Annals of Tropical Paediatrics International Child Health

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Cerebrospinal fluid investigations in tuberculous meningitis P. R. Donald, J. F. Schoeman, M. F. Cotton & L. E. Van Zyl To cite this article: P. R. Donald, J. F. Schoeman, M. F. Cotton & L. E. Van Zyl (1991) Cerebrospinal fluid investigations in tuberculous meningitis, Annals of Tropical Paediatrics, 11:3, 241-246, DOI: 10.1080/02724936.1991.11747509 To link to this article: http://dx.doi.org/10.1080/02724936.1991.11747509

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Date: 19 July 2017, At: 09:59

Annals of Tropical Paediatrics (1991) 11, 241-246

Cerebrospinal fluid investigations in tuberculous meningitis P. R. DONALD, J. F. SCHOEMAN, M. F. COTTON & L. E. VAN ZYL

Department of Paediatrics & Child Health, Tygerberg Hospital and The University of Stellenbosch, Tygerberg, South Africa (Received 27 August 1990)

Summary The results of conventional cerebrospinal fluid (CSF) investigations (CSF cell count, protein and glucose concentrations and Pandy's test for CSF globulin) obtained on admission and sequentially from weekly follow-up lumbar punctures for 4 weeks were evaluated in 99 children (median age 28 months) with stage 11 (50 children) and stage Ill (49 children) tuberculous meningitis. On admission, six children (6 ~o) had a CSF cell count > 500 x 106 /1 and nine (9%) a polymorphonuclear predominance. ACSFprotein 2.2 mmol/1 on admission or after having risen to > 2.2 mmol/1. Fluctuations in the CSF cell count and the protein and glucose concentrations during the 1st month of therapy even when intrathecal therapy is not administered are not unusual and should not deter the clinician from continuing antituberculous therapy. Initial CSF findings within the range expected for a viral meningitis occurred in 15 (15%) of the children.

Introduction Tuberculous meningitis (TBM), although now relatively rare in the developed world, remains an important manifestation of the continuing high incidence of tuberculosis in the developing world. The importance of the early diagnosis and treatment of TBM has been repeatedly emphasized, l-J but all too often the disease is not recognized until

Reprint requests to: Dr P. R. Donald, Dept. of Paediatrics & Child Health, University of Stellenbosch, P.O. Box 63, Tygerberg, 7505 South Africa.

irreparable neurological damage has been done or death has intervened. This is also true of developed countries where the disease may not be recognized initially because of its rarity.4-6 Because of the uncertainty which surrounds the diagnosis of TBM, follow-up lumbar puncture (LP) is often undertaken to document changes occurring in the cerebrospinal fluid (CSF). However, the sequence of changes occurring in the CSF in TBM in children following the initiation of modern anti-tuberculous chemotherapy is not well known. In view of the consequences of delayed diagnosis ofTBM, we review in this

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report our experience with conventional CSF investigations in a consecutive series of 99 children with TBM and give details of the sequential changes in the CSF findings occurring in 63 children during the 1st 4 weeks of treatment.

Patients and methods During a 3-year period 99 children with TBM were admitted to our hospital and enrolled in a current study of raised intracranial pressure and hydrocephalus in TBM. 7 The children's ages ranged from 5 months to 156 months (median 28 months). Fifty children were at stage II and 49 at stage II I of the disease as described by the British Medical Research Council classification. 8 Patients at stage II of the disease are mentally confused and/ or have neurological signs such as cranial nerve palsies or hemiparesis. Patients at stage Ill are comatose and/or have complete hemiplegia or, more rarely, paraplegia. The diagnosis of TBM was confirmed by culture of M. tuberculosis from the CSF in 15 children (15%). In a further seven children (7%) M. tuberculosis was cultured from gastric aspirate. Supporting evidence for the diagnosis of TBM was obtained from radiographic appearances compatible with pulmonary tuberculosis in 73 children (7 4%) and a Mantoux test giving an induration > 10 mm in 47 children (47%). Computerized tomography showed a basal exudate compatible with a granulomatous meningitis in 85 children (86%) and hydrocephalus in 84 children (85%). As part of the study of raised intracranial pressure (ICP) in these children, lumbar puncture (LP) was undertaken at weekly intervals for the 1st 4 weeks after admission and I CP recorded over a period of 1 hour. The CSF results reported here are those obtained on admission and at follow-up pressure studies during the 2nd, 3rd and 4th week after the start of treatment. Ten children (10%) died during the 1st month of treatment and a further four (4%) during the subsequent 5 months. A

ventriculo-peritoneal (VP) shunt was undertaken in 14 children ( 14%) for relief of raised ICP which was not responding to medical treatment, after which further pressure studies were not undertaken. In a further 19 children CSF studies could not be undertaken when pressure measurements were not possible for technical reasons or because insufficient CSF was obtained. A total of334 CSF specimens were available for final evaluation. In nine cases CSF total protein was not determined, in six CSF glucose was not determined and the results of Pandy's test for CSF globulin were not available in four cases. CSF cell counts were undertaken by light microscopy using a Fuchs-Rosenthal counting chamber. CSF protein determination was by a sulpho-salicylic acid method and CSF glucose determination by a glucose oxidase method. Opalescence resulting from the addition of CSF to Pandy's solution was scorerd as absent, a trace, +, + +, + + + or

++++. All the children were treated with isoniazid 20 mg/kg/day, rifampicin 20 mg/ kg/day, pyrazinamide 40 mg/kg/day, ethionamide 20 mg/kg/day and also received furosemide 1 mg/kg/day and acetazolamide lOOmg/kg/day to aid the lowering of ICP. None of the children received corticosteroids. This study and the study of raised ICP were approved by the Ethical Committee of the Faculty of Medicine of the University of Stellenbosch.

Results The results of conventional CSF investigations obtained on admission and during the 1st 4 weeks of treatment are illustrated in Figure 1. CSF cell count

Six children (6%) had a CSF cell count on admission of > 500 x 106 /1 and nine children

FIG. I. Cerebrospinal fluid (CSF) cell count, protein and glucose concentrations during the I st 4 weeks of treatment of tuberculous meningitis. polymorphonuclear leucocytes on CSF cell count.

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P. R. Donald et al.

(9%) had a polymorphonuclear (PMN) predominance. Of the six children with a cell count >500 x 106/1, two (33%) had a PMN predominance. During the 2nd week of treatment, although no child had a CSF cell count > 500 x 106 /1, nine CSF's (11 %) had a PMN predominance. During the 3rd week, three children (4%) had a PMN predominance and four (6%) during the 4th week. One child maintained a PMN predominance throughout the 1st 4 weeks of treatment. One child had a PMN predominance in three specimens and two children had two specimens with a PMN predominance. In 63 children a full set of four CSF cell counts was available. In 23 children (37%) an uninterrupted downward trend in the CSF cell count was evident. In 27 children (43%) a fluctuating downward trend could be seen with the final cell count lower than on admission but with higher counts obtained in the 2nd or 3rd specimens. In 13 children (21 %) a fluctuating upward trend was seen with the 4th cell count higher than that on admission.

CSFprotein

In two children insufficient CSF for protein determination was obtained on admission. In the remaining 97 specimens a protein concentration of < 0.8 g/1 was found in 17 (18%) and < 1.2 g/1 in 38 (39%). By the 4th week of treatment, only seven children (10%) had a CSF protein concentration of < 0.4 g/1. In 57 children all four CSF protein determinations were available. In 22 of these children (39%) the final CSF protein was higher than on admission. In three children (5%) this was the result of an uninterrupted rise, while in 19 children (33%) it was the result of a fluctuating upward course. Thirty-five children (61 %) had a CSF protein concentration lower than on admission. In 28 children (49%) this level was reached by a fluctuating downward course, while in seven (12%) the downward trend was uninterrupted.

Pandy's test for CSF globulin

Pandy's test was carried out on 97 of the CSF specimens on admission. No turbidity or a trace only was reported in 26 children (27%) and a + of turbidity was found in a further 29 children (30%). By the 4th week of treatment no turbidity or a trace was found in 29 (39%) of the 70 specimens evaluated and a + in a further 15 (21 %). CSFglucose

Of the 97 CSF glucose values determined on admission, 58 (60%) were 2.2 mmol/1. It was notable that of the nine children with a CSF glucose < 2.2 mmol/1 by the 4th week, five had had a persistently low CSF glucose throughout. CSF glucose and protein concentration and Pandy's test combined

Fifteen children (15%) had, on admission, a glucose concentration ~ 2.2 mmol/1, a protein concentration of :::;:; 1.0 g/1 and a + or less of turbidity on Pandy's test. An additional five children had a glucose concentration ~ 1.8 mmol/1 and a protein concentration of :::;:; 1.2 mmol/1.

Discussion The classical CSF findings in TBM are well known and include a clear CSF, a relatively low cell count ( 2.2 mmol/1 and 31% > 2.5 mmol/1. When the CSF cell count, protein concentration and glucose concentration and the results of Pandy's test for CSF globulin are combined, 15 children (15%) had values compatible with the diagnosis of a viral meningitis. The apparently incongruous finding of such values in a group of children with advanced complicated TBM is not necessarily unexpected. 12 While the CSF response in TBM appears to be dependent upon the tuberculin response elicited in the meninges by tuberculous antigens, 13 the clinical staging of the disease is determined by the neurological damage caused by the tuberculous lesions. On one hand, the tuberculin response in the CSF may be depressed by the malnutrition which frequently accompanies TBM while on the other hand an identical tuberculous process may prove relatively innocuous at one site but cause gross neurological damage at another. In meningitis cases where diagnostic doubt exists, the clinician will often resort to combined therapy for TBM and other bacterial meningitides. In these cases, follow-up LP to document CSF changes and to evalu-

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ate the appropriateness of therapy is recommended. 14' 15 Fluctuations in the CSF protein concentration and cell count following intrathecal therapy with streptomycin or PPD for TBM are well known 16 and thought to result from an intrathecal tuberculin reaction. 13 In a small number of patients on oral therapy for TBM the occurrence of a transient CSF PMN pleocytosis detected at follow-up LP has also been described. 17 Our experience with modern oral therapy for TBM illustrates further that even in the absence of intrathecal therapy fluctuation in the values of CSF cell count, protein and glucose concentration in the weeks following the initiation of therapy is the rule rather than the exception. Our previous experience with two patients who underwent direct ventricular drainage for relief of raised intracranial pressure also suggests that the fluctuation in CSF protein values may occur from hour to hour. 18 Although none of the children in this study developed a CSF pleocytosis > 500 x 106 /1 in the 4 weeks following the start of therapy, considerable fluctuations within this range occurred and a PMN predominance was particularly likely to be seen during the 1st 2 weeks of therapy. CSF protein concentrations were particularly likely to rise during the 2nd week oftherapy and by the 4th week were higher than on admission in more than a third of the patients. Below a level of 4 g/1, this rise did not necessarily presage the development of a spinal block, while of the eight children with values > 4 g/1 in the 4th week only two ultimately required a ventriculo-peritoneal (VP) shunt to relieve raised ICP. Fluctuation in the CSF glucose concentration was less frequently seen than was the case with the CSF cell count and protein concentration but did occur in 11 (17%) of the children from whom a complete set of specimens was available. Of the five children with persistently low CSF glucose values, two subsequently required a VP shunt for failure of raised ICP to respond to medical treatment.

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In conclusion, while there is little difficulty in the majority of cases in recognizing the CSF changes accompanying TBM in children, the occurrence of values falling either within the range of those seen during a viral meningitis or even within the range of normal values must be remembered. Once having commenced therapy for TBM, fluctuations in the CSF cell count and the protein and glucose concentrations during the 1st month of therapy are common and should not deter the clinician from continuing antituberculous therapy. References 1 Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979;241:264-8. 2 Delage G, Dusseault M. Tuberculous meningitis in children: a retrospective study of79 patients, with an analysis of prognostic factors. Can Med J 1979; 120: 305-9. 3 Cybulska E. Tuberculous meningitis. Br J Hosp Med 1988; 39:63-6. 4 Swart S, Briggs RS, Millac PA. Tuberculous meningitis in Asian patients. Lancet 1981; ii:15-16. 5 Naughten E, Weindling AM, Newton R, Bower BD. Tuberculous meningitis in children. Recent experience in two English centres. Lancet 1981; ii: 973-5. 6 Roberts FJ. Problems in the diagnosis of tuberculous meningitis. Arch Neurol1981; 38:319-20.

7 Schoeman JF, Le Roux D, Bezuidenhout PB, Donald PR. Intracranial pressure monitoring in tuberculous meningitis. Clinical and computerised tomographic (CT) correlation. Dev Med Child Neurol1985;27:644-54. 8 Medical Research Council. Streptomycin treatment of tuberculous meningitis. Lancet 1948; i:582-96. 9 Merritt HH, Fremont-Smith F. Cerebrospinal fluid in tuberculous meningitis. Arch Neurol Psych 1935; 33:516-36. 10 Lincoln EM, Sordillo SVR, Davies PA. Tuberculous meningitis in children. J Pediatr 1960; 57:807-23. 11 Taylor KB, Smith HV, Vollum RL. Tuberculous meningitis of acute onset. J Neurol Neurosurg Psychiatry 1955; 18:165-73. 12 Smith HV. Tuberculous meningitis. Int J Neurol 1964; 4:134-57. 13 Swithinbank J, Smith HV, Vollum RL. The intrathecal tuberculin reaction. J Pathol Bacteriol 1953; 65:565-96. 14 Parsons M. Tuberculous meningitis. Br J Hosp Med 1982; 27:682-4. 15 Girling DJ, Darbyshire JH, Humphries MJ, O'Mahoney G. Extra pulmonary tuberculosis. Br Med Bull 1988; 44:738-56. 16 Smith HV, Vollum RL. Effects of intrathecal tuberculin and streptomycin in tuberculous meningitis. Lancet 1950; ii:275-86. 17 Teoh R, O'Mahoney, Young VTF. Polymorphonuclear pleocytosis in the cerebrospinal fluid during chemotherapy for tuberculous meningitis. J Neurol 1986; 233; 237-41. 18 Donald PR, Malan C, Schoeman JF. Adenosine deaminase as a diagnostic aid in tuberculous meningitis. J Infect Dis 1987; 156:1040-1.

Cerebrospinal fluid investigations in tuberculous meningitis.

The results of conventional cerebrospinal fluid (CSF) investigations (CSF cell count, protein and glucose concentrations and Pandy's test for CSF glob...
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