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ORIGINAL ARTICLE
Year : 2010  |  Volume : 4  |  Issue : 2  |  Page : 51-54

Evaluation of cerebrospinal fluid adenosine deaminase levels as an ancillary diagnostic test for tuberculous meningitis and its correlation with adverse neurological outcome


1 Department of Medicine, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
2 Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication24-Mar-2011

Correspondence Address:
Arjun Khanna
Department of Medicine, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh - 226 004
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0331-3131.78272

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   Abstract 

Background : Tuberculous meningitis (TBM) is often under and over diagnosed, thereby making the ancillary diagnostic tests important for establishing the diagnosis of TBM. The objective of this study was to evaluate cerebrospinal fluid adenosine deaminase (CSF-ADA) as an ancillary test for the diagnosis of TBM, and further, its correlation with adverse neurological outcome in these patients.
Materials and Methods : This was a prospective study of 83 patients. The diagnosis of TBM was established by Thwaites criteria. CSF-ADA levels were measured in all these patients and were taken to be positive at levels >10 IU/l. These patients were followed up at 1 and 3 months after discharge, and the resultant neurological deficit was measured as per the modified Rankin score and correlated with the initial CSF-ADA levels. Mann-Whitney U test, χ2 test, Kruskall-Wallis tests were used for statistical analyses.
Results : CSF-ADA values were higher than 10 IU/l in all the 83 patients diagnosed to be suffering from TBM. It was seen that the mean ADA level for patients with stage I/II was 18.23 ± 8.64 IU/l, while it was 31.97 ± 226 004, India.

Keywords: Cerebrospinal fluid adenosine deaminase, modified Rankin score, Thwaites criteria, tuberculous meningitis


How to cite this article:
Khanna A, Atam V, Patel M L, Verma R, Gupta A. Evaluation of cerebrospinal fluid adenosine deaminase levels as an ancillary diagnostic test for tuberculous meningitis and its correlation with adverse neurological outcome. Ann Nigerian Med 2010;4:51-4

How to cite this URL:
Khanna A, Atam V, Patel M L, Verma R, Gupta A. Evaluation of cerebrospinal fluid adenosine deaminase levels as an ancillary diagnostic test for tuberculous meningitis and its correlation with adverse neurological outcome. Ann Nigerian Med [serial online] 2010 [cited 2019 Jun 20];4:51-4. Available from: http://www.anmjournal.com/text.asp?2010/4/2/51/78272


   Introduction Top


Tuberculous meningitis (TBM) is a major global health problem and is the most severe form of extrapulmonary tuberculosis with a high mortality rate. [1] Its reported prevalence varies from 5 to 15% in various cohorts of population of patients with tuberculosis. Even after years of experience with the disease, proper diagnosis of TBM remains problematic. Early diagnosis and treatment are of paramount importance, as any delay in treatment can lead to irreversible CNS damage and mortality. The challenge facing new diagnostic strategies in TBM is that they must improve on the sensitivity of conventional Ziehl-Neelsen staining and culture, but maintain the specificity. In the developing world, cost considerations mandate tests that are cheap and are technically undemanding. The nonavailability of a clear-cut gold standard has hampered the validation of the usefulness of newer diagnostic tools for the diagnosis of TBM. As the yield of conventional methods such as culture is low when applied to the CSF in patients with suspected TBM, these methods cannot be considered to be a gold standard against which other tests can be compared. [2] CSF adenosine deaminase (CSF-ADA) is another such marker, which has been proposed to aid in the diagnosis of TBM. [3],[4],[5],[6] The Thwaites diagnostic score takes into account age of the patient (years), total leukocyte count, history of illness in days, CSF total leukocyte count and percentage neutrophils in CSF. In resource-poor countries, such a clinicopathological diagnostic score may help in making a preliminary diagnosis of TBM. This study aimed at evaluating the role of CSF-ADA levels as a diagnostic test for TBM, its correlation with the stage of disease, neuroimaging findings and adverse neurological outcome (morbidity and mortality) in TBM.


   Materials and Methods Top


This was a prospective study done over a period of 1 year. Patients who presented with history and clinical features suggestive of TBM were included in this study. To label a patient as the one suffering from TBM, criteria of Thwaites [7] et al, were used. These are clinicopathological criteria, which take into account age of the patient (years), history of illness (days), blood total leukocyte count (10 3 /ml), CSF total leukocyte count (TLC) (10 3 /ml) and percentage neutrophils in CSF. A score of ≤4 is taken as a presumptive diagnosis of TBM. A total of 83 patients met the required criteria over 1 year duration of study period and were included in the study.

All patients included in the study were then evaluated clinically and were appropriately investigated. The patients were classified based on the disease stages as proposed by the Medical Research Council (MRC). Measurement of complete blood counts and electrolytes, and liver function tests (LFT) and kidney function tests (KFT) were done for all the patients. Computed tomography (CT) scan head was done in all 83 patients; magnetic resonance imaging (MRI) brain was done for 28 patients. CSF analysis was done for TLC, differential leukocyte count (DLC), total protein, sugar, Gram and AFB staining, ADA, TB-polymerase chain reaction (TB-PCR) (10 patients), Mycobacterium tuberculosis culture and sensitivity (13 patients).

CSF-ADA values above 10 IU/l were taken to be significant. These patients were treated for TBM as per the standard protocol. The stage of the disease, abnormalities on neuroimaging, morbidity and mortality at 30 and 90 days using the modified Rankin scale (MRS) were assessed and correlated with CSF-ADA levels at the time of diagnosis.

Statistical analyses were done using Mann-Whitney U test, χ2 test and Kruskall-Wallis test.


   Results Top


A total of 83 patients were included in the study; 34 patients were females (41%) and 49 (59%) were males. In the patients studied, as per the MRC classification of TBM, [8] more than four fifths (85.5%, n = 71) presented to hospital with TBM stage III, 13.3% patients (n = 11), presented with stage II TBM, and only one patient presented with stage I. The CSF was analyzed in all patients, and the findings were as follows. CSF-ADA: The mean value of CSF-ADA was 29.98 IU/l. The minimum value was 10 IU/l and the maximum was 251 IU/l. CSF-protein: The mean value was 148.49 ± 119.97 mg/dl. The range was from 60 to 606 mg/dl. CSF sugar: The mean value was 34.64 mg/dl. The range was from 5 to 80 mg/dl. CSF-TLC: The mean CSF-TLC was 249.65. Range was 56-1800 cells. Percentage lymphocytes: The mean lymphocyte count was 89.04. Neuroimaging findings: 51.8% (n = 43) had normal CT/MRI scans; 14 (16.9%) had evidence of hydrocephalus on their CT scans; 4 (4.8%) patients had infarcts on the CT scan; 13 patients had basal exudates; and 9 (10.8%) had diffuse cerebral atrophy. The follow-up of the patients was done using the modified Rankin score at 1 and 3 months, which is described as in [Table 1].
Table 1: Modified Rankin Score

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At discharge, there were 52 (62.7%) cases with no symptoms at all (MRS-1). No significant disability (MRS-2) was seen in 13 (15.7%), slight disability (MRS-1) in 3 (3.6%), and moderate disability (MRS-4) in 5 (6.0%) patients. Moderately severe disability (MRS-5) was seen in 4 (4.8%) subjects A total of 7.2% (n = 6) subjects expired (MRS-6) during the course of hospital stay. At the end of 1 month, majority of patients (63.9%) did not have any symptom at all on day 30 (MRS-1). No significant disability was seen in 14.5% (MRS-2), slight disability in 1.2% (MRS-3), moderate disability in 2.4% (MRS-4), while moderately severe disability was seen in 10.8% (MRS-5) subjects. At 3 months, no symptoms were observed in 54 (65.1%) patients and no significant disability was seen in 9 (10.8%) patients, while slight disability and moderate disability were seen in 3 (3.6%) and 1 (1.2%) cases, respectively. Moderately severe disability was noticed in 10 (12%) patients.


   Discussion Top


A number of etiological agents can cause chronic meningitis. [9] Establishing the exact cause is often not an easy task. Even though TBM remains the commonest cause of chronic meningitis in our country, a number of other diseases can show the clinical and laboratory findings. Missing the diagnosis of TBM would mean that the patient is not given timely anti-tubercular therapy (ATT) which can be curative for this otherwise fatal disease. Hence, any investigation which adds to our armamentarium in diagnosing TBM would be welcome. CSF-ADA is one such marker which has been used to differentiate TBM from other causes of meningo-encephalitis; however, it has rarely, if ever, been correlated with the outcome of the disease. [10] The first part of our study assessed whether the standard cut-off value of CSF-ADA could be applied to our patients. We found that in all patients labeled as TBM, as per the clinicopathological Thwaites criteria, the CSF-ADA was more than the accepted levels of 10 IU/l. [11] Very high variability was seen in ADA values. It ranged from 10 to 251 IU/l with a mean value of 29.98 ± 34.57 IU/l (median 19.70). These ADA values were correlated with the stage of the disease, Thwaites score, and outcome in terms of morbidity and mortality.

CSF-ADA levels were compared in patients presenting with different stages of TBM. It was seen that the mean ADA level for stage I/II was 18.23 ± 8.64 IU/l, while it was 31.97 ± 36.89 IU/l for stage III (P = 0.043). Thus, higher mean levels of CSF-ADA were observed in patients with more advanced disease as compared to those with lesser degrees of the disease. The diagnosis of TBM was made as per the Thwaites criteria which range from −5 to 13. Patients with a score of ≤4 are taken to be suffering from TBM. The lower the Thwaites score, the higher is the probability of a patient suffering from TBM. 65.1% patients (n = 54) had a Thwaites score of -5. It was -3 in 24 patients (28.9%), -2 in 1 patient and 0 in 2 patients. It was seen that for Thwaites score of -5, the mean ADA value was 35.34 ± 41.40 IU/l, while for Thwaites scores from 0 to -3, the mean ADA value was 20.01 ± 9.88 IU/l (P = 0.023). Thus, patients with more probable Thwaites score suggestive of TBM had higher mean values of CSF-ADA. CSF-ADA values also correlated with abnormalities on neuroimaging. Maximum mean value of CSF-ADA was seen for hydrocephalus (73.29 IU/l), while minimum was seen for normal scans (17.37 IU/l) (P < 0.001). Higher mean values of CSF-ADA were also derived for infarcts and diffuse cerebral atrophy, but these were not statistically significant. The values of CSF-ADA were correlated with morbidity and mortality. A total of six patients expired during the study. The mean CSF-ADA values for these patients were significantly higher than the mean (125.75 IU/l) (P < 0.001). The association of CSF-ADA with the modified Rankin score, which was used to gauge the outcome at 1 and 3 months after discharge, is shown below in [Table 2] and [Table 3], respectively.

Thus, the CSF-ADA levels were maximum for the worst outcome (death), while for the best outcome (no symptom) they were found to be minimum. An inverse association between ADA scores and outcome at 30 and 90 days was seen.
Table 2: Association of ADA with MRS scores at 1 month

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Table 3: Association of ADA with MRS scores at 3 months

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   Conclusions Top


We arrive at the following conclusions:

  1. CSF-ADA levels were found to be above 10 IU/l in all the patients enrolled and presumptively diagnosed as TBM based on the Thwaites criteria, thus suggesting its important value as an ancillary tool for the diagnosis of TBM. Further, ADA levels correlated well with the stage of the disease. Patients with advanced stages of TBM (stage III and above) had mean ADA values significantly higher than patients with less advanced TBM (P = 0.043).
  2. Patients with lower Thwaites scores had higher probabilities to be suffering from TBM. In patients with the lowest Thwaites scores (-5), CSF-ADA levels were significantly higher than the other groups with lower Thwaites score, thus indicating that CSF-ADA levels may be used for the diagnosis of TBM (i.e. clinical and lab/CSF/radiological profile).
  3. Highest CSF-ADA levels were seen in patients with evidence of hydrocephalus (P < 0.001) and no correlation was seen between development of infarcts, diffuse cerebral atrophy, and normal CT/MRI scans.
  4. CSF-ADA levels correlated inversely with morbidity and mortality, and were found to be higher in patients with remnant neurologic deficit and in those who expired.


 
   References Top

1.Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316-53.  Back to cited text no. 1
    
2.Tandon PN, Bhatia R, Bhargava S. TBM. In: Harris AA, editor. Handbook of clinical neurology. Amsterdam: Elsevier Science; 1998. p. 195-226.  Back to cited text no. 2
    
3.Chotmongkol V, Teerajetgul Y, Yodwut C. Cerebrospinal fluid adenosine deaminase activity for the diagnosis of tuberculous meningitis in adults. Southeast Asian J Trop Med Public Health. 2006;37:948-52.  Back to cited text no. 3
[PUBMED]    
4.Petterson T, Klockars M, Weber TH, Somer H. Diagnostic value of cerebrospinal fluid adenosine deaminase determination. Scand J Infect Dis 1992;24:121-2.  Back to cited text no. 4
    
5.Eintracht S, Silber E, Sonnenberg P, Koornhof HJ, Saffer D. Analysis of adenosine deaminase isoenzyme-2 (ADA-2) in cerebrospinal fluid in the diagnosis of TB meningitis. J Neurol Neurosurg Psychiatry 2000;69:137-8.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Gambhir IS, Mehta M, Singh DS, Khanna HD. Evaluation of CSFadenosine deaminase activity in tubercular meningitis. J Assoc Physician India 1999;47:192-4.  Back to cited text no. 6
    
7.Sunbul M, Atilla A, Esen S, Eroglu C, Leblebicioglu H, Thwaites. Diagnostic scoring and the prediction of tuberculous meningitis. Med Princ Pract 2005;14:151-4.  Back to cited text no. 7
    
8.Medical Research Council. Streptomycin treatment of Tuberculous Meningitis: Report of the committee on streptomycin in tuberculosis trials. Lancet 1948;1:582-97.  Back to cited text no. 8
    
9.Sharma SK. Tuberculosis, 2 nd ed. Jaypee Publishers; chp. 21, p. 307.  Back to cited text no. 9
    
10.Ribera E, Martinez-Vazquez JM, Ocaña I, Segura RM, Pascual C. Activity of adenosine deaminase in cerebrospinal fluid for the diagnosis and follow-up of tuberculous meningitis in adults, J Infect Dis 1987;155:603-7.  Back to cited text no. 10
    
11.Ungerer JP, Oosthuizen HM, Retief JH. Significance of adenosine deaminase activity and its isoenzymes in tuberculous effusions. Chest 1994;106:33-7.  Back to cited text no. 11
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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