The discovery of other novel proteins in brains ofAlzheimer patients has led to investigations of addi-tional potential CSF markers. Neuronal thread pro-tein, a 20-kDa protein normally secreted in the brain,is found at higher concentrations in Alzheimer diseasebrains than in aged-matched controls (128): 4.15 ±0.25 gIL in 84 Alzheimer patients, 1.96 ± 0.16 tgiL in45 nondemented Parkinson patients, 1.60 ± 0.14 pgfLin 73 MS patients, and 1.27 ± 0.06 g/L in 73 controls.Unfortunately, 25 of the 84 Alzheimer patients did notdisplay concentrations greater than that of the defined“normal range,” which suggests that neuronal threadprotein in CSF may lack sensitivity or be applicableonly to some yet-undefined subclass of Alzheimer pa-tients. Perhaps in anticipation of widespread use, theauthors have recently modified this test to a moreaccessible format, automated microparticle enzyme im-munoassay (129).

Glutamine synthetase, an enzyme present in astro-cytes and responsible for conversion of the excitotoxicneurotransmitter glutamate into glutamine, has alsobeen associated with end-stage Alzheimer disease. Onepreliminary study (130) reported increased CSF activ-ities of this enzyme in 38 of 39 samples from Alzheimerpatients and in only 1 of 44 controls (patients withepilepsy, Parkinson disease, and amyotrophic lateralsclerosis). As with many other newly discovered mole-cules associated with this complex disease process(131), proven clinical utility of gluta.mine synthetaseawaits larger, controlled studies.

Several considerations will make such studies diffi-cult. First, the diagnosis of Alzheimer dementia re-quires excluding all other causes of dementia (e.g.,infection, neoplasia, trauma, vascular disease, psychi-atric illness, toxicity, metabolic dysfunction) in thepresence of declining cognitive function; a definitivediagnosis requires histopathological examination of

brain tissue. Therefore, apart from brain biopsy (whichwould seldom be performed), there is no antemortemgold standard with which to compare potential CSFmarkers. In addition, selection of control populationsmay affect the predicted utility of any given marker.Conclusions from studies that rely on nondementedcontrol populations (e.g., subjects with disk injury,

viral meningitis) may differ considerably from thoseinvolving patients with symptoms closely resemblingAlzheimer disease. Of course, this is a limitation ofmost case/control studies, but the inherent inability toaccurately differentiate Alzheimer disease from otherdementias such as multi-infarct dementia compoundsthe problem. Finally, if (as some suggest) Alzheimerdisease is not a homogeneous disorder, the ability toevaluate any clinical marker may be severely ham-pered by an inability to distinguish among diseasetypes (121).

Autoimmunity (Table 3)

Most studies used to evaluate CNS autoimmunediseases such as MS, Guillain-Barr#{233} syndrome, andamyotrophic lateral sclerosis involve protein electro-phoresis and immunological typing of CSF. These as-says have been reviewed elsewhere (7, 8) and are notdiscussed here. However, several studies suggest thatother molecules in the CSF may be used to chart thecourse of CNS autoimmune diseases.

As previously discussed, CSF neopterin is increased

in several inflammatory conditions. An initial study(132) attempting to use this marker to predict episodesof exacerbation and remission in MS patients foundthat CSF neopterin concentrations were generally (10of 12 patients) greater during exacerbations (mean3.95 nmol/L, range 2.0-10.0) than in periods of remis-sion (mean 2.9 nmol/L, range 1.6-5.7). Bjerrum et a!.(133) investigated 132-M concentrations during periodsof exacerbation but noted only modest increases in asmall proportion of severely affected patients.

More recent studies have examined various cyto-kines in CSF. IL-2 was significantly increased amongpatients with active MS (n = 10) compared with thosewith stable disease (n = 7), those with other noninflam-matory neurological disease (n = 20), and controlsubjects (n = 7) (134); however, a large degree ofoverlap between groups precluded definitive conclu-sions. Other studies (135-137) reported increased CSFIL-2 in patients with active MS, but seldom exceeded20% of cases. Measurement of IL-i has been repeatedly

shown to be of no diagnostic value in MS (137, 138).Determinations of soluble IL-2 receptor (137, 139-141)are equivocal, and measurements of IL-6, determinedin most studies by bioassay, detected only 29-43% ofactive MS cases (138, 142). Studies with a TNFa assaywere equally disappointing (137, 138).

One explanation for the poor performance of thesemarkers is the known lack of correlation betweenclinical symptoms, i.e., the characteristics used to di-agnose a patient as exacerbated or remitting, andactual immune activity, i.e., that which is measured incytokine assays. Because most studies involve onlysingle determinations of CSF cytokines, variable de-lays in sampling with respect to onset of inflammationmay adversely affect the usefulness of such assays. Iffuture studies could make serial determinations in agiven patient, perhaps some of these analytes might


have some utility in predicting clinical course. How-ever, such is currently not the case.

Conclusions

From our survey of the literature, we have formedseveral general conclusions regarding the clinical util-ity of CSF analytes: Most studies that have investi-gated the usefulness of CSF measurements have doneso in small, retrospective studies with preselected pa-tient populations. Any conclusions reported from suchstudies should be interpreted with caution for applica-tion to a more general population of neurological pa-tients (e.g., an emergency room patient who presentswith changes in mental status and no available clinicalhistory). Indeed, not only do the clinical presentationsof the neurological pathologies discussed here oftenoverlap but also do the sequelae of the different diseaseprocesses indicated by these biochemical markers ofmetabolic change, cell death, immune activity, or cel-lular function. Moreover, in all studies reviewed here,the reported cutoff values for discriminating patients’populations were optimized from and then applied tothe same test population-a process that artificiallyinflates sensitivities and specificities. Furthermore,because few studies compare the utility of multiplemarkers in the identical patient population, it is diffi-cult to evaluate whether any one marker has greaterdiagnostic power than another. No study we reviewedsought to determine whether multiple markers (e.g.,glucose, lactate, and CRP) had independent predictivepower. In fact, while most studies demonstrated acorrelation between CSF measurements and variousdisease processes, very few claimed diagnostic value.

This should not be surprising because, with fewexceptions, these markers detect sequelae, not thedisease process itself. In the few examples where thebiochemical marker is directly indicative of the pathol-ogy (i.e., traditional tumor markers, including 132-M),the tests can perform well but are essentially “one-way” tests. j32-M is further limited because it can beincreased as an indicator of increased immune activitysequelae in several CNS diseases. CSF lactate as asequela of septic meningitis may be useful as anadjunct marker because of its greater sensitivity and

obviation of the need for simultaneous serum measure-ments, but its delayed disappearance from CSF aftersuccessful treatment makes it less optimal for monitor-ing therapy. Other sequelae markers (e.g., CRP, TNFa,

IL-i) are too insensitive or too nonspecific for use inroutine analysis. Although we have received manyrequests for determinations of CSF (32-M to diagnoseH1V dementia, few studies have documented the clin-ical value of this assay. When interpreting these val-ues, like those of most CSF analytes, one must remem-ber their dependence on patient’s age, bbood-CSFbarrier competence, and coexisting neurological dis-ease. Similarly, cell death markers of CNS neoplasiaare nonspecific and, unless tumor cells have invadedthe leptomeninges or parenchyma adjacent to CSFflow, insensitive. In patients who have suffered stroke

or CNS trauma, CK-BB, S-100, and possibly LDH maybe useful in quantifying the extent of physical damage,perhaps with greater sensitivity and accuracy thanimaging studies, but these analytes cannot be fullyrelied upon for predicting functional outcome. Finally,markers used to evaluate neurodegenerative diseaseare difficult to assess because of the lack of an ante-mortem gold standard.

The limited diagnostic utility of most CSF biochem-ical analytes, compared with that of cardiac (119) orhepatic (143, 144) disease markers, also can be attrib-uted to several theoretical considerations. First, thetiming of sample acquisition is extremely important. Indisease processes such as MS, the onset of clinicalsymptoms and thus, the time at which CSF samplesare obtained, may be poorly correlated with diseaseactivity; the time of appearance of an analyte may alsodepend on the nature of the insult (e.g., stroke vs headtrauma). Future studies with serial determinations ofan analyte in a single patient may provide furtherinsight as to the optimum time at which measurementof the analyte is diagnostically most useful. Unfortu-nately, indications for serial lumbar punctures are notas easy to justify as those for routine blood drawing, aproblem that will severely limit the feasibility of suchstudies. Second, several commonly used markers (e.g.,132-M, glucose) lack neurospecificity and, in patientswith questionable blood-CSF barrier competence (CNStrauma, meningitis, tumor invasion), diagnostic valuesof intrathecal concentrations may be masked by spill-over from serum sources. Third, even neuronal-specificproteins (e.g., S-i00, NSE) may be increased in avariety of neurological disease states, many of whichare difficult to distinguish on clinical grounds (e.g.,CNS lymphoma vs fungal brain abscess vs ADC).Fourth, because the CNS is highly specialized withregard to function (unlike the liver, and less like theheart), analytes that measure extent of damage maybear no relation to functional outcome. Fifth, manyCNS disease processes (e.g., Alzheimer disease, MS)are poorly understood and thus lack a reliable goldstandard assay or definitive diagnostic criteria; thismakes evaluation of newer markers difficult. Indeed,the complexity of the CNS simultaneously necessitatesthe development of analytical markers to diagnosedisease, while also hindering the evaluation and utilityof such potential diagnostic tools.

References1. Gjerris A. Baseline studies on transmitter substances in cere-brospinal fluid in depression. Acta Psychiatr Scand 1988;346(Suppl):1-35.2. Roy A, De Jong J, Linnoila M. Cerebrospinal fluid monoaminemetabolites and suicidal behavior in depressed patients. A 5-yearfollow-up study. Arch Gen Psychiatry 1989;46:609-12.3. Cooper SJ, Kelly CB, King DJ. 5-Hydroxyindoleacetic acid incerebrospinal fluid and prediction of suicidal behavior in schizo-phrenia. Lancet 1992;340:940-1.4. Kjeldsberg CR, Knight JA. Body fluids, 2nd ed. Chicago:American Society of Clinical Pathologists Press, 1986:231-74.5. Gray LD, Fedorko DP. Laboratory diagnosis of bacterial men-ingitis. Clin Microbiol Rev 1992;5:130-45.6. Greenlee JE. Approach to diagnosis of meningitis: cerebrospi-


nal fluid evaluation [Review]. Infect Dis Clin North Am 1990;4:583-98.7. Rosenthal A. The cerebrospinal fluid proteins in multiplesclerosis [Review]. Clin Lab Med 1986;6:457-75.8. Mehta PD. Diagnostic usefulness of cerebrospinal fluid inmultiple sclerosis. Crit Rev Cliii Lab Sci 1991;28:233-51.9. Fishman RA. Cerebrospinal fluid in diseases of the nervoussystem, 2nd ed. Philadelphia: WE Saunders, 1992:7-42, 183-344.10. Shapiro WR. Cerebrospinal fluid circulation and the blood-brain barrier. Ann N Y Acad Sci 1988;531:9-14.11. Cutler RWP, Spertell RB. Cerebrospinal fluid: a selectivereview. Ann Neurol 1982;11:1-1O.12. Thompson EJ, Keir G. Laboratory investigation of cerebro-spinal fluid proteins. Ann Clin Biochem 1990;27:425-35.13. Bonadio WA.The cerebrospinal fluid; physiologic aspects andalterations associated with bacterial meningitis. Pediatr InfectDis J 1992;11:423-32.14. Lutz CT, Cornell SH, Goeken JA. Establishment of a refer-ence interval for 32-microglobulin in cerebrospinal fluid with useof two commercial assays. Cliii Chem 1991;37:104-7.15. van Engelen BG, Lamers KJ, Gabreels FJ, Wevers RA, vanGeel WJ, Borm GF. Age-related changes of neuron-specific eno-lase, S-100 protein, and myelin basic protein concentrations incerebrospinal fluid. Clin Chem 1992;38:13-6.16. Knight JA, Dudek SM, Haymond RE. Early (chemical) diag-nosis of bacterial meningitis-cerebrospinal fluid glucose, lac-tate, and lactate dehydrogenase compared. Clin Chem 1981;27:1431-4.17. Powers WJ. Cerebrospinal fluid to serum glucose ratios indiabetes mellitus and bacterial meningitis. Am J Med 1981;71:217-20.18. Lerman-Sagie T, Shohat M, Nitzan M. CSF glucose levels infebrile infants. Eur J Pediatr 1988;147:416-7.19. Donald PR, Malan HC, van der Walt A. Simultaneous deter-mination of cerebrospinal fluid glucose and blood glucose concen-trations in the diagnosis of bacterial meningitis. J Pediatr 1983;103:413-5.20. Genton B, Berger JP. Cerebrospinal fluid lactate in 78 casesof adult meningitis. Intensive Care Med 1990;16:196-200.21. Donald PR, Malan C. Cerebrospinal fluid lactate and lactatedehydrogenase activity in the rapid diagnosis of bacterial mernn-gitis. S Afr Med J 1986;69:39-42.22. Posner JB, Plum F. Independence of blood and cerebrospinalfluid lactate. Arch Neurol 1967;16:492-6.23. Kohnel 11W, von Maravic M. Correlation of lactic acid level,cell count and cytology in cerebrospunal fluid of patients withbacterial and non-bacterial meningitis. Acta Neurol Scand 1988;78:6-9.24. Ruuskanen 0, Stahlberg M-L, Korvenranta H, Nikoskel-amen J, li:jala K CSF lactate in bacterial meningitis withminimal CSF abnormalities. Acta Paediatr Scand 1985;74:292-3.25. Nelson N, Eeg-Olofsson 0, Larsson L, Ohman S. The diag-nostic and predictive value of cerebrospinal fluid lactate inchildren with meningitis. Its relation to current diagnostic meth-ods. Acta Paediatr Scand 1986;75:52-7.26. Komorowski RA, Farmer SG, Knox KK. Comparison of cere-brospinal fluid C-reactive protein and lactate for diagnosis ofmeningitis. J Cliii Microbiol 1986;24:982-5.27. Lundquist L, Linne T, Hansson LO, Kalin M, Axelsson G.Value of cerebrospunal fluid analysis in the differential diagnosisof meningitis: a study in 710 patients with suspected centralnervous system infection. Eur J Clin Microbiol Infect Dis 1988;7:374-80.28. Cameron PD, Boyce JMH, Ansari BM. Cerebrospinal fluidlactate in meningitis and meningococcaemia. J Infect 1993;26:245-52.29. Neches W, Platt M. Cerebrospinal fluid LDH in 287 children,including 53 cases of meningitis of bacterial and non-bacterialetiology. Pediatrics 1968;41:1097-103.30. Feldman WE. Cerebrospinal fluid lactic acid dehydrogenaseactivity: levels in untreated and partially antibiotic-treated men-ingitis. Am J Dis Child 1975;129:77-80.31. Landaas S, VonderLippe B. Chemical analyses for earlydifferential diagnosis between bacterial and viral meningitis.Scand J Clin Lab Invest 1985;45:525-9.32. Donald PR, Malan C, van der Walt A, Schoeman JF. The

simultaneous determination of cerebrospinal fluid and plasmaadenosine deaminase activity as a diagnostic aid in tuberculousmeningitis. S Afr Med J 1986;69:505-7.33. Chawla RK, Seth RK, Raj B, Sairn AS. Adenosine deamunaselevels in cerebrospinal fluid in tuberculosis and bacterial menin-gitis. Tubercie i991;72:190-2.34. da Cunha JG, Pereira E, Melico-Silvestre A, Gaspar E,Azevedo-Bernarda R, da Costa RC. Prognostic significance ofcerebrospinal fluid adenosune deaminase in acute bacterial men-ingitis. Infection 1990;18:125.35. Corrall CJ, Peppie JM, Moxon ER, Highes WT. C-reactiveprotein in spinal fluid of children with meningitis. J Pediatr1981;99:365-9.36. Macfarlane DE, Narla VR. Cerebrospinal fluid C-reactiveprotein in the laboratory diagnosis of bacterial meningitis. ActaPaediatr Scand 1985;74:560-3.37. BenGershom E, Briggeman-Mol GJ, de Zegher F. Cerebrospi-nal fluid C-reactive protein in meningitis: diagnostic value andpathophysiology. Ear J Pediatr 1986;145:246-9.38. Gray BM, Simmons DR, Mason H, Barnum S, Volanakis JE.Quantitative levels of C-reactive protein in cerebrospinal fluid inpatients with bacterial meningitis and other conditions. J Pediatr1986;108:665-70.39. Arditi M, Manogue KR, Caplan M, Yogev R. Cerebrospinalfluid cachectin/tumor necrosis factor-alpha and platelet-activat-ing factor concentrations and severity of bacterial meningitis inchildren. J Infect Dis 1990;162:139-47.40. GlimAker M, Kragsbjerg P, Forsgren M, Olcen P. Tumornecrosis factor-alpha (TNF alpha) in cerebrospinal fluid frompatients with meningitis of different etiologies: high levels of TNFalpha indicate bacterial meningitis. J Infect Din 1993;167:882-9.41. Lopez-Cortes LF, Cruz-Ruiz M, Gomez-Mateos J, Jimenez-Hernandez D, Palomino J, Jimenez E. Measurement of levels oftumor necrosis factor-alpha and interleukin-1-beta in the CSF ofpatients with meningitis of different etiologies: utility in thedifferential diagnosis. Clin Infect Dis 1993;16:534-9.42. Mustafa MM, Label MB, Ramilo 0, Olsen KD, Reisch JS,Beutler B, McCracken GH Jr. Correlation of interleukin-1 betaand cachectin concentrations in cerebrospinal fluid and outcomefrom bacterial meningitis. J Pediatr 1989;115:208-13.43. McCracken GIl, Mustafa MM, Ramilo 0, Olsen KD, RisserRC. Cerebrospunal fluid interleukin-1-beta and tumor necrosisfactor concentrations and outcome from neonatal gram-negativeenteric bacillary meningitis. Pediatr Inf Dis J 1989;8:155-9.44. Torre D, Zeroli C, Ferraro G, Speranza F, Tambini R, Mar-tegani R, Fiori GP. Cerebrospinal fluid levels of IL-6 in patientswith acute infections of the central nervous system. Scand JInfect Dis 1992;24:787-91.45. Sen GC, LengyelP. The interferon system. A bird’s eye viewof its biochemistry. J Biol Chem 1992;267:5017-20.46. Abbott RJ, Bolderson I, Gruer PJ. Assessment of an immu-noassay for interferon-alpha in cerebrospinal fluid as a diagnosticaidin infections of the central nervous system. J Infect 1987;15:153-60.47. Chonmaitree T, Baron S. Bacteria and viruses induce pro-duction of interferon in the cerebrospinal fluid of children withacute meningitis: a study of 57 cases and review. Rev Infect Dis1991; 13: 106 1-5.48. Campbell DR, Skikne BS, Cook JD. Cerebrospinal fluidferritin levels in screening for meningism. Arch Neurol 1986;43:1257-60.49. Torre D, Zeroli C, Issi M, Fiori GP, Ferraro G, Speranza F.Cerebrospinal fluid concentration of fibronectin in meningitis. JClin Pathol 1991;44:783-4.50. Hagberg L, Dotevall L, Norkrans C, Larsson M, Wachter H,Fuchs D. Cerebrospinal fluid neopterin concentrations in centralnervous system infection. J Infect Dis 1993;168:1285-8.51. Hoffman lID, Donald PR, Hanekom C, Do Beer FC. Cerebro-spinal fluid alpha-1-antitrypsin alpha-1-antitrypsin-elastasecomplex levels in meningitis. Ear J Clin Invest 1989;19:26-9.52. Hourani BT, Hamhn EM, Reynolds TB. Cerebrospinal fluidglutamine as a measure of hepatic encephalopathy. Arch InternMed 1971;127:1033-6.53. Boeckx RL, Iosefsohn M, Hicks JM. Reference values forcerebrospinal fluid glutamine concentration in infants. CliiiChem 1980;26:601-3.


54. Hiraoka A, Miura I, Tominaga I, Hattori M. Capillary-isotachophoretic determination of glutamine in cerebrospinalfluid of various neurological disorders. Cliii Biochem 1989;22:293-6.55. Perrella 0, Carrieri PB, Izzo E, Marotta A, Liberti A, SosciaM, Buscaino GA. Cerebrospinal fluid beta-2-microglobulin inHIV-1 infection, as a marker of neurological involvement. NeurolRes 1991;13:131-2.56. Brew BJ, Bhalla RB, Fleisher M, Paul M, Khan A, SchwartzMK, et al. Cerebrospinal fluid beta-2 microglobulin in patientsinfected with human immunodeficiency virus. Neurology 1989;39:830-4.57. Sonnerborg AS, vonStedingk L-V, Hansson L-O, Stranne-gard 00. Elevated neopterin and beta-2-microglobulin levels inblood and cerebrospinal fluid occur early in HIV-1 infection. AIDS1989;3:277-83.58. McArthur JC, Nance-Sproson TE, Griffin DE, Hoover D,Sehnes OA, Miller EN, et al. The diagnostic utility of elevation incerebrospinal fluid beta 2-microglobulin in HW-i dementia. Neu-rology 1992;42:1707-12.59. Brew BJ, Bhalla RV, Paul M, Gallardo H, McArthur JC,Schwartz MX, Price RW. Cerebrospinal fluid neopterin in humanimmunodeflciency virus type 1 infection. Ann Neurol 1990;28:556-60.60. Griffin DE, McArthur JC, Cornblath DR. Neopterin andinterferon-gamma in serum and cerebrospinal fluid of patientswith HIV-associated neurologic disease. Neurology 1991;41:69-74.61. Perrella 0, Carrieri PB, Guarnaccia D, Soscia M. Cerebrospi-nal fluid cytokines in AIDS dementia complex. J Neurol 1992;239:387-8.62. Perrella 0, Finelli L. Cerebrospinal fluid ferritin in humanimmunodeflciency virus infection: a marker of neurologic involve-ment. J Infect Dis 1993;168:1079-80.63. Torre D, Zeroli C, Ferrario G, Bonetta G, Fiori GP, MarteganiR. Cerebrospinal fluid concentration of fibronectin in patientswith 11W-i infection and central nervous system disorders. J ClinPathol 1993;46:1039-41.64. Liuzzi GM, Mastroianni CM, Vullo V, Jirillo E, Delia 5, RiccioP. Cerebroapinal fluid myehn basic protein as predictive markerof demyelination in AIDS dementia complex. J Neuroimmunol1992;36:251-4.65. Seldenfeld J, Marton U. Biochemical markers of centralnervous system tumors measured in cerebrospinal fluid and theirpotential use in diagnosis and patient management: a review. JNatl Cancer Inst 1979;68:919-3i.66. Edwards MS, Davis RL, Laurent JP. Tumor markers andcytologic features of cerebrospinal fluid [Review]. Cancer 1985;56(Suppl):1773-7.67. Jaeckle KA.. Assessment of tumor markers in cerebrospinalfluid [Review]. Cliii Lab Med 1985;5:303-15.68. Koskiniemi M. Malignancy markers in the cerebrospinalfluid [Review]. Ear J Pediatr 1988;i48:3-8.69. Mavlight GM, Stuckey SE, Cabanillas FF, Keating MJ,TourtellotteWW, Schold SC, Freireich EJ. Diagnosis of leukemiaor lymphoma in the central nervous system by beta-2-microglobu-liii determination. N Engl J Med 1980;303:718-22.70. Storti 5, Pagano L, Marra R, Teofili U, Ricerca BM, Leone C,Bizzi B. Cerebrospinal fluid beta-2-microglobulin: a reliable indexof leukaemic infiltration of central nervous system. Scand JHaematol i986;37:30i-5.71. Starmans JJP, Vos J, Van der Helm HJ. The beta-2-micro-globulin content of the cerebrospinal fluid in neurological disease.J Neurol Sd i977;33:45-9.72. Adachi N. Beta-2-microglobulunlevels in the cerebrospinalfluid: their value as a disease marker. A review of the recentliterature. Ear Neurol 1991;3i:i81-5.73. Pudek MR, Chan KW, Rogers PC, Teasdale JM. Beta 2-mi-croglobulin levels in cerebrospinal fluid of children with leukemiaand lymphoma. Clin Biochem i985;18:i80-3.74. Weller M, Stevens A, Sommer N, Schabet M, Wietholter H.Humoral CSF parameters in the differential diagnosis of hema-tologic CNS neoplasia. Acta Neurol Scand i992;86:i29-33.75. Hansen PB, Kjeldsen U, Dalhoff K, Olesen B. Cerebrospinalfluid beta-2-microglobulin in adult patients with acute leukemia

or lymphoma: a useful marker in early diagnosis and monitoringof CNS-involvement. Acta Neurol Scand 1992;85:224-7.76. Musto P, Tomasi P, Cascavilla N, Ladogana S, La Sala A,Melillo U, et al. Significance and limits of cerebrospinal fluidbeta-2-microglobulin measurement in course of acute lympho-blastic leukemia. Am J Hematol 1988;28:213-8.77. Twijnstra A, VanZanten AP, Nooyen WJ, Hart AAM, Onger-border de Visser BW. Cerebrospinal fluid beta-2-microglobulun: astudy in controls and patients with metastatic and non-mete-static neurological diseases. Eur J Chin Oncol 1988;22:387-91.78. Ongerboer de Visser BW, van Zanten AP, Twijnstra A,Nooyen WJ, Hart AA. Sensitivity and specificity of cerebrospinalfluid biochemical markers of central nervous system metastases.Prog Exp Tumor Res 1985;29:105-15.79. van Zanten AP, Twijnstra A, Hart AAM, Ongerboer de VisserBW. Cerebrospinal fluid lactate dehydrogenase activities in pa-tients with central nervous system metastases. Chin Chim Acta1986;i61:259-68.80. Twijnstra A, Ongerboer de Visser BW, van Zanten AP, HartAA, Nooyen WJ. Serial lumbar and ventricular cerebrospinalfluid biochemical marker measurements in patients with lepto-meningeal metastases from solid and hematological tumors. JNeurooncol 1989;7:57-63.81. Lampl Y, Paniri Y, Eshel Y, Sarvora-Pinhas I. LDH isoen-zymes in cerebrospinal fluid in various brain tumors. J NeurolNeurosurg Psychiatry i990;53:697-9.82. Chatterley S, Sun T, Lien Y. Diagnostic value of lactatedehydrogenase isoenzymes in cerebrospinal fluid. J Chin Lab Anal199i;5:168-74.83. Taliman RD, Kimbrough SM, O’Brien JF, Goeliner JR,Yanagihara T. Assay for beta-glucuronidase in cerebrospinalfluid: usefulness for the detection of neoplastic meningitis. MayoCliii Proc 1985;60:293-8.84. Bach F, Bach FW, Pedersen AG, Larsen PM, DombernowskyP. Creatine kinase-BB in the cerebrospinal fluid as a marker ofCNS metastases and leptomeningeal carcinomatosis in patientswith breast cancer. Ear J Cancer Chin Oncol 1989;25:1703.-9.85. Pfeiffer FE, Homburger HA, Yanagihara T. Creatine kinaseBB isoenzyme in CSF in neurologic diseases. Arch Neurol 1983;40:169-72.86. Beelen NAA, Twijnstra A, van de Pol M, Menheere PPCA.Neuron-specific enolase in cerebrospinal fluid of patients withmetastatic and non-metastatic neurological disease. Ear J Can-cer 1993;29A:193-5.87. Lampi Y, Paniri Y, Eshel Y, Sarova-Punchas I. Alkalinephosphatase level in CSF in various brain tumors and pulmonarycarcinomatous meningitis. J Neurooncol 1990;9:35-40.88. Newton HB, Fleisher M, Schwartz MK, Malkin MG. Glucose-phosphate isomerase as a CSF marker for leptomeningeal metas-tasis. Neurology 1991;41:395-8.89. Jacobs EL. Haskell CM. Clinical use of tumor markers inoncology. Curr Probl Cancer 199i;15:299-360.90. Yoshida J, Yamamoto R, Wakabayashi T, Nagata M, Seo H.Radioimmunoassay of glioma-associated antigen in cerebrospinalfluid and its usefulness for the diagnosis and monitoring ofhuman glioma. J Neurooncol 1990;8:23-31.91. Pedersen AG, Hansen M, Hummer L, Rogowski P. Cerebro-spinal fluid ACTH as a marker of central nervous system metas-tases from small cell carcinoma of the lung. Cancer 1985;56:2476-80.92. Pedersen AG, Hammer M, Hansen M, Sorensen PS. Cerebro-spinal fluid vasopressin as a marker of central nervous systemmetastases from small-cell bronchogenic carcinoma. J Clin Oncol1985;3:48-53.93. Bach F, Soletormos G, Dombennowsky P. Tissue polypeptideantigen activity in cerebrospinal fluid: a marker of central ner-vous system metastases of breast cancer. J Natl Cancer Inst1991;83:779-84.94. Segatore M, Way C. The Glasgow Coma Scale: time forchange. Heart Lung 1992;21:548-57.95. Bakay RA, Sweeney KM, Wood JH. Pathophysiology of cere-brospinal fluid in head injury: part 2. Biochemical markers forcentral nervous system trauma [Review]. Neurosurgery 1986;18:376-82.96. Fernandez F, Verdu A, Quero J, Ferreiros MC, Daimiel E,Roche MC, Lopez-Martin V. Cerebrospinal fluid lactate levels in

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term infants with perunatal hypoxia. Pediatr Neurol 1986;2:39-42.97. Fernandez F, Quero J, Verdu A, Ferreiros MC, Daimiel E,Roche MC. LDH isoenzymes in CSF in the diagnosis of neonatalbrain damage. Acts Neurol Scand 1986;74:30-3.98. De Praeter C, Vanhaesebrouck P. Govaert P, Delanghe J,Leroy J. Creatine kinase isoenzyme BB concentrations in thecerebrospinal fluid of newborns: relationship to short-term out-come. Pediatrics 1991;88:1204-10.99. Kjekshus JK, Vaagenes P, Hetland 0. Assessment of cerebralinjury with spinal fluid creatine kinase (CSF-CK) in patientsafter cardiac resuscitation. Scand J Chin Lab Invest 1980;40:437-44.100. Roine RO, Somer H, Kaste M, Viinikka U, Karonen SL.Neurological outcome after out-of-hospital cardiac arrest. Predic-tion by cerebrospinal fluid enzyme analysis. Arch Neurol 1989;46:753-6.101. K#{228}rkel#{228}J, Bock E, Kaukinen S. CSF and serum brain-specific creatine-kinase isoenzyme (CK-BB), neuron-specific eno-lase (NSE) and neural cell-adhesion molecule (NCAM) as prog-nostic markers for hypoxic brain injury after cardiac-arrest inman. J Neurol Sci 1993;116:100-9.102. DeSalles AA, Kontos HA, Becker DP, Yang MS, Ward JD,Moulton R, et al. Prognostic significance of ventricular CSF lacticacidosis in severe head injury. J Neurosurg 1986;65:615-24.103. Shimoda M, Yamada SH, Yamamoto I, Tsugane R, Sato 0.Time course of CSF lactate level in subarachnoid hemorrhage.Correlation with clinical grading and prognosis. Acts Neurochir(Wien) i989;99:127-34.104. Vaagenes P, Urdal P, Melvoll R, Valnes K. Enzyme levelchanges in the cerebrospinal fluid of patients with acute stroke.Arch Neurol 1986;43:357-62.105. Lamph Y, Paniri Y, Eshel Y, Sarova-Pinhas I. Cerebrospinalfluid lactate dehydrogenase levels in early stroke and transientisehemic attacks. Stroke 1990;21:854-7.106. Hatfield RH, McKernan EM. CSF neuron-specific enolase asa quantitative marker of neuronal damage in a rat stroke model.Brain Res 1992;577:249-52.107. Hardemark HG, Persson L, Bolander HG, Hillered U, Ohs-son Y, Pahiman S. Neuron-specific enohase is a marker of cerebralischemia and infarct size in rat cerebrospinal fluid. Stroke 1988;19:1140-4.108. Hay E, Royds JA, Aelwyn G, Davies-Jones B, Lewtas NA,Timperley WR, Taylor CB. Cerebrospinal fluid enolase in stroke.J Neurol Neurosurg Psychiatry 1984;47:724-9.109. Persson U, Hardemark HG, Gustafsson J, Rundstrom G,Mendel-Hartvig I, Esscher T, Pahlman S. S-100 protein andneuron-specific enolase in cerebrospinal fluid and serum: mark-ers of cell damage in human central nervous system. Stroke1987;18:911-8.110. Vermuyten K, Lowenthal A, Karcher D. Detection of neuronspecific enolase concentrations in cerebrospinal fluid from pa-tients with neurological disorders by means of a sensitive enzymeimmunoassay. Chin Chim Acts 1990;187:69-78.111. Jacobi C, Reiber H. Clinical relevance of increased neuron-specific enolase concentration in cerebrospinal fluid. Chin ChimActs 1988;177:49-54.112. Persson L, Hardemark H, Edner C, Ronne E, Mendel-Hartvig I, Pahlman S. S-100 protein in cerebrospinal fluid ofpatients with subarachnoid haemorrhage: a potential marker ofbrain damage. Acts Neurochir (Wien) 1988;93:116-22.113. Sindic CJM, Chalon MP, Cambiaso CL, Laterre EC, MassonPL. Assessment of damage to the central nervous system bydetermination of S-100 protein in the cerebrospinal fluid. JNeurol Neurosurg Psychiatry 1982;45:1130-5.114. Aurehl A, Rosengren LE, Karhsson B, Olsson JE, ZbornikovaV, Haglid KG. Determination of S-100 and ghial fibrillary acidicprotein concentrations in cerebrospinal fluid after brain infarc-tion. Stroke 1991;22:1254-8.115. Matias-Guiu J, Martinez-Vazquez J, Ruibal A, Colomer R,Boada M, Codina A. Myelin basic protein and creatine kinase BBisoenzyme as CSF markers of intracranial tumors and stroke.Acta Neurol Scand 1986;73:461-5.116. Noseworthy TW, Anderson BJ, Noseworthy AF, Shustack A,Johnston RG, Petruk KC, McPherson TA. Cerebrospinal fluid

myelin basic protein as a prognostic marker in patients with headinjury. Crit Care Med 1985;13:743-6.117. Strand T, Ailing C, Karlason B, Karlason I, Winbhad B.Brain and plasma proteins in spinal fluid as markers for braindamage and severity of stroke. Stroke 1984;15:138-44.118. Kiyosawa K, Mokuno K, Murakami N, Yasuda T, Kume A,Hashizume Y, et al. Cerebrospinal-fluid28-kDa calbundin-Dasapossible marker for Purkinje-cell damage. J Neuroh Sci 1993;118:29-33.119. Lee TH, Goldman U. Serum enzyme assays in the diagnosisof acute myocardial infarction. Recommendations based on aquantitative analysis. Ann Intern Med i986;105:221-33.120. Bodvarsson A, Franzson I, Briem H. Creatine kunase isoen-zyme BB in the cerebrospinal fluid of patients with acute neuro-logical diseases. J Intern Med 1990;227:5-9.121. van Gool WA, Boihuis PA. Cerebrospinal fluid markers ofAlzheimer’s disease [Review]. JAm Geriatr Soc 199 1;39:1025-39.122. SirvioJ, Riekkinen PJ. Brain and cerebrospinal fluid cho-linesterases in Alzheimer’s disease, Parkinson’s disease andaging. A critical view of clinical and experimental studies. JNeural Transm Park Dis Dement Sect 1992;4:337-58.123. Ehlenberg JH. Prechinicaldetection in studies of the etiol-ogy, natural history, and treatment of Parkinson’s disease. Neu-rology 1991;41:14-20.124. Navaratnam DS, Priddle JD, McDonald B, Esiri MM, Rob-inson JR, Smith AD. Anomalous molecular form of acetylcholines-terase in cerebrospinah fluid in histologically diagnosed Alzhei-mer’s disease. Lancet 1991;337:447-50.125. Van Nostrand WE, Wagner SL, Shankle WR, Farrow JS,Dick M, Rozemuller JM, et al. Decreased levels of soluble amyloidbeta-protein precursor in cerebrospinal fluid of hive Alzheimerdisease patients. Proc Nath Aced Sci USA 1992;89:2551-5.126. Farlow M, Ghetti B, Benson MD, Farrow JS, van NostrandWE, Wagner SU. Low cerebrospinal-fluid concentrations of solu-ble amyloid beta-protein precursor in hereditary Alzheimer’sdisease. Uancet 1992;340:453-4.127. Van Nostrand WE, Wagner SU, Haan J, Bakker E, Roos RA.Alzheimer’s disease and hereditary cerebral hemorrhage with amy-loidosis-Dutchtype share a decrease in cerebrospinal fluid levels ofamyloid beta-protein precursor. Ann Neurol 1992;32:2i5-8.128. Delamonte SM, Vohicer U, Hauser SL, Wands JR. Increasedlevels of neuronal thread protein in cerebrospinal-fluid of pa-tients with Ahzheimers disease. Ann Neurol 1992;32:733-42.129. Chong JK, Cantrehl U, Husain M, Riesing 5, Miller BE,Wands J, et al. Automated micropartiche enzyme immunoassayfor neural thread protein in cerebrospinal fluid from Alzheimer’sdisease patients. J Chin Lab Anal 1992;6:379-83.130. Gunnersen D, Haley B. Detection of glutamine synthetasein the cerebrospinal fluid of Alzheimer diseased patients: apotential diagnostic biochemical marker. Proc Natl Aced Sci USA1992;89:11949-53.131. Mullan M, Crawford F. Genetic and molecular advances inAhzheimer’s disease. Trends Neurosci 1993;16:398-403.132. Fredrikson S, Link H, Eneroth P. CSF neopterin as markerof disease activity in multiple sclerosis. Acts Neurol Scandi987;75:352-5.133. Bjerrum OW, Bach YW, Zeeberg I. Increased level of cere-brospinal fluid beta 2-microghobulin is related to neurologicimpairment in multiple sclerosis. Acts Neurol Scand 1988;78:72-5.134. Tomioka R, Hamaguchi K, Ohno R, Hosokawa T, Kaneko A,Tsuji T, Kurihara K Elevated interleukin 2 levels in serum andcerebrospinal fluid of patients with relapsing-remitting multiplesclerosis. Ann N Y Acad Sci 1992;650:347-50.135. Gallo P, Piccinno M, Pagni 5, Tavolato B. Interheukun-2levels in serum and cerebrospinal fluid of multiple sclerosispatients. Ann Neurol 1988;24:795-7.136. Gallo P, Piccinno MG, Pagni 5, Argentiero V, Giometto B,Bozza F, Tavolato B. Immune activation in multiple sclerosis:study of IU-2, sIL-2R, and ganima-IFN levels in serum andcerebrospinal fluid. J Neuroh Sci i989;92:9-15.137. Peter JB, Boctor FN, Tourtellotte WW. Serum and CSFlevels of IL-2, sIL-2R, TNF-alpha, and IL-i bets in chronicprogressive multiple sclerosis: expected hack of clinical utility.Neurology 1991;41:121-3.138. Maimone D, Gregory 5, Arnason BG, Reder AT. Cytokine


levels in the cerebrospinal fluid and serum of patients withmultiple sclerosis. J Neuroimmunol 1991;32:67-74.139. Kittur SD, Kittur DS, Soncrant‘I’F,RapoportSI, Tourtel-lotte WW, Nagel JE, Adler WH. Soluble interleukin-2 receptors incerebrospinal fluid from individuals with various neurologicaldisorders. Ann Neurol 1990;28:168-73.140. Fesenmeier JT, Whitaker JN, Herman PK, Walker DP.Cerebrospinal fluid levels of myelin basic protein-like materialand soluble interleukin-2 receptor in multiple sclerosis. J Neuro-immunol 1991;34:77-80.141. Chalon MP, Sindic CJM, Uaterre EC. Serum and CSF levels

of soluble interleukin-2 receptors in MS and other neurologicaldiseases-a reappraisal. Acta Neural Scand 1993;87:77-82.142. Maimone D, Annunziata P, Simone IL, Livrea P, Guazzi GC.Interleukun-6 levels in the cerebrospinal fluid and serum of patientswith Guillaun-Barre syndrome and chronic inflammatory demyeli-nating pohyradicuhoneuropathy. J Neuroimmunol 1993;47:55-61.143. Reichling JJ, Kaplan MM. Clinical use of serum enzymes inliver disease. Dig Dis Sci 1988;33:i601-i4.144. Pappas NJ Jr. Theoretical aspects of enzymes in diagnosis.Why do serum enzymes change in hepatic, myocardial, and otherdiseases? Chin Lab Med 1989;9:595-626.

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