**4.1 CSF examination**


other useful explorations for the diagnosis of TBM are as follows:


A high index of clinical suspicion is where the patient is in contact with a confirmed case of tuberculosis.

Several studies reveal decreased CSF leukocyte counts and protein levels in HIV-positive patients. CSF examination may even be normal in 5% of HIV-positive patients with TBM [16].

The identification of Mycobacterium tuberculosis in CSF by direct smear or cultures remains the gold standard for confirming TBM, but CSF being a paucibacillary liquid, isolation is only possible in a small number of cases. Moreover, the growth time of the cultures being 3–6 weeks, the diagnosis and the initiation of the treatment can be delayed [14, 17]. For these reasons, the diagnosis of TBM is based in many cases only on the clinical manifestations with slow onset and the neurological signs, associated with the characteristic cytochemical changes in the CSF: moderate inflammatory reaction with a predominance of lymphocytes, low levels of glucose and increased proteins.

The differential diagnosis of TBM is sometimes difficult to make with other forms of meningitis with clear fluid, such as viral meningitis, fungal meningitis, carcinomatous meningitis, partially treated bacterial meningitis, brain abscesses, brucellosis, neurosyphilis and neurosarcoidosis [18]. Meningitis with Cryptococcus neoformans has the same clinical picture and changes in CSF as TBM, but with a delayed evolution (sometimes 2–6 months) and occurs more frequently in immunocompromised people, such as patients with HIV infection [19].

New diagnostic methods of TBM based on the CSF study have been developed to make it more efficient and faster. The BACTEC method allows reducing the time until obtaining a positive culture for M.tuberculosis to 1–3 weeks, and microscopic observed drug susceptibility (MODS) allows the microscopic highlighting of the unique growth characteristics of the Koch bacillus in 5–7 days, also allowing testing simultaneous resistance to antituberculosis medication [20]. Unfortunately, these modern methods are not widely available in all countries.

Nucleic acid amplification (NAA) tests represented by the chain polymerization reaction or M.tuberculosis DNA amplification in CSF ensure a faster diagnosis of TBM, the execution time being 24–48 hours. Being specific, more sensitive and faster than culture, PCR for mycobacteria in CSF constitutes a modern and very useful method in the diagnosis of TBM.

The detection of the IS6110 insertion sequence, used in the initial studies, had a sensitivity between 32–100% and a specificity of 38–100% [21]. Many initial studies conducted to establish the effectiveness of the PCR technique in the detection of M.tuberculosis in CSF used a single target gene, which can cause false negative results. Currently, the multiplex-PCR technique is used, which targets and simultaneously amplifies several genes, such as protein antigen B, MBP64 and IS6110. According to some studies, the sensitivity of this technique is 94.4%, and the specificity is 100% [22].

The Gene Xpert MTB/RIF method is an RT-PCR technique used for the simultaneous detection of M.tuberculosis and sensitivity to rifampicin. It is a quick diagnostic technique, the result being obtained in 2–3 hours. The Gene Xpert technique has a sensitivity of approximately 95% and a specificity of up to 99% for sputum

#### *Hydrocephalus in Tuberculous Meningitis DOI: http://dx.doi.org/10.5772/intechopen.110251*

samples, but the sensitivity in CSF is much lower (approximately 80%) and the specificity is around 97.8%. This is due to the fact that CSF is paucibacillary and the possible presence of substances that inhibit amplification [23].

Molecular diagnostic tests cannot replace direct microscopic bacteriological examination and CSF culture for M.tuberculosis, but they are useful as complementary tests, especially when direct smears are negative. Currently, most experts conclude that commercial NAA tests can confirm TBM but cannot rule it out [22–24].

Another diagnostic method of TBM is the measurement of adenosine deaminase (ADA) activity in CSF. ADA is an element of cellular immunity, its activity being increased in diseases in which cellular immunity is involved, a fact also found in TBM. The sensitivity of ADA varies between 60–90% and the specificity between 80–90%, but the method has not yet been well standardized and is not routinely recommended in the diagnosis of TBM [24, 25]. The detection of M.tuberculosis specific antibodies or antigens in the CSF is a rapid method of diagnosing TBM. The direct detection of cells secreting specific antibodies by the ELISPOT method has a sensitivity of 84% and a specificity of 91.8%, the sensitivity being higher if the test is performed in the first 4 weeks after the onset of the disease [26].

In recent years, two blood tests for in vitro diagnosis of tuberculosis: Quantiferon TB. Gold (Cellestis, Australia) and T-SPOT.TB (Oxford, Immunotec, United Kingdom), based on the pathogenic specificity of ESAT-6 (Early Secretory Antigen Target) and CFP-10 (Culture Filtrate Protein -10) have been developed for clinical use. The cellular immune response is an important component of the immune response regarding M. tuberculosis, the induction of a protective response translating into the synthesis of TH1-type cytokines, especially gamma interferon (IFN-gamma). IFNgamma detection is the basis of the principle of these two tests. The sensitivity (approximately 89%) and specificity (approximately 98%) are clearly improved compared to those of the PPD skin test [27]. The Quantiferon TB.Gold (QFT-G) test produced by the Cellestis company measures the amount of interferon gamma cytokine released by T lymphocytes after stimulation with ESAT-6 and CFP-10, through a sensitive ELISA technique. QFT-G is a rapid immunological test, with results obtained in 24–48 hours. With its help and in conjunction with clinical, epidemiological data and the CSF examination, it allows a rapid diagnosis, before obtaining a positive culture for M. tuberculosis. QFT-G can be performed from both blood and CSF, a positive result in CSF being a solid argument for the diagnosis of TBM [28].

## **5. Imaging exploration in TBM**

**Chest X-ray** can be normal in 20–50% of cases; There is usually some evidence of pulmonary tuberculosis (hilar adenopathy, pneumonia or miliary tuberculosis). **Computed tomography (CT**) and **nuclear magnetic resonance (MRI**) of the brain are normal in the early stages of the disease, but as TBM progresses they may show increased basal contrast, communicating hydrocephalus, signs of cerebral edema, one or more clinically silent tuberculomas, most often in the cerebral cortex or thalamic regions [29, 30].

In various studies, MRI has been shown to be more sensitive than a CT scan, but cerebral CT is easier to perform in children, MRI requiring general anesthesia in small children. A CT scan may initially be normal in nearly 30% of cases, which does not

#### *Frontiers in Hydrocephalus*

initially exclude the possibility of a TBM [31]. Common neuroimaging findings seen in TBM are outlined below:

Communicating hydrocephalus—80%; basal meningeal enhancement—75%; cerebral infarctions—8–44%; tuberculomas—8–31% [29, 30].

Thwaites performed computed tomography in 60 cases of tuberculous meningitis and found hydrocephalus in 87% of cases in children compared to 12% in adults [32]. In children, this complication appears after 6 weeks of infection. Vascular infarcts were found in 28% of cases, most of them being located in the territory of the middle cerebral artery. Severe prognosis is associated with basal and periventricular exudate [33].

The performance of the magnetic resonance images is due to the intravenous use of gadolinum. Hyperdensity in the basal cisterns is a good predictor for tuberculous meningitis [33, 34]. Both imaging methods give suggestive information on when neurosurgical intervention for hydrocephalus should be performed.

Imaging differences were also noted depending on the age group and the association or non-association of HIV infection.

In the statistics of Thwaites, the presence of basal exudate in 82% of cases and hydrocephalus in 77% of patients is reported in adults who underwent cerebral magnetic resonance [34]. During treatment, 74% of patients develop tuberculoma, most cases being asymptomatic. Children and adults with tuberculous meningitis and HIV infection have less hydrocephalus and basal exudate, and more frequent infarcts, increased convolutions, and multiple lesions compared with patients without HIV [35–37].

Patients with HIV infections more frequently develop cerebral atrophy [35, 36].
