| Abstract|| |
Tubercular meningitis is a type of septic meningitis and is a significant cause of morbidity and mortality in developing countries like India due to lack of early and timely diagnosis and so the case of fatality remains higher. Cerebrospinal fluid (CSF) evaluation is single most important aspect of lab diagnosis in meningitis. Aims: 1. To evaluate the diagnostic significance of CSF adenosine deaminase (ADA) activity in tuberculous meningitis. 2. To compare the values of CSF ADA in different types of meningitis and with that of controls. Materials and Methods: It was clinical cross-sectional study of 25 cases of tuberculosis, 25 cases of pyogenic meningitis, and 25 cases of aseptic meningitis. Twenty five controls with age and sex matched individuals without evidence of any neurological diseases served as control for CSF ADA. Results: In this study of 100 patients, 25 (100%) patients of the tubercular group had CSF ADA levels of more than 10 IU/dL with a mean of 13.68 IU/dL with 80% of the patients having ADA levels between 11 and 15 IU/dL. Mean ADA levels of aseptic meningitis was 8.00 IU/dL, pyogenic was 5.76 IU/dL, and control group had mean ADA of 2.12 IU/dL. Conclusion: All patients with tuberculous meningitis had elevated CSF ADA activity. CSF ADA activity in tuberculous meningitis was significantly higher when compared with pyogenic meningitis, aseptic meningitis, and controls.
Keywords: ADA(adenosine deaminase) TBM, aseptic meningitis, pyogenic meningitis
|How to cite this article:|
Chetan Reddy K B, Durbesula AT, Usham G. Study of adenosine deaminase levels in Tb meningitis and its comparision with other types of meningitis. Ann Trop Med Public Health 2017;10:544-50
|How to cite this URL:|
Chetan Reddy K B, Durbesula AT, Usham G. Study of adenosine deaminase levels in Tb meningitis and its comparision with other types of meningitis. Ann Trop Med Public Health [serial online] 2017 [cited 2019 May 23];10:544-50. Available from: http://www.atmph.org/text.asp?2017/10/3/544/213172
| Introduction|| |
Meningitis is an inflammation of membranes of brain and spinal cord. The various types of meningeal inflammation are classified into two syndromes.
- Septic meningitis: caused by bacterial or fungal organisms.
- Aseptic meningitis: caused by viral, spirochetal, protozoal, and neoplastic disorders.
Among the septic meningitis syndrome, the two most common presentations are pyogenic (bacterial) meningitis and tuberculous meningitis.
Tuberculous meningitis is a cause of significant morbidity and mortality in developing countries like India. With the onset of HIV (Human immunodeficiency virus) pandemic, the incidence of tuberculous meningitis is increasing even in Western countries due to lack of early and timely diagnosis of tuberculous meningitis, rate of fatality case remains high. Even when it is not fatal, the sequelae are distressing and disabling.
Cerebrospinal fluid (CSF) evaluation is the single most important aspect of laboratory diagnosis of meningitis. Analysis of CSF abnormalities to a great deal facilitates the diagnosis and influences of the initial therapy. Basic studies of CSF that should be performed in meningitis include measurement of pressure, cell count and differential count, estimation of glucose and protein levels, Gram's stain and culture.
The definitive diagnosis of tuberculous meningitis depends on the detection of acid fast bacilli (AFB) and culture of Mycobacterium Tuberculosis from CSF. AFB is seen on direct smear of CSF sediment in only 20% of the cases. However, it takes 4-8 weeks for the bacilli to be grown in culture. Even the characteristic of CSF cytological and biochemical changes is also variable and be even absent. Hence, there is a need for a simple, rapid, accurate, and specific test to confirm the diagnosis of tuberculous meningitis.
Adenosine deaminase (ADA) is an enzyme of purine catabolism leading to hydrolytic deamination of adenosine to inosine and ammonia. ADA is secreted by T lymphocytes and macrophages during infections. Therefore, ADA estimation has shown promising results in the diagnosis of tuberculous pleural, peritoneal, pericardial effusions, and tuberculous meningitis.
There are several forms of ADA but the prominent once are ADA1 and ADA2. ADA1 isoenzyme is found in all cells, with highest concentration founds in lymphocytes and monocyte, whereas ADA2 isoenzyme is found only in monocytes. The ADA2 is the predominant form of TB fluid.
ADA1 and ADA2 ratio less than 0.45 is high that suggests TB.
In the present study, we have made an attempt for early diagnosis of tuberculous meningitis by estimating ADA activity in CSF.
| Methodology|| |
In the present clinical cross-sectional study, 25 cases of tuberculous meningitis, 0.25 cases of pyogenic meningitis, 25 cases of aseptic meningitis, and 25 controls were included. Age and sex matched individuals without evidence of any neurological disease served as controls for CSF ADA assay (individual subjected to elective surgery under spinal anesthesia).
Cases of tuberculous meningitis, pyogenic meningitis, and aseptic meningitis were diagnosed on the basis of diagnostic criteria.
Diagnostic criteria for tuberculous meningitis
The diagnosis of tuberculous meningitis was made on the basis of a. Characteristic of CSF finding in association with one of the first two criteria.,
- Prolonged symptomatic history of meningitis (>l–2 weeks)
- Evidence of extrameningeal tuberculosis.
- Characteristic of CSF findings: low glucose (<40 mg/dL), raised protein (<40 mg/dL), and high leukocyte count (10–500 cells/mm 3) with lymphocytic pleocytosis.
- Detection of AFB from CSF directly or after culture in L.J. Medium.
Diagnostic criteria for pyogenic meningitis
Clinical features suggestive of pyogenic meningitis
Diagnosis of pyogenic meningitis was made on the basis of clinical features supported by at least one of the laboratory criteria.
A. Laboratory criteria:
- Gram's staining of CSF allowing identification of causative microorganism.
- Positive CSF bacterial culture.
- Classic CSF abnormalities:
- Polymorphonuclear leukocytosis (<100 cells/microliter)
- Decreased glucose concentration (<40 mg/dL)
- Increased protein concentration (<45 mg/dL)
- Increased opening pressure.
Diagnostic criteria for aseptic meningitis
- Clinical features suggestive of aseptic meningitis.
- Characteristic CSF findings:
- Lymphocytic pleocytosis (25–500 cell/microliter)
- Normal or slightly elevated protein level (20–80 mg/dL)
- Normal glucose level.
- Organisms not seen on Gram's stain or acid-fast stained smears or India ink wet mounts of CSF.
Clinical features and CSF analysis suggest a diagnosis of tuberculous, pyogenic, and aseptic meningitis.
- Meningitis due to other etiologies, cerebrovascular accidents, and space occupying lesions.
- Those who have already received specific therapy before.
- HIV infected patients.
After selection, detailed history and clinical examination was done as per the predesigned proforma. In history and examination, special emphasis was given to detect the presence of extrameningeal tuberculosis and predisposing factors. Routine laboratory tests like hemoglobin, complete blood count, ESR (Erythrocyte sedimentation Rate) blood chemistry were done in all the cases. Chest x-ray was obtained in most of the cases. Sputum in available cases was sent for AFB smear, Gram's stain and culture. In cases of meningitis associated with otitis media, ear discharge was sent for Gram's stain and culture.
Lumbar puncture was done with full aseptic precautions and CSF was sent for biochemical (sugar and protein), cytological (cell type and count), bacteriological (AFB smear and culture, Gram's stain and culture), and Adenosine deaminase estimation. Cryptococcal meningitis was ruled out by India Ink staining.
Other tests like chest x-ray, complete blood picture with ESR, CT brain were done along with CSF analysis.
Results are presented as mean ± SD and range values, frequency as numbers and percentages.
Unpaired and test was used, to compare mean value of any two groups.
Diagnostic validity tests were performed to assess diagnostic value of ADA, as a biomarker to differentiate TBM (Tuberculous Meningitis) from other non-tubercular meningitis. P value of 0.05 or less was set for statistical significance.
| Results:|| |
CSF ADA was > 10 in 25 patients with TBM (100%) with a mean value of 13.68 IU/dL with 20 (80%) patients having ADA levels between 11 and 15 IU/dL.
Mean ADA of aspetic meningitis was 8 IU/dL and pyogenic 5.76 IU/dL with control having mean ADA of 2.12 IU/dL. [Table 1],[Graph 1]
The mean CSF ADA activity was highest in tuberculous meningitis compared with other groups. [Table 2].
t value and P value [Table 3].
Table showing diagnostic efficacy of CSF ADA in TBM using 10.0 u/L as cut off value [Table 4].
|Table 4: Showing diagnostic efficacy of CSF ADA in TBM using 10.0 u/L as cut off value.|
Click here to view
The other important observations made during the study of patients with tuberculous meningitis are as follows.
The age of patients with tuberculous meningitis varied from 18 to 52
Years with a mean of 31.04. The majority of patients were in the age group of 31–40 years [Table 5],[Graph 2].
The incidence of tuberculous meningitis was more common in males compared with females with male:female ratio of 1.4:1.[Table 6],[Graph 3].
The commonest presenting complaint in the present study was fever followed by headache, altered sensorium, vomiting, focal deficits, and seizures [Table 7],[Graph 4].
Four cases (16%) of tuberculous meningitis had papilloedema.
Cranial nerve palsies
Cranial nerve palsies were more common in tuberculous meningitis (28% of the cases). Commonest cranial nerve involved was abducent nerve followed by facial nerve.
Motor deficits: Four patients (16%) had hemiparesis while rest of the patients were normal.
| Csf Analysis|| |
Appearance of CSF
The majority of patients with tuberculous meningitis had opalescent CSF (60%), whereas only six patients had clear CSF.
Protein in CSF
In TBM patients mean value of protein is 78.42 mg/dL with 10 (40%) patients having range from 41 to 70 mg/dL.
Mean value of protein in pyogenic meningitis was 69.98 mg/dL and aseptic was 49.76 mg/dL, respectively [Table 8],[Graph 5].
Sugar level in CSF
Mean value of sugar was found to be 45.24 mg/dL in pyogenic meningitis with 20 (80%) of cases having <50 mg/dL. In TBM mean value was 57.9 mg/dL and aseptic 65 mg/dL, respectively [Table 9],[Graph 6].
Lymphocyte count in CSF
All patients in TBM had lymphocyte predominance in CSF with mean value of 75.12 cells/cumm with 40% of the patients having lymphocytes ranging from 60 to 90 cells /cumm. Lymphocyte count in aspect and pyogenic meningitis was <25 cells/cumm [Table 10],[Graph 7].
Neutrophil count in CSF
Neutrophil predominantly seen in pyogenic meningitis with mean value of 70.12 cells/cumm with 17 patients (68%) having >60 neutrophils. In TBM neutrophil count had a mean value of 11.04 with 16 (64%) having neutrophil count of <10 [Table 11],[Graph 8].
Most of the patients with tuberculous meningitis and total blood count within normal limits.
Majority of patients with tuberculous meningitis had elevated ESR (<30 mm/h). The majority of patients with tuberculous meningitis had hemoglobin value more than 10 gm/dL while some cases had hemoglobin value less than 10 gm/dL.
In the present study, chest x-ray was obtained in 25 patients. Evidence of tuberculosis was found in six patients (24% of the cases) and was normal in 19 patients.
CT scan brain
CT scan brain was obtained in 25 cases of tuberculous meningitis. Four cases had basal exudates, 5 cases had cerebral edema. One case had right middle cerebral artery infarction. Two patients had tuberculoma, while the other 13 patients had normal CT scan.
| Discussion|| |
Tuberculosis continues to be a major health problem of developing countries like India. Neurotuberculosis is the most dreaded complication. Tuberculous meningitis is the commonest manifestation of neurotuberculosis.
There is considerable urgency in establishing the correct diagnosis of tuberculosis in patients with meningitis, because specific therapy is most effective when instituted early in the course of illness. Irreverisble brain damage may result while waiting for culture to confirm the diagnosis. Therefore, determining ADA level in CSF can be a simple and very useful test for early diagnosis of tuberculous meningitis.
Tuberculous meningitis can occur in any age group, but is common in young children. In the present study, age of patients ranged from 18 years to 52 years and mean age was 31.04 years. Majorities of patients were in 3rd decade. The observations of present study correlate with that of Corral et al. (mean age: 29.1 ± 19.4), Kent et al. (mean age: 31 years), and Srivatsa et al. (maximum incidence: 21-30 years).
In the present study, out of 25 patients of tuberculous meningitis 14 were males and 11 were females, with male to female ratio of 1.4:1. The observations of our study correlate with that of Virmani et al. (male:female ratio = 1.398:1), Klein et al. (ratio = 1.23:1).
Clinical features of tuberculous meningitis
- Fever: In the present study, fever was present in 22 patients (88%), similar observations were made by Thomas et al. (78.44%), Alarcon et al. (89.2%), and Hosoglu et al. (91%).
- Headache: In the present study, headache was present in 80% of patients of tuberculous meningitis. Similar observations were made by Alarcon et al. (86%), Hosoglu et al. (73%), and Mohapatra et al. (66%).
- Altered sensorium: In the present study, altered sensorium was present in 18 patients (72% of cases) of tuberculous meningitis. Similar observations were made by Klein et al. (72%), Ahuja et al. (83%).
- Vomiting: In the present study, vomiting was present in 16 cases (64%) of tuberculous meningitis. Similar observations were made by Mohapatra et al. (60%) and Kennedy et al. (71%).
- Seizures: In the present study, seizures were present in 28% of the cases of tuberculous meningitis (seven cases). Similar observations were made by Thomas et al. (21%) and Verdon et al. (17%).
Signs of meningeal irritation
In the present study, signs of meningeal irritation were present in all but two patients (92% of cases). Neck rigidity was present in 21 cases (84%), Kernig's sign was present in 14 cases (56%), and Brudzinski's sign was present in two cases (8%). The present study correlates with that of Kennedy et al. (90%), Alarcon et al. (92.8%), Ahuja et al. (95.74%), and Mohapatra
et al. (100%).
In the present study, fundoscopic examination revealed papilloedema (or incipient papilloedema) in four patients (16% of cases), Choroid tubercles were not seen in any of the patients that of Srivatsa et al.(22.2%).
Cranial nerve palsies
Paresis of cranial nerves (ocular nerves in particular) is frequent finding in TBM. In the present study, eight cases (28%) had cranial nerve palsies. The results of the present study correlate with that of Verdon et al. (31.25%).
In the present study, occulomotor nerve palsy was observed in one patient (4%). Virmani et al. (4%) and Thomas et al. (6.03%) made similar observations. Trochlear nerve palsy was observed in one patient (4%), similar observations were made by Thomas
et al. (3.44%). Abducent nerve palsy was observed in three patients (12%), similar observations were made by Thomas et al. (18%) and Traub et al. (12.5%). In the present study, facial nerve palsy was observed in two patients (6%).
Focal neurological deficits and common in TBM and they may precede signs of meningeal irritation. In the present study, focal motor deficits in the form of hemiplegia were observed in four patients (16%). Similar observations with regard to hemiplegia were made by Traub et al. (12.5%), Thomas et al. (18.53%), and Mohopatra et al. (13.3%).
CSF analysis in meningitis
In the present study, CSF was clear in six cases (24%). Similar observations were made by Singh et al. (16.69%).
CSF was opalescent in 15 cases (60%) in present study. Similar observations were made by Singh et al. (67.4%).
CSF was turbid in four cases (16%) in present study. Similar observations were made by Srivatsa et al. (5.85%).
Lymphocytes in CSF
In the present study, all the patients with TBM had lymphocyte predominance in CSF with mean value of 75.12 cells/cumm with 40% of the people having lymphocytes ranging 60-90.
The present study correlate with Swart et al. had lymphocytic predominance in 87.5% patients, Traub
et al. (100%), Klein et al. (71.4%), Alcaron et al. (71.4%), and Kent et al. (83%).
Neutrophils in CSF
Neutrophilic predominance seen in pyogenic meningitis with mean value of 70.12 cells/cumm with 17 (68%) of patients having neutroplhils > 60 cells/cumm.
In the present study, CSF protein was elevated in all cases. The mean CSF protein was 78.24 mg/dL and ranged from 41 to 130 mg/dL. Similar observations were made by Swart et al. (165.29 ± 70.30) and Klein et al. (192 ± 204.52).
In the present study, six cases (24%) had CSF protein between >100. Similar observations made by Mohapatra et al (36.67%) and Klein et al (31.57%). In the present study, nine cases (36%) had CSF protein 71–100. Similar observations were made by Mohapatra et al.,(30%) and Klein et al. (31.57%).
In the present study, CSF glucose ranged from 30 to 130 mg/dL with a mean of 57.9 mg/dL. 40% of patients had CSF glucose values less than 50 mg/dL and 14 patients had 51-100 mg/dL.
The study of Singh et al. (70.3% of patients with low glucose), Klein et al. (52.63% with low glucose), and Verdon et al. (69.75% of patients with low glucose) showed similar results.
Evidence of old pulmonary lesions or military pattern is usually found in more than half of cases of TBM on chest radiography. In the present study, chest x-ray features suggestive of pulmonary tuberculosis were present only in six cases (24%). The result of the present study correlates with that of Mehrotra et al.(24%) and Verdon et al. (30%).
CSF ADA activity in meningitis
In the present study, CSF ADA levels were elevated in all cases of tuberculous meningitis with a mean of 13.68 ± 2.21 (range 11–19) when compared with pyogenic meningitis, aseptic meningitis, and controls, the differences being statistically significant (P < 0.05).
In the present study, CSF ADA level of 10 U/L was used as cut off value for diagnosis tuberculous meningitis, as all the patients with TBM had the level more than 10. Sensitivity of the test was 100% and specificity was also 100%, when TBM was compared with controls. When TBM was compared with non-group (pyogenic and aseptic meningitis), the sensitivity and specificity were 100% and 92%, respectively, tuberculous meningitis.
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| References|| |
Menkes JH. Infections of die nervous system. Child Neurology. 6th Philadelphia Lippincott Williams and Wilkins; 2000;467-592.
Rajendra Prasad, Anil Kumar, B.K. Khanna, P.K. Mukerji, S.K. Agarwal, A. Kumar, et al.
Adenosine deaminase activity in cerebrospinal fluid for diagnosis of tuberculous meningitis. Ind J Tub 1991;38:99-101.
Gambhir IS1, Mehta M, Singh DS, Khanna HD, et al.
Evaluation of CSF adenosine deaminase activity in tuberculous meningitis'. J Assoc Physicians Ind 1999;47:192-94.
Raviglione MC, O'Brien RJ. Tuberculosis In: Braunwald F
Kasper H Longo J (editors). Harrison's Principles of Internal Medicine 15th ed, vol 1. New York: McGraw Hill; 2001. pl024-35.
G Thwaites, T T H Chaub, N T H Maib, F Drobniewskic, K McAdamd, J Farrare, et al.
Tuberculous meningitis. J Neurol Neurosurg Psychiatry 2000;68:289-99.
Roos KL, Tyler KL. Bacterial meningitis and other suppurative infection. In: Braunwald F, Kalper H, Longo J (editors) Harrison's Principles of Internal Medicine 15th ed., Vol. 2, New York: McGraw Hill; 2001. 2462-71.
Tyler KL. Viral meningitis and encephalitis. In: Braunwald F, Kasper H, Longo J (editors) Harrison's Principles of Internal Medicine 15th edn, Vol. 2, New York: McGraw Hill, 2001. 2471-81.
Corral I, Quereda C, Navas E, Martín-Dávila P, Pérez-Elías MJ, Casado JL, et al.
Adenosine deaminase activity in cerebrospinal fluid of HIV-infected patients: limited value for diagnosis of tuberculous meningitis. Eur J Clin Microbiol Infect Dis 2004;23:471-6.
Kent SJ1, Crowe SM, Yung A, Lucas CR, Mijch AM, et al.
Tuberculous meningitis: a 30 year review. Clin Infect Dis 1993;17:987-94.
Srivatsa BN, Tejwani BM, Khare U. Clinical profile of meningitis in adults. J Assoc Phys Ind 1984;32:35.
Virmani V, Venkatraman S, Sarsawani V Rao. Clinical spectrum of neurotuberculosis in adults. J Assoc Physicians Ind 1980;28:431-39.
Klein NC, Damsker B, Hirschman SZ. Mycobactrial meningitis- retrospective analysis from 1970 to 1983. Am J Med 1985;79:29-34.
Thomas MD, Chopra JS, Walia BNS. Tuberculous meningitis- a clinical study of 232 cases. J Assoc Physicians Ind 1977;25:633-39.
Alarcon V, et al.
Tuberculous meningitis short course chemotherapy. Arch Neurol 1998;47:1313-17.
Hosoğlu S1, Ayaz C, Geyik MF, Kökoğlu OF, Ceviz A, et al.
Tuberculous meningitis in adults-an eleven years review. Int J Tuber Lung Dis 1998;2:553-57.
Mohapatra MK, et al.
CSF adenosine deaminase activity for the diagnosis of tuberculous meningitis. Ind Pract 1997;50:929-32.
Klein NC, Damsker B, Hirschman SZ. Mycobactrial meningitis- retrospective analysis from 1970 to 1983. Am J Med 1985;79:29-34.
Kumarvelu S1, Prasad K, Khosla A, Behari M, Ahuja GK, et al.
Randomized controlled trial of dexamethasone in tuberculous meningitis. Tuber Lung Dis 1994;75:203-07.
Kennedy Dermot H, Fallon Ronald J. Tuberculous meningitis. JAMA 1979;241:264-68.
Verdon R 1, Chevret S, Laissy JP, Wolff M, et al.
Tuberculous meningitis in adults:review of 48 cases. Clin Infect Disc 1994;22:982-88.
Traub M, Colchester AEF, Kingsley DPE, Swash M. Tuberculosis of the central nervous system. Q J Med 1984;209:81-100.
Singh RG, et al.
Study of tuberculous meningitis in adults. J Assoc Phys India 1980;28:256-58.
Swart S, Rs Briggs, Millag PA. Tuberculous meningitis in Asian patients. Lancet 1981;4:15-1.
Mehrotra, Pursnani ML, Patney NL, Tandon RK, Jain RK, et al.
Tuberculous meningitis – Its neurological complications with special reference to their prognostic significance. J Assoc Physicians India 1982;30:869-73.
K B Chetan Reddy
Sai Shankar Apartments, C.CE. Colony, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]