**6. Clinical data on NTB in HIV patients**

**a.** A paradoxical reaction emerging in patients with NTB correctly diagnosed and appro‐ priately treated in which HIV infection is subsequently detected and also treated but new severe neurological manifestations arise during treatment (paradoxical NeuroIRIS-TB).

**b.** An unmasking reaction appears in patients with HIV and latent unknown NTB in which the successful antiretroviral treatment unexpectedly induces neurological manifestations

TheneurologicmanifestationofIRIS-TBare rare (19%ofthe total cases)butwithamortalityrisk that is three times higher than other IRIS localisations [42]. The specific features related to NeuroIRIS-TB reside in the excessive CNS inflammatory reactions generated by the activation of microglia. The excessive inflammatory response is linked to the abundance of mycobacteri‐ al antigens and their high immunogenicity. Various studies have approached the immunolog‐

The observations below on the pathogenesis of IRIS-TB were selected according to the potential

**•** The release of multiple mycobacterial antigens in the first 2 months of antituberculous therapy and concurrent wide distribution of sequestered CD45RO memory lymphocytes in the bloodstream during HIV antiretroviral treatment are the principal mechanisms inducing an excessive inflammatory response. To avoid the overlap of these events the current WHO recommendations advocate an initial antituberculous treatment followed at a minimum interval of 2 weeks by the antiretroviral treatment in patients with a low level of Th CD4+

**•** The pathological overproduction of Th1 cytokines particularly IFN-γ was noticed in IRIS-TB/ HIV co-infection [44,45].Taking into account the experimentally increased levels of IFNγ in IRIS the blood interferon-gamma (IFN-γ) release assays (IGRA) could be implemented to monitor IRIS evolution in the future. In addition the pathological overproduction of chemokines CXCL9 and CXCL10 induced by IFN-γ was observed in IRIS-TB/HIV coinfection [46]. The development of therapeutic strategies which could reduce the intracere‐ bral level of these chemokines are essential to prevent and decrease ensuing granulomas

**•** The excessive release of IgG antibodies to PPD was observed in patients with IRIS-TB/HIV co-infection [45] Nonetheless the level of antibodies against the phenolic glycolipid antigen (PGL-TB1) was lower in IRIS hosts. The IgG anti PPD and especially the intrathecal synthesis of IgG/PPD could provide additional information on the humoral immune response in

**•** The restoration of a delayed type of hypersensitivity to mycobacterial antigens was reported in HIV patients with latent TB after starting the antiretroviral therapy [50,51]. All the same recent studies cast doubt on the tuberculin-specific Th1-responses in prompting IRIS [52] **•** The profile of cytokines differs between the 2 types of IRIS as well as between TB infection and IRIS-TB. Hence certain cytokines (IFN-γ,TNF-α and IL-6) are more elevated in IRIS-TB than compared with patients presenting only TB. [53,54]. This finding could help distinguish

of TB (unmasked NeuroIRIS-TB)

298 Tuberculosis - Current Issues in Diagnosis and Management

thus protecting against IRIS.[47,48]

NeuroIRIS – TB [49].

clinical application.

cells [43]

ic mechanisms and risk factors for IRIS in HIV-TB patients.

NTB is frequent in HIV patients compared with non-HIV patients. Reactivation of latent forms of TB is accelerated in HIV patients with a 10% annual risk of progression to active infection compared with 10-20% lifetime risk of developing TB in non-HIV patients. Literature data is contradictory as to the role of HIV on the clinical presentation or evolution of NTB. Although some studies found significant differences between HIV and non-HIV NTB [67-69] others


initial presentation of AIDS in 42% of cases. A study performed in Kenya, a state with an increasing incidence of TB and HIV, revealed that 80% of the necropsies performed on HIV patients exhibited disseminated TB and 26% of these also displayed meningeal involve‐ ment [72].On the other hand the frequency of disseminated tuberculosis based on clinical and bacteriological criteria only did not exceed 14,5% of cases [73-74]. The conclusion arising from these studies is that the extent of the CNS invasion is highly variable and a

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 301

**Neurological presentation.** TBM is the most frequent form of NTB in HIV patients. The

**•** *TBM in the early stages of HIV immunodepression.* The onset of TBM is insidious. Fever and meningeal signs develop progressively (7-30 days) paralleling the changes in the cognitive status and mental state. Once the meningeal syndrome is established the evolution is rapid. The meningeal syndrome is intense and progressive. Under such circumstances the diagnosis could be aided by recognizing the paralysis of certain cranial nerves (mostly involving the sixth cranial nerve but also the second, third, fourth and eighth nerves) as well as the signs of hydrocephalus or cerebral edema (headache, convulsions, pyramidal or cerebellar signs). Encephalitic forms display an altered level of consciousness with progres‐ sive evolution to coma. In forms with major spinal involvement (TB spinal meningitis, spinal arachnoiditis ) the inflammatory exudate surrounds the spinal cord and induces radicular compression. As a result radicular pains develop along with sings of transverse mielitis

**•** *TBM in advanced stage of HIV immunodepression*. In advanced stage of immunodepression the inflammatory exudate is decreased and the clinical presentation is atypical. Fever could be absent in these patients. The meningeal sings are discrete or missing [75]. Hydrocephalus is delayed. Tuberculous vasculopathy prompts frequent complications following thrombosis, or hemorrhagic infarcts. Focal lesions related to the vasculopathy are common. The cogni‐ tive dysfunction is severe [76] with a rapid evolution to profound coma [8].In this advanced stage of AIDS NTB rarely evolves as a solitary finding. Usually other infections or tumors are also associated with NTB and the wide spectrum of clinical manifestations implies various

**CSF data.** The aspect of the initial CSF could be suggestive disclosing lymphocytic pleocytosis, elevated proteins and low glucose levels. Nevertheless the etiologic confirmation is based on bacteriological criteria only. In patients with severe immunodeficiency the CSF white cell count is usually only slightly increased but could also be normal [67] The low number of lymphocytes in HIV could modify the differential count in the CSF to a predominant number of neutrophils [67] causing confusion with bacterial meningitis. Elevated proteins are a typical finding in TBM in non-HIV patients. However 43% of the HIV reported cases presented low or even normal protein values [5,8]. The most difficult cases are those in which the CSF is reported as normal, a common finding in patients with severe immunodeficiency. In the absence of a strong inflammatory response acid-fast bacilli smear retrieves positive results [67] in up to 67% of cases and the cultures are positive in 40 – 87,9% of cases [76,77].High rates of smear and culture

*neurological patterns with focal, perypheral or central nervous signs.*

large number of disseminated TB in AIDS probably remains undiagnosed.

(paraplegia and urine retention).

neurological manifestations differ according to the degree of immunodeficiency.

**Table 1.** Comparative aspects of the CNS invasions with M. tbc and nontuberculous mycobacteria in HIV hosts

argued that the HIV co-infection does not influence the clinical evolution [70]. Nevertheless the differential diagnosis between NTB and numerous systemic and neurologic nontubercu‐ lous complications emerging in AIDS is difficult. Thus the clinical presentation of NTB in HIV patients could be influenced by numerous factors such as:


All these interfering factors could explain the variable descriptions of the clinical presentation, CSF manifestations or imaging aspects in the numerous studies on NTB in HIV patients.

NTB in HIV patients encompasses the following forms: TBM, disseminated TB of the nevrax, tuberculoma, and tuberculous abcess. En plaque tuberculoma, chronic spinal pahymeningitis and serous TBM are rare forms of TB not described in HIV patients.

#### **6.1. Tuberculous meningitis in HIV patients**

The real frequency of TBM in HIV patients is hard to assess as the various clinical presentations related to immunodepression could be confused with other neurologic manifestations. The epidemiological data on the subject is contradictory. Current statis‐ tics in areas with an increased prevalence of TB disclose M. tbc as the most frequent etiologic agent of meningitis in HIV patients [71]. Moreover TBM was recorded as the initial presentation of AIDS in 42% of cases. A study performed in Kenya, a state with an increasing incidence of TB and HIV, revealed that 80% of the necropsies performed on HIV patients exhibited disseminated TB and 26% of these also displayed meningeal involve‐ ment [72].On the other hand the frequency of disseminated tuberculosis based on clinical and bacteriological criteria only did not exceed 14,5% of cases [73-74]. The conclusion arising from these studies is that the extent of the CNS invasion is highly variable and a large number of disseminated TB in AIDS probably remains undiagnosed.

**Neurological presentation.** TBM is the most frequent form of NTB in HIV patients. The neurological manifestations differ according to the degree of immunodeficiency.

**•** *TBM in the early stages of HIV immunodepression.* The onset of TBM is insidious. Fever and meningeal signs develop progressively (7-30 days) paralleling the changes in the cognitive status and mental state. Once the meningeal syndrome is established the evolution is rapid. The meningeal syndrome is intense and progressive. Under such circumstances the diagnosis could be aided by recognizing the paralysis of certain cranial nerves (mostly involving the sixth cranial nerve but also the second, third, fourth and eighth nerves) as well as the signs of hydrocephalus or cerebral edema (headache, convulsions, pyramidal or cerebellar signs). Encephalitic forms display an altered level of consciousness with progres‐ sive evolution to coma. In forms with major spinal involvement (TB spinal meningitis, spinal arachnoiditis ) the inflammatory exudate surrounds the spinal cord and induces radicular compression. As a result radicular pains develop along with sings of transverse mielitis (paraplegia and urine retention).

argued that the HIV co-infection does not influence the clinical evolution [70]. Nevertheless the differential diagnosis between NTB and numerous systemic and neurologic nontubercu‐ lous complications emerging in AIDS is difficult. Thus the clinical presentation of NTB in HIV

Prognosis Reserved Terminal infections (frequently)

**Table 1.** Comparative aspects of the CNS invasions with M. tbc and nontuberculous mycobacteria in HIV hosts

Mycobacteria strain M tbc, rarely M bovis 98% MAC, rarely other mycobacteria Primary infection Usually respiratory Gastrointestinal or respiratory

Frequency Moderate Low/very low

CD4+ T cell count < 200 cells/mm3 <10% cells/mm3 ( usually) Clinical forms Meningitis, Tuberculoma, Abscess Disseminated, Abscess Diagnosis Established diagnosis criteria No standard diagnosis criteria

M. tbc Nontuberculous mycobacteria

Essential to diagnosis confirmation Not essential to diagnosis confirmation

disseminated infections)

In blood In faeces (frequently), in blood (if

**•** other opportunistic infections with CNS tropism, mainly toxoplasma, criptococcus, papil‐

**•** simultaneous evolution of various forms of NTB (meningitis, tuberculoma)- a characteristic

All these interfering factors could explain the variable descriptions of the clinical presentation, CSF manifestations or imaging aspects in the numerous studies on NTB in HIV patients.

NTB in HIV patients encompasses the following forms: TBM, disseminated TB of the nevrax, tuberculoma, and tuberculous abcess. En plaque tuberculoma, chronic spinal pahymeningitis

The real frequency of TBM in HIV patients is hard to assess as the various clinical presentations related to immunodepression could be confused with other neurologic manifestations. The epidemiological data on the subject is contradictory. Current statis‐ tics in areas with an increased prevalence of TB disclose M. tbc as the most frequent etiologic agent of meningitis in HIV patients [71]. Moreover TBM was recorded as the

**•** concurrent cerebral tumors : non-Hodkin cerebral lymphoma, Kaposi sarcoma;

patients could be influenced by numerous factors such as: **•** various neurological manifestations caused by HIV itself;

**•** extra-neurological infections or malignancies related to HIV.

and serous TBM are rare forms of TB not described in HIV patients.

loma or herpes viruses infections;

300 Tuberculosis - Current Issues in Diagnosis and Management

**6.1. Tuberculous meningitis in HIV patients**

finding in HIV patients;

CSF mycobacteria detection

Mycobacteria detection (other than CSF)

> **•** *TBM in advanced stage of HIV immunodepression*. In advanced stage of immunodepression the inflammatory exudate is decreased and the clinical presentation is atypical. Fever could be absent in these patients. The meningeal sings are discrete or missing [75]. Hydrocephalus is delayed. Tuberculous vasculopathy prompts frequent complications following thrombosis, or hemorrhagic infarcts. Focal lesions related to the vasculopathy are common. The cogni‐ tive dysfunction is severe [76] with a rapid evolution to profound coma [8].In this advanced stage of AIDS NTB rarely evolves as a solitary finding. Usually other infections or tumors are also associated with NTB and the wide spectrum of clinical manifestations implies various *neurological patterns with focal, perypheral or central nervous signs.*

> **CSF data.** The aspect of the initial CSF could be suggestive disclosing lymphocytic pleocytosis, elevated proteins and low glucose levels. Nevertheless the etiologic confirmation is based on bacteriological criteria only. In patients with severe immunodeficiency the CSF white cell count is usually only slightly increased but could also be normal [67] The low number of lymphocytes in HIV could modify the differential count in the CSF to a predominant number of neutrophils [67] causing confusion with bacterial meningitis. Elevated proteins are a typical finding in TBM in non-HIV patients. However 43% of the HIV reported cases presented low or even normal protein values [5,8]. The most difficult cases are those in which the CSF is reported as normal, a common finding in patients with severe immunodeficiency. In the absence of a strong inflammatory response acid-fast bacilli smear retrieves positive results [67] in up to 67% of cases and the cultures are positive in 40 – 87,9% of cases [76,77].High rates of smear and culture

positivity facilitate the diagnosis in patients with an atypical clinical presentation and normal CSF exam.

**Laboratory diagnostic criteria.** The degree of immunodeficiency in HIV patients with NTB could be assessed using the CD4+T cell count. Most studies on TBM disclose a CD4+T cell count between 32-200 /mm3 [5,81,82].Other findings including a lower hematocrit, periph‐ eral low neutrophils, lower plasma sodium level [76] and moderate to severe anemia Hb < 8 gm/dl [69] were not constantly present in all studies and could be mostly related to the HIV infection than to TB. Moreover hyponatremia in patients with HIV-TB co-infec‐ tion could arise due to the following: a) cerebral salt wasting syndrome observed in 65% of patients with numerous cerebral lesions, including patients with TBM [83]; b) the syndrome of inappropriate release of antidiuretic hormone secretion; c) hypothalamus pituitary-adrenal axis suppresion. Hyponatremia is a marker of the disease severity and the mortality in this patient group is significantly higher than that of patients with normal

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 303

**The CSF exam** is decisive for the diagnosis. The specificity of the bacteriological diagnosis is 100% but its implication in the final diagnosis is quite low since the Ziehl-Neelsen stain is positive in less than 20% of cases and Lowenstein culture confirmation although positive in 73% of cases is tardy [85]. Methods of improving the sensibility of Ziehl-Neelsen stain have been described [86] but are less implemented. Tuberculin skin test and Interferon-gamma release assays if positive do not distinguish between latent TB and active disease. As well negative results should be evaluated with caution in severely immunodepressed patients. Several complementary diagnostic tools were explored in certain studies like specific antigens and antibodies detection, adenosine deaminase detection, PCR techniques, detection of tuberculostearic acid or IFN-γ levels in the CSF. However their use is limited due to discordant results or other inconveniences related to the cost, cross-reactivity, specificity or sensibility [87-90]. Recently the improvement of nucleic acid amplification assay techniques, particularly polymerase chain reaction (PCR) assay (especially nested PCR assay technique) increased the diagnostic sensitivity and specificity but its use in AIDS related CNS TB is still unconfirmed [91]. All in all the bacteriological confirmation is difficult and belated but remains the only

**Imaging diagnostic criteria.** Imaging studies are required in the evaluation of neurological complications of TBM, in the treatment follow-up and differential diagnosis. Contrast en‐ hanced MRI and Positron emission computed tomography – computed tomography (PET-CT) display the highest sensibility. Unfortunately most literature studies are based on the more inexpensive CT scans. No aspects are definitely characteristic to CNS TB in HIV patients. Atypical results showing the absence or minimal meningeal enhancement [8] or the absence of communicating hydrocephalus were reported on the CT scan in 69% of AIDS cases [5,8]. Nevertheless other studies found no significant radiological differences between HIV and non-

\*In addition to the clinical, CSF and radiologic criteria, a medical history of TB and positive tuberculin skin test could help raise the diagnostic suspicion of a tuberculous infection.

sodium levels (36,5% versus 19.7%) [84].

diagnostic tool in AIDS related CNS TB.

HIV patients.

**Neuroradiological findings.** The classic CT neuroradiological findings in TBM include basal meningeal enhancement, hydrocephalus, and infarctions in the supratentorial brain paren‐ chyma and brainstem [78]. The concurrent finding of basal meningeal enhancement, tubercu‐ loma or both on CT scans could disclose a sensitivity of 89% and 100% specificity for TBM in non-HIV patients [79]. In HIV patients contrast-enhanced MRI is generally considered superior to CT results [78]. Some MRI studies indicated that meningeal enhancement and cerebral infarctions were more common in HIV-infected individuals with TBM by comparison with non-HIV patients [5,70]. However the basal meningeal enhancement and hydrocephalus rarely occur in advanced stages of AIDS with reduced inflammatory response [76]. On the other hand cerebral infarctions and focal mass lesions are frequently encountered in late stages of AIDS [80-82]. In addition to the previous aspects imaging studies also disclose cerebral atrophy due to HIV infection. Tubeculomas also were reported in 15-24% of cases [5].

#### *6.1.1. The diagnosis of TBM in HIV infected patients*

The diagnosis is urgent and extensive including all tuberculous lesions, HIV status and other HIV associated lesions, bacteriological confirmation and neurological complications. It is based on clinical features, CSF analysis and MRI imaging. (table 2). A belated diagnosis increases the mortality, complications and the risk of relapse.

**Clinical diagnostic criteria.** Clinical features in HIV patients with TBM reflect the atypical inflammatory response and the extensive vasculopathy. The meningeal sings are inconstant and discrete especially in patients with severe immunodepression. The signs of encephalitis emerge from the onset and could be the first significant manifestation of the disease. The gravity of the altered level of consciousness parallels the increased mortality [8].Cerebral nerve paralysis is a common finding but could be also induced by other associated conditions such as HIV neurotoxicity, the cerebral reactivation of opportunistic infections (toxoplasma, JS virus, Herpes simplex virus) or cerebral malignancies (Non-Hodgkin lymphoma, Kaposi sarcoma). These patients particularly exhibit multiple extraneurologic manifestations. The presence of other active lesions like pulmonary TB or other extrameningeal sites of TB is highly suggestive for the CNS TB diagnosis [5,67,81]. Thus the presentation of HIV patients unlike non-HIV patients often includes peripheral, intrathoracic and intraabdominal adenopathies. The etiology of these adenopathies does not always imply a diagnosis of TB. The differential diagnosis for adenopathies should always include other lymphotropic opportunistic infections with neurologic manifestations (toxoplasma, CMV, syphilis). The tuberculous origin of adenopathies could be overestimated in the clinical diagnosis if the histological confirmation is not obtained. The histological examination is thus a prerequisite for a correct diagnosis of these adenopathies. Hepatosplenomegaly is commonly reported but could also occur as a result of other HIV associated infections (B or C hepatitis, CMV infections).To conclude no clinical criteria is highly suggestive for CNS TB in HIV patients. Moreover any neurologic or extraneurologic finding should prompt a thorough differential diagnosis that includes any other HIV related affections.

**Laboratory diagnostic criteria.** The degree of immunodeficiency in HIV patients with NTB could be assessed using the CD4+T cell count. Most studies on TBM disclose a CD4+T cell count between 32-200 /mm3 [5,81,82].Other findings including a lower hematocrit, periph‐ eral low neutrophils, lower plasma sodium level [76] and moderate to severe anemia Hb < 8 gm/dl [69] were not constantly present in all studies and could be mostly related to the HIV infection than to TB. Moreover hyponatremia in patients with HIV-TB co-infec‐ tion could arise due to the following: a) cerebral salt wasting syndrome observed in 65% of patients with numerous cerebral lesions, including patients with TBM [83]; b) the syndrome of inappropriate release of antidiuretic hormone secretion; c) hypothalamus pituitary-adrenal axis suppresion. Hyponatremia is a marker of the disease severity and the mortality in this patient group is significantly higher than that of patients with normal sodium levels (36,5% versus 19.7%) [84].

positivity facilitate the diagnosis in patients with an atypical clinical presentation and normal

**Neuroradiological findings.** The classic CT neuroradiological findings in TBM include basal meningeal enhancement, hydrocephalus, and infarctions in the supratentorial brain paren‐ chyma and brainstem [78]. The concurrent finding of basal meningeal enhancement, tubercu‐ loma or both on CT scans could disclose a sensitivity of 89% and 100% specificity for TBM in non-HIV patients [79]. In HIV patients contrast-enhanced MRI is generally considered superior to CT results [78]. Some MRI studies indicated that meningeal enhancement and cerebral infarctions were more common in HIV-infected individuals with TBM by comparison with non-HIV patients [5,70]. However the basal meningeal enhancement and hydrocephalus rarely occur in advanced stages of AIDS with reduced inflammatory response [76]. On the other hand cerebral infarctions and focal mass lesions are frequently encountered in late stages of AIDS [80-82]. In addition to the previous aspects imaging studies also disclose cerebral atrophy due

The diagnosis is urgent and extensive including all tuberculous lesions, HIV status and other HIV associated lesions, bacteriological confirmation and neurological complications. It is based on clinical features, CSF analysis and MRI imaging. (table 2). A belated diagnosis

**Clinical diagnostic criteria.** Clinical features in HIV patients with TBM reflect the atypical inflammatory response and the extensive vasculopathy. The meningeal sings are inconstant and discrete especially in patients with severe immunodepression. The signs of encephalitis emerge from the onset and could be the first significant manifestation of the disease. The gravity of the altered level of consciousness parallels the increased mortality [8].Cerebral nerve paralysis is a common finding but could be also induced by other associated conditions such as HIV neurotoxicity, the cerebral reactivation of opportunistic infections (toxoplasma, JS virus, Herpes simplex virus) or cerebral malignancies (Non-Hodgkin lymphoma, Kaposi sarcoma). These patients particularly exhibit multiple extraneurologic manifestations. The presence of other active lesions like pulmonary TB or other extrameningeal sites of TB is highly suggestive for the CNS TB diagnosis [5,67,81]. Thus the presentation of HIV patients unlike non-HIV patients often includes peripheral, intrathoracic and intraabdominal adenopathies. The etiology of these adenopathies does not always imply a diagnosis of TB. The differential diagnosis for adenopathies should always include other lymphotropic opportunistic infections with neurologic manifestations (toxoplasma, CMV, syphilis). The tuberculous origin of adenopathies could be overestimated in the clinical diagnosis if the histological confirmation is not obtained. The histological examination is thus a prerequisite for a correct diagnosis of these adenopathies. Hepatosplenomegaly is commonly reported but could also occur as a result of other HIV associated infections (B or C hepatitis, CMV infections).To conclude no clinical criteria is highly suggestive for CNS TB in HIV patients. Moreover any neurologic or extraneurologic finding should prompt a thorough differential diagnosis that includes any

to HIV infection. Tubeculomas also were reported in 15-24% of cases [5].

*6.1.1. The diagnosis of TBM in HIV infected patients*

302 Tuberculosis - Current Issues in Diagnosis and Management

other HIV related affections.

increases the mortality, complications and the risk of relapse.

CSF exam.

**The CSF exam** is decisive for the diagnosis. The specificity of the bacteriological diagnosis is 100% but its implication in the final diagnosis is quite low since the Ziehl-Neelsen stain is positive in less than 20% of cases and Lowenstein culture confirmation although positive in 73% of cases is tardy [85]. Methods of improving the sensibility of Ziehl-Neelsen stain have been described [86] but are less implemented. Tuberculin skin test and Interferon-gamma release assays if positive do not distinguish between latent TB and active disease. As well negative results should be evaluated with caution in severely immunodepressed patients. Several complementary diagnostic tools were explored in certain studies like specific antigens and antibodies detection, adenosine deaminase detection, PCR techniques, detection of tuberculostearic acid or IFN-γ levels in the CSF. However their use is limited due to discordant results or other inconveniences related to the cost, cross-reactivity, specificity or sensibility [87-90]. Recently the improvement of nucleic acid amplification assay techniques, particularly polymerase chain reaction (PCR) assay (especially nested PCR assay technique) increased the diagnostic sensitivity and specificity but its use in AIDS related CNS TB is still unconfirmed [91]. All in all the bacteriological confirmation is difficult and belated but remains the only diagnostic tool in AIDS related CNS TB.

**Imaging diagnostic criteria.** Imaging studies are required in the evaluation of neurological complications of TBM, in the treatment follow-up and differential diagnosis. Contrast en‐ hanced MRI and Positron emission computed tomography – computed tomography (PET-CT) display the highest sensibility. Unfortunately most literature studies are based on the more inexpensive CT scans. No aspects are definitely characteristic to CNS TB in HIV patients. Atypical results showing the absence or minimal meningeal enhancement [8] or the absence of communicating hydrocephalus were reported on the CT scan in 69% of AIDS cases [5,8]. Nevertheless other studies found no significant radiological differences between HIV and non-HIV patients.

\*In addition to the clinical, CSF and radiologic criteria, a medical history of TB and positive tuberculin skin test could help raise the diagnostic suspicion of a tuberculous infection.

#### **Neurotuberculosis suspicion**

*6.1.2. The evolution of TBM in HIV patients*

*6.1.3. Conclusion*

**6.2. CNS disseminated TB**

studies.

included: a) the CD4+ count lower than 50 cells/mm3

linked to a high mortality rate. IRIS prognosis is generally good.

In the HIV-TB co-infection TBM is frequently associated with pulmonary TB or tuberculous lymphadenopathies. *The risk of a relapse* is considered 23%. The most important risk of relapse is the lack of adherence to the antituberculous and antiretroviral treatment. CSF blood glucose ratio and the presence of pulmonary TB could also be linked with the risk of relapse according to a study performed in Vietnam [92]. *The mortality rate* is high; the survival rate is difficult to evaluate taking into account the increased mortality of HIV patients due to other opportunistic infections or specific complications. Risk factors for death during hospitalization for TBM

signs or hydrocephalus on admission; c) a diagnosis and treatment delay with more than 3 days [80];d) the absence of the antiretroviral treatment or failure of the highly active antire‐ troviral therapy (HAART) [93].TBM relapsing forms and multidrug resistant mycobacteria are

TBM comprises variable manifestations in HIV patients. Early stages of immunodepression in HIV patients usually set the same diagnostic difficulties as in non-HIV patients as a result of the variable clinical presentations and delayed bacteriological results. In the advanced stages of HIV the clinical presentation is atypical and the CSF cytochemical profile could be within normal parameters. Other concurrent lesions of active TB could ease the diagnosis. The differential diagnosis should always include other HIV-associated manifestations, other opportunistic infections or malignancies. The bacteriological exam is still the only tool able to confirm the diagnosis. The prognosis of TBM in HIV patients is shadowed by numerous

Below are NTB diagnosis criteria (table 2) and imaging aspects found in our clinical practice in patients with HIV and NTB: meningoencephalitis (figure 1), cerebral tuberculoma (figure

CNS disseminated TB (CNS milliary TB, cerebrospinal granulia) is a form of cerebral milliary frequently associated with disseminated TB. It is rarely limited to the CNS. The diagnosis is usually based on findings at the necropsy or MRI results. *Constitutional symptoms develop progressively even in the absence of neurologic signs; mycobacteria could also be isolated in other pathological products than the CSF (most frequently from the blood). The eye fundus exam could disclose characteristic choroid tubercles*. A classical miliary pattern on chest radiograph frequently complements the aspects of cerebral miliary. Postconstrast MR brain images reveal intense nodular enhancing granulomas located at cortico-medulary junction and throughout the brain parenchyma. The differential diagnosis of cerebral military should include other opportunistic disseminated infections or secondary metastatic lesions. It is possible to underestimate this form of CNS TB as a result of the diagnostic difficulties and required expensive imaging

diagnostic difficulties, increased risk of relapse and associated HIV pathology.

2) and cerebral tuberculoma in context of IRIS (figure 3)

; b) the presence of advanced neurologic

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 305

Clinical investigations (assessing the risk of tuberculosis, neurological manifestations, other manifestations)

History of tuberculosis (TB antecedents, risk of exposure)

Physical examination disclosing:

1. Signs of menigeal irritation (suggesting meningitis or a meningeal reaction to localized cerebral lesions)

2. Neurologic examination (mental status, sensory and motor exam, focal signs, intracranial hypertension)

3. Other manifestations suggesting TB and nontuberculous lesions induced by HIV activity, opportunistic infections or malignancies like lymphadenopathy (given attention to lymphoma, syphilis, toxoplasmosis), pleural or pericardial effusion (given attention to Kaposi sarcoma), pulmonary lesion (given attention to pneumocystosis, Kaposi sarcoma, fungal pneumonia,CMV pneumonia, lymphocytic interstitial pneumonitis), skin lesions (given attention to Kaposi sarcoma, Moluscum contagiosum, fungal lesions, meningococcal purpura)

Laboratory data assessing the immune status, HIV activity, risk of opportunistic infections or malignancies

Complete blood count (pancytopenia suggests medullar invasion with mycobacteria but also invasive malignancies or drug toxicities)

Biochemical evaluation of liver and renal function; indicate associated co-morbidities; important for drug regimen recomandation,

Serum sodium level (hyponatremia is linked to disseminated mycobacteriosis and cerebral lesions/ it corelates with the mortality risk)

Immune status: CD4+ T cell count (CD4<200 cells/mm3 is related to the risk of NTB and major HIV-related

opportunistic infections; CD4< 50 cells/mm3 is related to the risk of nontuberculous mycobacteriosis or to the risk of IRIS)

HIV viral status: blood/CSF RNA HIV viral load (if positive it point to the antiretroviral failure and needing to swich the regimen)

Serologic assays: serum specific antibodies IgG and IgM related to other HIV-opportunistic infections,mainly toxoplasma, CMV, syphilis.

Imaging studies: cerebral or spinal CT/MRI; (important in localized NTB and other cerebral opportunistic infections or malignancies

Eye fundus examination : shows choroid tubercles in disseminated tuberculosis

#### **Neurotuberculosis confirmation**

Lumbar puncture (if the MRI does not indicate mass lesions!): CSF analysis: cytochemistry, stains\*, culture \*\*, or complementary exams \*\*\*!

Other specimens analysis: sputum, pleural fluid, blood, urine, tissue specimens (lymph node, hepatic or cerebral

biopsy): stains\*, culture\*\* other examination\*\*\*

, human immunodeficiency virus; CSF, cerebrospinal fluid; TB, tuberculosis; NTB, neurotuberculosis; MRI, magnetic resonance imaging;CMV, citomegalvirus; \* stains: Ziehl Neelsen (acid-fast bacilli), India ink (fungi), Gram smear (bacteria); \*\* culture on specific media: Lowestein or Bactec(mycobacteria), Sabourraud (fungi), blood agar (bacteria); \*\*\* PCR,polymerase chain reaction, detection of ADA activity, detection of antigens/ antibodies for toxoplasma, CMV, criptococcus, meningococcus, pneumococcus

**Table 2.** Neurotuberculosis diagnosis in HIV patients
