268 Tubercle, Lond., (1957) 38, 26B

Cerebrospinal Fluidin Tuberculous

Fructose LevelsMeningitis

By DAVID A. SYMERSfrom St. Mary's Hospital and the Wright-Fleming Institute of .I\tficrobiology, Puddington;

London, VV. '2

Until recently it has been generally accepted that the level of glucose" in the cerebro­spinal fluid in the early phase of acute tuberculous meningitis does not exceed 50 mg ..per roo ml. (Cruickshank, 195r). However, it has been shown (Alexander, 1954;McKendrick, r954; Fluker, 1954; Welbourn, 1954) that this low level is by no means.a universal finding. Eastham and Keay (1952) examined the cerebrospinal fluid of 4cases of acute tuberculous meningitis and found reduced fructose levels in all. Thelevels in these acute cases were from 0'2 to ['0 mg. per roo ml, as against a normalrange of 1'5 to 7'0 mg. per [00 mi.

In view of these findings it was decided to conduct an investigation into the cere­brospinal fluid fructose levels in cases of tuberculous meningitis in order to assess thevalue of the estimation in the diagnosis of this condition, and to find out whether or'not it was of value in assessing the severity, prognosis and short-term progress of theestablished disease. In addition the relationship between fructose and total reducingsubstances (T.R.S.) in the cerebrospinal fluid in tuberculous meningitis, and levels forfructose in clinically cured patients was investigated.

MethodFructose levels were assessed by the Roe method ([934) as modified by Cole (1948).Protein was precipitated by the method of Somogyi (r930), the final protein free'filtrate being a dilution of 1'4 : 1 of the original sample. The precipitate was separatedby centrifugation. T.R.S. levels were estimated by the routine chemical pathologylaboratory using the method of Folin and Wu (19~;20). Cerebrospinal fluid samples.were taken by lumbar puncture. In patients undergoing treatment, i.e. those in groupsA and B (see below), the samples were taken immediately before the streptomycin andisoniazid were g-iven for that day. Streptomycin (50 /A.g./ml.), isoniazid, piperocainehydrochloride ('metycaine') and procaine were tested for colour reactions in the'Cole-Roe method. All were negative.

MaterialFour groups ofpatients were studied.

Group A -'Acute tuberculous meningitis' (9 patients, 21 samples). This group comprises thosewithin foul' weeks of the disease being detected,

Group B - 'Under treatment' (9 patients, 51 samples). Patients who had been under treatment fora period of at least foul' weeks and who had not yet left hospital. In the earlier stages these patientswere having daily streptomycin (I g. intramuscularly and roo mg. intrathecally) and isoniazid (100mg. orally). Later in the treatment these doses and their frequency were reduced.

Group C - 'Follow-up cases' (13 patients, 16 samples). This group comprises those attending forfollow-up examination three, six, twelve and eighteen months after having been discharged fromhospital following treatment for tuberculous meningitis.

Grouj: D - 'Controls' (28 patients, 28 samples). It was decided to utilize all the available cerebro­spinal fluid samples in the hospital, other than those of the tuberculous meningitis cases, to establisha control group. I t was thought that, if anything, this would give a wider range of cerebrospinal fluid.fructose levels than might be expected from a 'normal' group. This group contains the following:Old 'cured' general paralysis of the insane, subacute combined degeration, disseminated sclerosis,Ioy.drocephaly, prolapsed Intervertebral disc, lead poisoning, myasthenia gravis, cerebral thrombosisand three in which no pathological abnormality was found.

*The term 'glucose level' is of course inaccurate in these cases, as total reducing substances (ToR.S.).are nearly always meant or implied.

CEREBROSPINAL FLUID IN MENINGITIS

ResultsGmup A

The range of fructose levels was from o·g to 1'4 mg. per 100 ml., the averagebeing 0'7 mg. per 100 ml., the T.R.S. levels being from 21 to 65 mg. per 100 mI.(Table I, Fig. r ), The proportion offructose in the T.R.S. varied between 0·8 per cent

7

Fructosel1g.JIDDrnl.

6

5

4

2

Gp A. Gp B, Gp C. Gp D.

Acute Under' Treatment Follow Up Controls

9 Patients 9 Patients 13 Patients 28 Patients

2i Samples 51 Samples 16 Samples 28 Samples

iO 20 30Number of samples Scale L./_-L._.........._ ...

aFIG. r, - The concentrations of fructose in the cerebrospinal fluid during and after

acute tuberculous meningitis and in a group of patients without meningitis.

TABLE 1. - FRUCTOSE LEVELS IN THE CEREBROSPINAL FLUID

Fructose levels (mg./Ioo mI.)

»: qj }fo. of Standard StandardjJatients samples JUcan Range deoiation error

Group A 9 21 0'7 0'3-1 '4 0'29 0'06Group B 9 51 1'4 0'7-2'5 0'42 0'06Group C 13 16 2'7 2'0-3'5 0'47 O"IQ

Group D 28 28 4'2 2'5-7'1 0'99 0'19

Group A - tuberculous meningitis within four weeks of diagnosis,GI'OUp B - tuberculous meningitis after at least four weeks' treatment,GI'OUp C - from three to eighteen months after discharge from hospital.Group D - no meningitis.

7

6

Eo 5o

~4E

(a)

TUBERCLE

(b)

-X- :xv_-- , -X~ - ---'I..'

(c)70

60

50 Eoo

40 :::..00E

30 ....;ci.

20 r-:

,0

o 10 20 30 40 50

__ Fruc.tose

o 10 20 30 40 0 10 20 30 40 SO

Days- •.••.Total reduCing substances

FrG. 2. - The concentrations of fructose and total reducing substancesin the cerebrospinal fluid of 3 patients with tuberculous meningitis

during treatment.

and 3'2 per cent. In 3 of the 9 cases the initial cerebrospinal fluid fructose levelsin mg. per roo ml. were 0'5, 0'9 and I -r, the T.R.S. levels being 60, 55 and 65respectively. The T.R.S. levels were, therefore, well above the accepted upper limitfor acute tuberculous meningitis.

Group BThe range of fructose levels was from 0'7 to 2'5 mg. per roo mI., the

average being 1'4 mg. per 100 mI. The T.R.S. levels were from 30-58 mg. per roo ml.The proportion offructose in the T.R.S. varied between 1'7 per cent and 5'7 per cent.In this group 4 patients were followed serially for periods ranging from five to sevenweeks. The results in 3 of them are shown in Fig. 2. There was no appreciable rise orfall in the cerebrospinal fluid fructose levels, although in cases (a) and (b) the patients'clinical condition had improved over the relevant period. In this group a comparisonwas made in individual cases of the cerebrospinal fluid fructose levels and the cellcount in the cerebrospinal fluid. Neither in individual cases nor in the group as awhole did there appear to be any relationship between high cell counts and lowfructose levels or vice versa.

Group CThe range of fructose levels was from 2'0 to 3'5 mg. per 100 mI., the

average being 2'7 mg. per 100 ml. The T.R,S. levels varied from 57-80 mg. per 100

ml. The proportion of fructose in the T.R.S. varied between 3'r per cent and 5'2 percent. In this group, the cerebrospinal fluid cell counts were all normal.

Group DThe range of fructose levels was from 2 '5-7' I mg. per 100 ml , the average being

4'2 mg. per roo ml.

Statistical analysis shows that the fructose levels of each of the four groups differsignificantly from one another. Student's t test gives values for P of < 0 '00 I betweengroups A-C and A-D.

CEREBROSPINAL FLUID IN MENINGITIS

DiscussionThe cerebrospinal fluid fructose level is significantly lowered in acute cases of tubercu­lous meningitis. Comparison with T.R.S. levels shows that the fructose is proportion­ally decreased to a greater extent than is the T.R.S., at least in the early phase of thedisease.

In the 3 cases where the T.R.S. levels were initially above 50 mg. per 100 ml. thisfinding would not have supported the diagnosis of tuberculous meningitis; thefructose levels, however, would have been in favour of it.

From Fig. '2 it would appear that estimations of cerebrospinal fluid fructose levelsare of no value in assessing the progress being made by a patient over periods fromfive to seven weeks. Furthermore, in comparing the patients in group B with oneanother, it appeared that the cerebrospinal fluid fructose levels were not directlyrelated to the clinical severity of the disease.

The range of fructose levels in Group D, the control group, agrees well with the17 'normals' estimated by Eastham and Keay (I9Y2).

The fructose levels in group C are significantly different from normal anel it wouldtherefore appear that the rate of return to a normal cerebrospinal fluid fructose level,if indeed there is a complete return to normal, is slow. In all cases in group C thecerebrospinal fluid cell count was normal, and in no case were acid-fast bacillidetected in the cerebrospinal fluid. Further, it was not possible in group B to correlatethe cerebrospinal fluid fructose level with the number of cells in the cerebrospinalfluid. It would therefore appear that, whatever may be the mechanism responsible forthe reduced cerebrospinal fluid fructose levels during and after an attack of tubercu­lous meningitis, it is not that of fructose utilization by the acid-fast bacilli or the freecells in the cerebrospinal fluid.

It may be concluded that the cerebrospinal fluid fructose level is significantlyreduced at the onset of tuberculous meningitis. As a working hypothesis, a cerebro­spinal fluid fructose concentration of 2 mg. per roo ml., is suggested as a diagnosticlevel, this figure being approximately mid-way between the highest level found inacute tuberculous meningitis and the lowest level found in the control group. Fructoselevels below this figure would support the diagnosis of tuberculous meningitis whilstfigures above would not substantiate the diagnosis.

The fall in fructose concentration is proportionately greater than is the fall oftotal reducing substances concentration. Furthermore, cerebrospinal fluid totalreducing substance may initially be above the suggested diagnostic level of 50 mg.per 100 ml. and only later fall below this value. It is therefore reasonable to postulatethat the estimation of fructose in the cerebrospinal fluid would be of greater diagnosticvalue in cases of tuberculous meningitis than the estimation of total reducingsubstances.

SummaryThe cerebrospinal fluid fructose levels were investigated to assess the value of this

estimation in the diagnosis of, tuberculous meningitis and to discover whetheror not there is a correlation between this level and the severity, prognosis or short­term progress of the disease.

Four groups of patients were investigated, viz. those in the acute phase of thedisease, those under treatment in hospital, those attending for follow-up examinations.and a control group.

272 TUBERCLE

The fructose level in the cerebrospinal fluid was significantly reduced at the onsetof the disease and it is postulated that this estimation is of greater diagnostic valuethan that of total reducing substances.

No correlation was proved between the fructose levels and the severity, prognosisor short-term progress of the disease.

The author is indebted to Professor R. Cruikshank, Principal of the Wright-Fleming Institute ofMicrobiology, for guidance and facilities, to Dr. W. F. Widdas for help with the statistics, and to theChemical Pathology Department for permission to use their estimations of total reducing substances.

References

Alexander, J. G. (1954) Brit. med. J., ii, 646 and 1051.Cole, S. W., quoted by Bacon, J. S. D., and Bell, B. J. (1948) Biochem, J., 42,397.Cruickshank, D. B. (1951) in Recent Advances in Clinical Pathology, cmd ed., ed. by S. C. Dyke,

p. 33. Churchill, London.Eastham, M. D., and Keay, K. R. (1952) J. elill. Path., 5, 319.Fluker,]. L. (1954) Brit. med.J., ii, 930.Falin, 0., and Wu, H. (1920)]. biol.Chem., 41,367.McKendrick, G. D. W. (1954) Brit. med.]., ii, 81 I.

Roe, J. H. (1934) J. biol. Chem., I07, 15.Somogyi, M. (1930)]. biol. Chem., 86, 655.Welbourn, E. (1954) Brit. med. ]., ii, 930.