DOSAGE OF LACTATE IN THE CEREBROSPINAL
FLUID IN INFECTIOUS DISEASES OF THE
CENTRAL NERVOUS SYSTEM
Hideraldo Luis Souza Cabeça
1, Hélio Rodrigues Gomes
2,
Luís dos Ramos M achado
3, José Ant onio Livrament o
4ABSTRACT - This paper analyzes t he diagnosis aid of t he dosage of lact at e in t he cerebrospinal fluid (CSF) in infect ious diseases of t he cent ral nervous syst em (CNS). We analyzed prospect ively 130 samples of CSF of 116 pat ient s w it h diagnoses of infect ious processes in t he CNS. The 130 samples of CSF w ere divided int o five groups: 28 samples of t he cont rol group, 40 of bact erial meningit is, 22 of viral meningit is, 16 of fungal meningit is and 24 of pat ient s present ing acquired immune deficiency syndrome (AIDS). The concent rat ion of lact at e in t he CSF w as elevat ed in t he group of pat ient s w it h bact erial meningit is (average = 46.2 mg/dL), fungal meningit is (average = 27.3 mg/dL) and in t he AIDS group (average = 23.5 mg/dL). In t he cont rol group and viral meningit is group t he lact at e cont ent in t he CSF present ed t he reference rat es according t o t he employed met hod. The lact at e dosage in t he CSF present ed a negat ive correlat ion w it h glycorrhachia and posit ive correlat ion w it h t he cellularit y and t ot al prot eins of t he CSF. We conclude t hat t he lact at e dosage in t he CSF, alt hough unspecific, helps t o dist inguish t he infect ious processes of t he CNS.
KEY WORDS: lact at e, cerebrospinal fluid, cent ral nervous infect ions.
Dosagem de lactato no líquido cefalorraqueano em moléstias infecciosas do sistema nervoso central
RESUM O - O present e est udo t em como objet ivo analisar o auxílio diagnóst ico da dosagem do lact at o no líquido cefalorraqueano (LCR) em molést ias infecciosas do sist ema nervoso cent ral (SNC). Foram est udadas, de modo prospect ivo, 130 amost ras de LCR de 116 pacient es com diagnóst ico de processos infecciosos do SNC. As 130 amost ras de LCR foram dist ribuídas em cinco grupos, sendo: 28 amost ras cont roles, 40 meningit e bact eriana, 22 meningit e viral, 16 meningit e fúngica e 24 pacient es com a síndrome da imunodeficiência humana adquirida (SIDA). A concent ração do lact at o no LCR est ava elevada no grupo de pacient es com meningit e bact eriana (média= 46,20 mg/dL), meningit e fúngica (média= 27,37 mg/dL) e no grupo SIDA (média= 23,54 mg/dL). Nos grupos cont role e de meningit e viral o t eor de lact at o no LCR encont rava-se ent re os valores de referência para o mét odo ut ilizado. A dosagem do lact at o no LCR apresent ou correlação negat iva com a glicorraquia, e posit iva com a celularidade e prot eínas t ot ais do LCR. Em conclusão, a dosagem do lact at o no LCR, apesar de inespecífica, auxilia na dist inção ent re processos infecciosos do SNC.
PALAVRAS-CHAVE: ácido láct ico, líquido cefalorraqueano, infecções do sist ema nervoso cent ral.
The study of infectious and inflammatory patholo-gies of t he cent ral nervous syst em (CNS) has alw ays raised a great int erest from t he scient ific communi-t y, for communi-t he epidemiological characcommuni-t eriscommuni-t ics of some of t hem or for t he sequelae t hat t hey can generat e if not diagnosed and t reat ed in t ime. The cerebrospi-nal fluid (CSF) plays a major role in t he evaluat ion of t he nat ural hist ory, in t he diagnosis and in t he fol-low -up of t he infect ious and inflammat ory pat holo-gies of t he CNS1-3. In many cases, t he rout ine
evalua-t ion of evalua-t he CSF is noevalua-t sufficienevalua-t for diagnosing evalua-t he
t ype of meningit is4-6. M enninger, in 1924, found
el-evat ed values of lact at e (LA) in CSF from pat ient s w it h bact erial meningit is7. Posner and Plum (1967)
confirm t he independence of LA in blood and in CSF and conclude t hat t he LA in CSF is a good indicat or of t he cerebral met abolism7,8. The LA is a product of
t he met abolism of t he carbohydrat es by anaerobic via. From a molecule of glucose, successive react ions lead t o a product ion of molecules of pyruvic acid in t he cellular cyt oplasm9. In anaerobic condit ions t he
pyruvic acid t urns int o LA, by t he act ion of t he
lac-Cent ro de Invest igações em Neurologia, LIM 15, Depart ament o de Neurologia da Faculdade de M edicina da Universidade de São Paulo. (FM USP) São Paulo SP, Brasil: 1M est re em Neurologia; 2Dout or em Neurologia; 3Professor Assist ent e em Neurologia; 4Livre Docent e de
Neurologia.
Received 30 M ay 2001, received in final form 20 July 2001. Accept ed 25 July 2001.
t at e dehydrogenase enzyme (LDH) and t he nicot ina-mide adenine dinucleot ide reduct ase (NADH
2). This
act ion is reversible so t hat , if t he condit ions of oxy-gen upt ake are reest ablished t he prior react ion in-vert it self and t he LA t urns again int o pyruvic acid and t his int o acet yl Coenzime A, w hich finally incor-porat es t o t he Krebs cycle10.
The st udy of Kleine et al. w as primordial for t he improvement of t he enzymat ic met hod t o det ermine t he LA in CSF11. M ost st udies indicat e normal
con-t encon-t s of LA in CSF uncon-t il 19mg/dL12,13; in cases of
bac-terial and fungal meningitis the contents of LA w ould be higher t han 30mg/dL and in viral meningit is infe-rior t o 25mg/dL or cont ent s according t o normali-t y12. When an infect ious process occur, t he great er
affluence of leukocyt es increases t he met abolism of glucose14. Besides, t here is a great er anaerobic
me-t abolism, producme-t s of arachidonic acid and me-t he lib-erat ion of free radicals and liblib-erat ion of t he t umor necrosis fact or-alpha (TNF-α) 15.Hypoglycorrhachia
and t he increase of t he LA in CSF during meningit is originat e primarily from t he increase of t he anaero-bic glycolysis in t he subarachnoid space and t hese met abolic disorders are induced by t he TNF-α and
by t he leukocyt es16.
This st udy aims t o evaluat e t he lact at e levels in t he CSF of pat ient s w it h bact erial, viral, fungal men-ingit is, in t he acquired immunodeficiency syndrome (AIDS) and in cont rol cases, checking t he relat ion-ship of lact at e, cellularit y, glucose and t ot al prot eins.
M ETHOD
A t ot al of 130 samples of CSF from 116 pat ient s of t he M edical School of t he Universit y of São Paulo, Infec-t ious Nervous SysInfec-t em Division w ere prospecInfec-t ively analyzed in t he t ime period bet w een M ay, 1996 and January, 2000. All t he CSF samples w ere analyzed for t ot al cell count ; cyt omorphologic assay; basic biochemical assay (concen-t ra(concen-t ion of (concen-t o(concen-t al pro(concen-t eins and glucose); dosage of lac(concen-t ic acid;17 general immunoassays (VDRL and react ions of
com-plement fixat ion t est s for syphilis and cyst icercosis); mi-crobiologic assay (direct bact eriologic, mycobact eriologic and mycologic assays, as w ell as t he adequat e cult ures)18
as necessary; immunologic complement ary specific assays as indicat ed.
For lact at e det erminat ion, t he CSF samples w ere pro-cessed according t o t he enzymat ic met hod w it hout prior deprot einizat ion, employing t he react ive commercial kit Lact -Boeheringer M annheim19. The analyze of t he LA w ere
performed in a maximum period of 48 hours aft er collect -ing t he CSF. The CSF w as st ored in a refrigerat ed environ-ment w it h t emperat ures bet w een 4 t o 8º C, because it w as report ed t hat values of LA w ere alt ered in t he CSF if it is kept in environment al condit ions, w it hout an adequat e
st orage17. Values bet w een 11 and 19 mg/dL w ere
consid-ered w it hin t he reference limit s for t his met hod11.
The Et hics Commit t ee of t he Universit y of São Paulo M edical School has approved t his st udy.
Samples w ere dist ribut ed in five groups, according t o diagnosis: (1) cont rol group, w it h 28 samples; (2) bact e-rial meningit is, w it h 40 samples; (3) lymphocyt ic viral me-ningit is, w it h 22 samples; (4) fungal meningoencephalit is w it h 16 samples; (5) pat ient s w it h AIDS present ing ant i-HIV in CSF and in blood serum, w it h 24 samples.
St at ist ical analysis - At first all t he variables w ere ana-lyzed descript ively. It w as performed t he measurement of averages and st andard deviat ions and medians (SD). Non parametric test w ere preferentially employed. For the study of t he correlat ion among t he st udied variables t he Spear-man Correlat ion Coeficient w as used. The significance level (alpha) used for all t he t est s w as 10%. This value w as cho-sen due t o t he int rinsic charact erist ics of t he st udied ma-t erial.
RESULTS
From the total of 130 samples studied, 71 (54.6%) w ere from female patients and 59 (45.4%) from male pat ient s. Ages ranged from 2 days t o 82 years, not present ing a significant difference from t he st at ist i-cal point of view t o t he analysis of t he five groups (p= 0.5419).
Cellularit y st udy among groups evidenced pleo-cyt osis in all groups, except t he cont rol group. This analysis show ed a significant st at ist ical difference (p< 0.0001). It w as observed an increase of cont ent s of t ot al prot eins in all groups, except t he cont rol group, show ing a significant difference from t he st a-t isa-t ical poina-t of view (p&la-t; 0.0001).
The glucose concent rat ion w as evaluat ed st at is-t ically among is-t he five groups, and had a significanis-t value from the statistical view (p< 0.0001), presented in Table 1. In t his t able t he average of glycorrhachia is inferior t o normalit y in samples of pat ient s w it h fungal and bact erial meningit is and in pat ient s w it h AIDS. Pat ient s of t he cont rol group and t he viral meningit is group present ed an average w it h values compat ible t o normalit y.
Table 2 show s t he values of lact at e in t he five groups. The analysis of lact at e in t he different st ud-ied groups show ed average values above normalit y in t he groups of fungal and bact erial meningit is and in pat ient s w it h AIDS. In t he cont rol and viral men-ingit is groups w e observed lact at e values consist ent t o normalit y. The evaluat ion of t he five groups sho-w ed a significant statistical difference concerning the lact at e averages (p< 0.0001).
lact at e in CSF. Table 3 show s a paired analysis of t he groups in relat ion t o t he average of glucose in CSF. The paired analysis in groups concerning t he lact at e dosage in CSF may be observed in Table 4.
Figure 1 show s a negat ive correlat ion bet w een t he averages of glucose and of lact at e in CSF in sam-ples from pat ient s w it h bact erial meningit is. Thereby t he increase of glycorrhachia implies t he decrease
of t he lact at e levels, and t he opposit e is also t rue. This correlat ion has a st at ist ical significance.
DISCUSSION
Due t o high morbidit y and mort alit y of many in-fect ious diseases w hich at t ack t he CNS, laborat ory t est s have been gauged so t hat t hey can est ablish an early et iologic diagnosis of t hese diseases. In t his
Table 3. Paired analysis of t he groups show ing t he glucose average in CSF (mg/dL).
Groups AIDS Bact erial meningit is Viral meningit is Cont rol
Bact erial meningit is + + +
Viral meningit is + + +
Fungal meningit is - - + +
AIDS + + +
P< 0,0001; + , significant st at ist ical difference; –, t here is no significant st at ist ical difference. Table 1. Glucose concent rat ion in CSF: average, st andard deviat ion, median, minimum and maximum values (md/dL).
Variables N Average SD M edian M inimum M aximum
Fungal meningit is 16 21.4 14.9 22 1 56
AIDS 24 35.1 15.7 36 4 67
Bact erial meningit is 40 20.2 21.4 16 1 114
Viral meningit is 22 51.8 15.1 51 28 79
Cont rol 28 60.0 7.6 60 47 77
Kruskal-Wallis t est : p< 0,001; N, number of samples; SD, st andard deviat ion.
Table 2. Lact at e concent rat ion in CSF: average, st andard deviat ion, median, minimum and maximum values (mg/dL).
Variables N Average SD M edian M inimum M aximum
Fungus 16 27.3 12.8 26.5 12 48
AIDS 24 23.5 10.1 21.5 10 49
Bact erial meningit is 40 46.2 33.5 34.5 10 150
Viral meningit is 22 17.2 5.6 15.5 7 33
Cont rol 28 12.6 3.3 12.5 4 19
Kruskal-Wallis t est : p< 0,0001. N, number of samples; SD, st andard deviat ion.
Table 4. Paired analysis of t he groups show ing lact at e average in CSF (mg/dl).
Groups AIDS Bact erial meningit is Viral meningit is Cont rol
Bact erial meningit is + + +
Viral meningit is - +
-Fungal meningit is - - - +
AIDS + - +
cont ext , alt hough lit t le specific by definit ion, some laborat ory t est s are ext rem ely im port ant because t hey can delimit in a valuable manner t he field of diagnost ic uncert aint y. Among t hese t est s, t he one for det erminat ion of t he lact ic acid levels is among t he most used20.
In t his st udy five groups of pat ient s w ere analy-zed and compared or relat ed: four w it h infect ious pat hologies of t he nervous syst em and a cont rol group, a t ot al of 130 samples analyzed. There w ere no differences w hich could represent rest rict ions t o t he int erpret at ion of t he result s as for t he dist ribu-t ion of ribu-t he casuisribu-t ry concerning age and gender.
Cellularit y behaved as expect ed, present ing pleo-cyt osis in all groups except in t he cont rol group, such as t he t ot al prot eins, w hich present ed elevat ed rat es in all groups, except the control group. Glycorrhachia is one of t he import ant element s in diagnosis of in-fect ious processes of t he nervous syst em. As classi-cal, bact erial meningit is and fungal meningoence-phalit is w ere follow ed by hipoglycorrhachia: (1) in bact erial meningit is, t he average w as 20.2 mg/dL; (2) in fungal meningoencephalit is, t he average w as 21.4 mg/dL. In t he group of pat ient s w it h AIDS w e observed a significant dispersion of t he values of gly-chorrhachia. As for t he viral meningit is group, al-t hough al-t he average values of glycorrhachia in al-t his group are w it hin normal ranges, it w as unusual t hat some pat ient s present ed hypoglycorrhachia. These samples w ere not excluded because, alt hough it is virt ually impossible t o follow informat ion about t he evolution of these patients, the diagnostic yield w hen
t he collect ion w as done left no doubt on t he benign nat ure of t he process.
The glucose dosage in CSF is of crucial import an-ce in diagnosis and cont rol of t he evolut ion of many infect ious diseases of CNS. M eanw hile, t he st rict re-lationship betw een glychorrhachia and glycemia w ith a short t ime int erval mediat ing t he chemical equili-brium bet w een t he t w o of t hem ends up bringing som e dif f icult ies t o t he int erpret at ion in t he CSF exam21,22.
There is an evident correlat ion among t he glu-cose levels and LA levels23. The elevat ion of t he LA in
CSF is relat ed t o t he decrease in t he cont ent s of gly-corrhachia and vice versa24, especially in bacterial
me-ningit is and micosis, of t he CNS. Furt hermore, t he LA show s reference int ervals w it h bet t er defined lim-it s concerning t o glycorrhachia4,25. In diabet ic pat
i-ent s, t he dosage of LA is not relat ed t o t he levels of glycemia in a linear manner7,9. Wit hout influence of
t he blood LA, t he det erminat ion of LA in CSF pro-vides import ant informat ion in t he evaluat ion of dia-bet ic pat ient s or in cases w hich glycorrhachia can not be of any help23,26.
The average of LA cont ent found in t he bact erial meningit is group (46.2 mg/dL) w as t he higher of t he five groups analyzed. Next one w as fungal meningi-t is (27.3 mg/dL) and afmeningi-t er meningi-t hameningi-t meningi-t he AIDS group (23.5 mg/dL). These values are significant ly above normal-it y st andard.
The average of LA values found in t he CSF of t he viral meningit is and cont rol groups does not differ
significant ly of t he values of normal reference (unt il 19 mg/dL). In t he viral meningit is group, t he maxi-mum value of LA found in CSF w as 33 mg/dL. Viral meningit is cases, in t he init ial phase of diagnost ic yield, w it h levels of LA in CSF above t he reference values are ment ioned in t he lit erat ure27.
In fungal meningit is t he maximum value found w as 48 mg/dL and corresponds t o a sample w hose diagnosis w as CNS hist oplasmosis.
Among t he AIDS group samples, t he values re-ferring t o t he dosage of LA in CSF present ed disper-sion. This dispersion is expect ed due t o t he mult ipli-cit y and diversit y of diseases, w it h or w it hout a de-fined diagnosis, w hich can comprise t he AIDS pa-t ienpa-t s. There w as no spa-t apa-t ispa-t ical difference among pa-t he levels of LA observed in t he samples from AIDS pa-t ienpa-t s w hich w ere submipa-t pa-t ed pa-t o CSF analysis due pa-t o complaint of cephalea or w it h opport unist associ-at ed est ablished disease. The lit erassoci-at ure does not present a support for t he adequat e int erpret at ion of t he result s of LA in CSF in pat ient s w it h reagent ant ibodies ant i-HIV. The LA levels in t his group are higher t han t he basal (t here is st at ist ical difference concerning t he cont rol group).
In bact erial meningit is, t he values of LA in CSF vary from 10 t o 150 mg/dL. The average recorded for t his group (46.2 mg/dL) is compat ible t o w hat are report ed in st udies about t his subject24,28. From
40 sam ples evaluat ed in t he bact erial m eningit is group, 32 present ed a percent age of neut rophil cell higher t han 50% in t he cyt om orphologic prof ile, associat ed t o LA cont ent s superior t o 19 mg/dL. In t his casuist ry t he LA levels recorded f or bact erial meningit is w ere significant ly higher t han t he ones observed in t he viral m eningit is group, t he AIDS group and t he cont rol group.
In fungal and bact erial meningit is t here is nega-t ive correlanega-t ion benega-t w een nega-t he glucose and nega-t he LA in CSF; w hile one increases t he ot her decreases24. In
t his st udy w e found a negat ive correlat ion bet w een t he glucose and LA in CSF, w hich corroborat es t he prior observat ion. Among t he cells w it h glycolyt ic capacit y, t hose, w hich can be a source of LA, are: leukocyt es, t umor cells, neurons, glial cells, as w ell as fungi29,30.
Low values of LA do not exclude t he diagnosis of bact erial meningit is31. Isolat ed dosages may present
reduced values due t o circumst ant ial fact ors, t here-fore t he int erpret at ion must alw ays be done in t he cont ext of t he remaing of t he CSF exam. Persist ing t he doubt , it is a consensus in lit erat ure t o repeat
t he dosages in a second CSF exam, in order t o ex-clude t he possible causes of non syst emat ic error12,32.
Analyzing t he dat a present ed w e m ay recom -mend t he dosage of LA in CSF in cases of suspicion of CNS infect ion, mainly in t he screening of bact e-rial and viral meningit is, as w ell as a helping mea-surer in t he clinic and t herapeut ic evolut ion.
CONCLUSIONS
After analyzing 130 samples of cerebrospinal fluid from 116 pat ient s it is possible t o conclude t hat33:
(1) in t he st udied pat hologies t he lact at e level in CSF behaved inversely proport ional t o glycorrhachia; (2) t he lact at e levels in CSF in t he cont rol group (aver-age 12.6 mg/dL) and in t he viral meningit is group (average 17.2 mg/dL) st udied are w it hin t he values of reference for t he met hod used; (3) t he lact at e level in CSF w as above normal in bact erial meningi-t is (average 46.2 mg/dL, SD 33.5), and in fungal me-ningit is (average 27.3 mg/dL, SD 12.85), t he values observed are according t o t he ones recorded by t he lit erat ure; (4) t he AIDS group show ed average 23.5 mg/dL and SD 10.1; (5) t he lact at e values st udied in CSF are elevat ed w it h st at ist ical significance in rela-t ion rela-t o rela-t he conrela-t rol group, in bacrela-t erial and fungal meningit is and in t he AIDS group, t his w as not ob-served in t he viral meningit is group; (6) according t o t he dat a present ed w e may recommend t he dos-age of lact at e in infect ious processes of t he CNS, mainly in viral and bact erial meningit is diagnosis.
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