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1969;44;1Pediatrics
John H. MenkesANOTHER LOOK
THE CAUSES FOR LOW SPINAL FLUID SUGAR IN BACTERIAL MENINGITIS:
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the World Wide Web at:The online version of this article, along with updated information and services, is located on
ISSN: 0031-4005. Online ISSN: 1098-4275.
PrintIllinois, 60007. Copyright © 1969 by the American Academy of Pediatrics. All rights reserved.by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarkedPEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication,
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\ ‘o i r’ 44NUMBER 1
COMMENTAR I E S
SUGAR
LOOK
1
P ed fa t r icsJU LY 1969
THE CAUSES FOR LOW SP INAL FLU ID
IN BACTER IAL M EN ING IT IS : ANO THER
Q Ni : of th e m ost charac te ristic abno r-
m alities o f ce reb rosp in al flu id (CSF)
in p atien ts w ith bac te ria l and tubercu lo iism enin g itis is a dec rease in its g lucose co n-
ten t. T h is find ing , firs t observed by L ich-
the im, was in itia lly a ttribu ted to u tiliza tio n
of g lu cose by the l)acte ria g row in g in the
flu id . T h is exp lana tion , as m any sub se -
quen t on es , has b een abandon ed in th e
l igh t of conf lic ting ex perim en tal ev idence ,
an d at presen t the m echan ism s induc’ing a
low C SF sug ar ar e en igm atic . R ecen t pub ii-
ca tion s bearing au th is P rO l)lem Pr0 IBP t a
rev iew of the fac to rs invo lved in low erin g
ce i’eb rosp in a l flu id sug ar .
G o id ring and H arfo rd it foun d tha t the
u tiliza tion of g lucose 1w concen tra tions of
pn eum ococc i equa l to o r h igher than those
usu ally seen in m en ing itis w as too sm all to
be measu red and cou ld , the re fo re, no t a f-
fec t the sp in a l flu id sug ar in th e face of a
norm a l m ech an ism for its rep len ishm en t.
Th is s tudy , and one by m o ,’ w ho d em on-
stra ted th at u nder norm al co nd itio ns g lu -
cose w as transpo rted in to the C SF m o re
rap id ly than its u tiliz atio n by lym phocy te s,
sug gested to P c te rsdorf and H arte r# {176 } tha t
the decrease in CSF sugar w as du e to its
enhanced u tiliza tion b y phag ocy tiz ing po ly -
m orph onu clea r leuko cy te s in th e ireseu ice
of l)ac te ria . W ork ing with dogs , P e tersdorf,
e t a !. #{176}‘ show ed th at 1 )0 th in civo an d in
citr() the in trodu ction of bac te ria in to CSF
con tain ing po lym orp honuc lea r ee l Is in -
du ced a low ering of CSF sugar. T h is d id
no t occur w hen live b ac te ria w ere in jec ted
in to n orm al CSF , o r in to f lu id of an im als inw hom th e ce llu la r respon se to the in jec tio n
o f s te rile sa line h ad been in h ib ited by irra -
d ia tion -ind uced leukop en ia . Two ob jections
can be ra ised to the hy po thesis tha t the
low ered CSF sug ar is the resu lt o f the com -
b in ed presen ce of b ac te ria and phago cy tes .
First, it fails to exp la in the low C SF sugar
seen in tub ercu lo us m en ing itis and in o ther
m en in g itides ch arac te rized b y a s ligh t m o-
n onuc lea r resp onse. T he secon d ob jection is
th a t, even w hen the m etabo lism of leuko-
cy tes is enhanced th rough the presence of
bac te ria , bac ter ia l g lu co se up take is bu t a
frac tion o f the am oun t m etabo lized by the
bra in .
A ssum ing th at a ty p ica l ch ild w ith b ac te -
ria l m en in g itis has a CSF vo lum e of 100 m l
and u sing the da ta o f P e te rsdo rf and
H arde r,# {17 6} 75 m g of g lu cose is consum ed iw
C SF po lym orphonuc lear ce lls in 2 hours.
S im ila r resu lts a re ob ta ined w hen w e us e
v alu es fou nd by C ohn and M orse fo r gh i-
cose u tiliza tion by endo tox in -s tim u la ted
p o lym orp honuc lea r leukocy tes . T h is co n-
trasts with the u tiliza tion of a l)o u t 75 rug
g luco se per m inu te by the res ting adu lt
b rain . F or these reasons an im p a irm en t in
th e tran sfe r o f g lu co se be tw een b lood and
C SF and bra in an d CSF h as been sug -
gested as con tribu ting to the redu c tion of
sp ina l flu id sug ar .
PEDIAT II I ( ; s , Vo l . 44 , No . 1 , Ju ly 1969
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2 SPIN AL FLU ID SUGAR
Fishmant and Crone’#{ 176 } have found that,
under physio lo g ical conditions, the transfer
o f g lucose from blood to CSF and brain is
dependent on tw o fac to rs : s imple diffus io n
and carrier-fac ilitated diffusion. In bacterial
mening itis , bo th mechanism s may func tion
abnormally . S ifontes, et hav e found
that g lucose transport from blood to CSF is
usually inhibited o r de layed in tuberculous
m ening itis , and a number o f o ther clinical
studie s hav e since confirm ed this defect in
non-v iral m ening itide s.
Recently , Prockop and Fishma&2 have
found both the fac ilitated diffusio n o f g lu-
co se from blood to CSF and the fac ilitated
outw ard diffusion o f g lucose from CSF to
blood to be impaired in bacterial meningitis
and, significantly , that a nonspec ific in-
crease in the perm eability o f the m em-
branes betw een blood and CSF, as m ea-
sured by the rates o f mannito l entry and
disappearance , allow ed more hexose to
enter the CSF than w ould be exc luded by
the inhibitio n o f the carrier sys tem .
It is there fore like ly that facto rs aside
from those already c ited contribute to the
reduced CSF sugar in mening itis . One of
these is the greater utilization of g luco se by
the brain as a consequence o f an increase in
the rate o f cerebral g ly co lysis re lative to
g lucose o x idatio n.U nder normal conditions, brain ox idize s
about 85% o f the g lucose it utilizes, while
but 15 % is converted to lac tic acid. S ince ,
theoretically , g ly co lysis y ie lds 2 mo les and
g lucose ox idation 36 mo les of high energy
phosphates per mo le o f g luco se utiliz ed, a
decrease [as fo r instance from 85% to 45% in
the re lativ e amount o f g lucose ox idized by
the tricarhoxy lic ac id (Krebs) cy c le] w ill
increase l)y 78% the amount o f g lucose re -
quired to maintain a constant rate o f en-
e rg y pro duc tio n.
The ev idence for a s ignif icant decrease in
cerebral g lucose ox idatio n, and an increase
in g lyco ly sis in bac terial m ening itis may be
summarized as fo llow s:
1 . A n increased CSF lactic ac id concen-
tratio n has been noted in patients w ith bac-
terial and tuberculous , but not w ith v iral,
mening itis.1 4 ’1 ’ A lthough lac tic ac id has
been cons idered to arise from the metabo-
lism of g luco se by phagocytiz ing leuko-
cy te s, a consideratio n of lac tic acid trans-
po rt mechanism s makes this highly unlike ly .
Po sner and Plum15 have show n that, in al-
te red phy sio lo g ic s tates , CSF lac tic ac id
concentratio ns paralle l those in the brain
rather than those in arterie s o r cerebral
ve ins. Therefore , the increased CSF lac tate
in bacterial mening itis re flec ts a propo rtio n-
al increase in brain lac tate . In the absence o f
impaired brain-CSF-brain transpo rt o f lac -
tic ac id, it is highly unlike ly that lac tic ac i-
dosis o f the CSF could be maintained so lely
through the anaerobic g lyco lysis by po ly -
morphonuc lear leuko cy tes, but it also re-
quires participatio n by the brain in lac tic
ac id production. The productio n of 12 mg of
lac tic ac id per m inute by the normal resting
adult brain, and 0 .06 0 mg lactic ac id by 1 X
10 endotox in stimulated po lymorphonu-
c lear ce lls per hours emphas ize s the re lativ e
dimens ions of the tw o sources fo r lactic ac id
production. W hile increased lactic ac id pro-
duc tion also occurs in status epilepticus and
fo llow ing experimentally induced se i-
zures,1 6 increased g lucose utilizatio n o ccur-
ring under these conditio ns is compensated
fo r by a tenfo ld increase in g lucose uptake
by the brain, and no chang e in CSF glucosew ould be expected.
2 . Reduction in the activ ity o f ox idativ e
enzymes in the neutrophil occurs w ith m ini-
m al degrees o f tissue damage , such as fo l-
low ing anox ia or head trauma, and is de -
tec table by histo chem ical techniques in the
absence o f any obv ious anatom ical or his-
to log ic alte rations. S Converse ly , w hole
body radiatio n has l)een shown to increase
g luco se o x i( latio n and decrease g lyco ly sis o f
adult rat cortex .1 9 The experiments o f Pc -
tersdorf, et a l.e show ing that a low ering of
CSF gluco se can be prevented by prior ir-
radiation of animals should perhaps be in-
terpreted in light o f this most recent find-
ing.
3 . Increased brain g lycogen has been
noted in anox ia and in a varie ty o f infec-
tious conditions, inc luding mening itis . In
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COMMENTARIES 3
experimental injurie s the increased g lycogen
finding corre lates w ell w ith a decrease in
the ac tiv ity o f enzymes partic ipating in the
ox idation of g lucose ,2#{ 17 6} a nd w ith the slow ing
of e lec trical ac tiv ity o f the e lectroencephalo -
gram which o ccurs w hen g lucose o x idation
has been reduced by 50 % or more . These
finding s sugg es t that g lycog en fo rmation,
proceeding v ia g lucose 6 -phosphate (an in-
termediate in the g ly co ly tic pathw ay ), m ay
be re lated to decreased func tion o f the tn-
carboxy lic ac id cy cle , and that it is a rela-
tiv ely common response to m ino r degrees o f
rev ersible cerebral damage .
To sun# { 238} marize, a combination o f in-
creased g lucose utilizatio n by the brain due
to increased g lyco lysis and a defec tive g lu-
cose transpo rt appears at present to repre-
sent the prim ary fac tors fo r the low spinal
f luid sugar in bacterial mening itis .
J O H N H. MENKES, M.D .
D iv ision of Pediatric N euro lo gy
UCLA S choo l o f M edicine
Los Angeles, California 90024
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1969;44;1Pediatrics
John H. MenkesANOTHER LOOK
THE CAUSES FOR LOW SPINAL FLUID SUGAR IN BACTERIAL MENINGITIS:
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Online ISSN: 1098-4275.Copyright © 1969 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005.American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007.has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by thePEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it
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