*6.1.2. The evolution of TBM in HIV patients*

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 included: a) the CD4+ count lower than 50 cells/mm3 ; b) the presence of advanced neurologic 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 linked to a high mortality rate. IRIS prognosis is generally good.

#### *6.1.3. Conclusion*

**Neurotuberculosis suspicion**

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

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)

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

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

Kaposi sarcoma, Moluscum contagiosum, fungal lesions, meningococcal purpura)

Eye fundus examination : shows choroid tubercles in disseminated tuberculosis

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

Complete blood count (pancytopenia suggests medullar invasion with mycobacteria but also invasive malignancies

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

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

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

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

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

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

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

, 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,

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

History of tuberculosis (TB antecedents, risk of exposure)

304 Tuberculosis - Current Issues in Diagnosis and Management

Physical examination disclosing:

or drug toxicities)

recomandation,

the mortality risk)

IRIS)

the regimen)

or malignancies

toxoplasma, CMV, syphilis.

complementary exams \*\*\*!

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

criptococcus, meningococcus, pneumococcus

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

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

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

#### **6.2. CNS disseminated TB**

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 studies.

**Figure 1. A-D. Cranio-cerebral** MR: axial (A), coronal (B and C), and saggital (D) images showing tuberculous meningi‐ tis, cerebral thrombosis and hidrocephalus in a 23-year-old patient with AIDS. He had been receiving antiretroviral treatment for 3 months prior to the present hospitalization. He was admitted with milliary TB and meningoencephalitis associated with oral HCV infection, candidiosis and reactivated CMV infection. The clinical evolution was complicated by toxic hepatitis due to antituberculous treatment and cerebral thrombosis. On admission the CD4 count was 244/mm3 and the RNA HIV load was 239 copies/ml. Contrast MRI before and after the administration of intravenous gadolinium and angioMRI(sag 3D PC phlebography) show: hyperintense lesions on FLAIR sequences and T2 weighted images, appearing hypointense on T1 with no contrast enhancement, located in the medial part of the lentiform nucleus and the head of the caudate nucleus; contrast filling of the basal cisterns extending to the sylvian fissure (more proeminent on the left side), the floor of the third ventricule and the infundibular area (involving the optic nerves, chiasm and optic tracts); asymmetric profound venous system with bilateral amputation of the superios talamostriate veins without the visualisation of the anterior left vein of the pellucid septum; enlargement of the ventricular system with no median shift or transependimar resorbtion. *Conclusions*: post ischemic sequelae, thrombosis of the profound venous system, basal meningeal contrast enhance‐ ment suggestive for meningitis and dilation of the ventricular system.

manifestations of TB such as TBM, pulmonary TB or other signs suggestive for CNS TB such as tuberculous vasculitis. The CSF usually displays no changes or few cytochemical abnormal findings (low glucose, elevated proteins); the acid-fast bacilli smear and culture are frequently negative. The aspect on the CT suggestive for a tuberculoma presents as isodense or lightly hypodense lesions with annular contrast enhancement and the ''target sign'' as a result of central calcifications. Nevertheless these aspects are not pathognomonic and the diagnosis requires a cerebral biopsy with histological and bacteriological confirmation. The histopatho‐ logical examination usually discloses a central region of caseous necrosis surrounded by a capsule with a granulomatous structure. This aspect evolves dynamically as follows: 1) noncaseating granuloma; 2) caseating granuloma with a solid center; 3) caseating granuloma with a liquid center. This dynamics could also be detected at the contrast enhanced MRI or MRI spectroscopy as opposed to the images induced by a cerebral abscess. The MRI exami‐ nation indicates a correspondent evolution with the histopatological examination as: 1) hypointense lesions on T1-weighted images (T1W) and hyperintense T2W lesions with nodular enhancemen postgadolinium administration; 2) hypointense lesions on T1W and T2W with peripheral rim enhancement postgadolinium ;3) hypointense T1W and hyperintense T2W with hypointense rim postgadolinium. Difussion weigthed images indicate diffusion restric‐ tion within the tuberculoma. The lesions are surrounded by edema. The lesions in HIV patients often appear as ring-enhancement lesions under 1 cm and the mass effect is rarely seen [97]. The CT/MRI aspect should be distinguished from other ring-enhancing lesions including bacterial cerebral abscesses, cerebral toxoplasmosis, CNS cryptococcosis, neurocysticercosis

**Figure 2.** Cranio-cerebral *MR images* showing cerebelous tuberculoma in a 41 year-old patient with a 5 year history of HIV infection nonadherent to the antiretroviral treatment.The patient was admitted with a cerebellous tuberculoma and acute ischemic stroke.The laboratory data on admission disclosed a CD4 count of 145cells/mm3 and RNA HIV load 240000 copies/ml.*Axial T1 weighted images shows (A)*: Focal enchancing triangular lesion in the anterolateral right‐ side of the pons of 5×9 mm with FLAIR hyperintensity, difussion restriction, no significant changes in the apparent diffusion coefficient (ADC) and no contrast enhancement (the aspect is suggestive for acute ischemia); a right focal cortico-subcortical cerebellous lesion with peripheral ring enhancement on T1 weighted images and mass effect (the aspect is compatible with a tuberculoma). *Coronal T1 weighted images shows (B)*: symmetrical enlargement of the ventricular system with no midline shift; transependimar circumferential resorbtion edema is present adjacent to the ventricular wall; no intraventricular obstruction or contrast enhancement. *Conclusions*: acute ischemic stroke in the an‐ terolateral right side of the pons; focalinferolateral parenchymal lesion suggestive for a tuberculoma; significant hy‐

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 307

(A) (B)

drocephalus with no intraventricular obstruction.

or CNS lymphomas.

#### **6.3. Intracranial mass lesions in HIV patients with CNS TB**

#### *6.3.1. Tuberculoma*

CNS tuberculomas develop insidiously in the cerebral parenchyma following either the reactivation of local granulomas [94] or a paradoxical response to the antituberculous therapy (figure 2,3). The lesions could be solitary or multiple and their localisations are diverse. Cerebral localisations are more frequent than spinal ones. Data on HIV patients presenting tuberculomas is scarce [95,96]. The diagnosis is probably underestimated in low income countries taking into account the expensive CT/MRI importance in the confirmation. The clinical presentation is pseudotumoral with fever and headaches. The neurologic signs vary according to localisation and may be absent. HIV patients rarely present signs of intracranial hypertension or convulsions. On the other hand tuberculomas could be associated with other

**Figure 2.** Cranio-cerebral *MR images* showing cerebelous tuberculoma in a 41 year-old patient with a 5 year history of HIV infection nonadherent to the antiretroviral treatment.The patient was admitted with a cerebellous tuberculoma and acute ischemic stroke.The laboratory data on admission disclosed a CD4 count of 145cells/mm3 and RNA HIV load 240000 copies/ml.*Axial T1 weighted images shows (A)*: Focal enchancing triangular lesion in the anterolateral right‐ side of the pons of 5×9 mm with FLAIR hyperintensity, difussion restriction, no significant changes in the apparent diffusion coefficient (ADC) and no contrast enhancement (the aspect is suggestive for acute ischemia); a right focal cortico-subcortical cerebellous lesion with peripheral ring enhancement on T1 weighted images and mass effect (the aspect is compatible with a tuberculoma). *Coronal T1 weighted images shows (B)*: symmetrical enlargement of the ventricular system with no midline shift; transependimar circumferential resorbtion edema is present adjacent to the ventricular wall; no intraventricular obstruction or contrast enhancement. *Conclusions*: acute ischemic stroke in the an‐ terolateral right side of the pons; focalinferolateral parenchymal lesion suggestive for a tuberculoma; significant hy‐ drocephalus with no intraventricular obstruction.

manifestations of TB such as TBM, pulmonary TB or other signs suggestive for CNS TB such as tuberculous vasculitis. The CSF usually displays no changes or few cytochemical abnormal findings (low glucose, elevated proteins); the acid-fast bacilli smear and culture are frequently negative. The aspect on the CT suggestive for a tuberculoma presents as isodense or lightly hypodense lesions with annular contrast enhancement and the ''target sign'' as a result of central calcifications. Nevertheless these aspects are not pathognomonic and the diagnosis requires a cerebral biopsy with histological and bacteriological confirmation. The histopatho‐ logical examination usually discloses a central region of caseous necrosis surrounded by a capsule with a granulomatous structure. This aspect evolves dynamically as follows: 1) noncaseating granuloma; 2) caseating granuloma with a solid center; 3) caseating granuloma with a liquid center. This dynamics could also be detected at the contrast enhanced MRI or MRI spectroscopy as opposed to the images induced by a cerebral abscess. The MRI exami‐ nation indicates a correspondent evolution with the histopatological examination as: 1) hypointense lesions on T1-weighted images (T1W) and hyperintense T2W lesions with nodular enhancemen postgadolinium administration; 2) hypointense lesions on T1W and T2W with peripheral rim enhancement postgadolinium ;3) hypointense T1W and hyperintense T2W with hypointense rim postgadolinium. Difussion weigthed images indicate diffusion restric‐ tion within the tuberculoma. The lesions are surrounded by edema. The lesions in HIV patients often appear as ring-enhancement lesions under 1 cm and the mass effect is rarely seen [97]. The CT/MRI aspect should be distinguished from other ring-enhancing lesions including bacterial cerebral abscesses, cerebral toxoplasmosis, CNS cryptococcosis, neurocysticercosis or CNS lymphomas.

**6.3. Intracranial mass lesions in HIV patients with CNS TB**

ment suggestive for meningitis and dilation of the ventricular system.

(A) (B)

306 Tuberculosis - Current Issues in Diagnosis and Management

(C) (D)

due to antituberculous treatment and cerebral thrombosis. On admission the CD4 count was 244/mm3

CNS tuberculomas develop insidiously in the cerebral parenchyma following either the reactivation of local granulomas [94] or a paradoxical response to the antituberculous therapy (figure 2,3). The lesions could be solitary or multiple and their localisations are diverse. Cerebral localisations are more frequent than spinal ones. Data on HIV patients presenting tuberculomas is scarce [95,96]. The diagnosis is probably underestimated in low income countries taking into account the expensive CT/MRI importance in the confirmation. The clinical presentation is pseudotumoral with fever and headaches. The neurologic signs vary according to localisation and may be absent. HIV patients rarely present signs of intracranial hypertension or convulsions. On the other hand tuberculomas could be associated with other

**Figure 1. A-D. Cranio-cerebral** MR: axial (A), coronal (B and C), and saggital (D) images showing tuberculous meningi‐ tis, cerebral thrombosis and hidrocephalus in a 23-year-old patient with AIDS. He had been receiving antiretroviral treatment for 3 months prior to the present hospitalization. He was admitted with milliary TB and meningoencephalitis associated with oral HCV infection, candidiosis and reactivated CMV infection. The clinical evolution was complicated by toxic hepatitis

load was 239 copies/ml. Contrast MRI before and after the administration of intravenous gadolinium and angioMRI(sag 3D PC phlebography) show: hyperintense lesions on FLAIR sequences and T2 weighted images, appearing hypointense on T1 with no contrast enhancement, located in the medial part of the lentiform nucleus and the head of the caudate nucleus; contrast filling of the basal cisterns extending to the sylvian fissure (more proeminent on the left side), the floor of the third ventricule and the infundibular area (involving the optic nerves, chiasm and optic tracts); asymmetric profound venous system with bilateral amputation of the superios talamostriate veins without the visualisation of the anterior left vein of the pellucid septum; enlargement of the ventricular system with no median shift or transependimar resorbtion. *Conclusions*: post ischemic sequelae, thrombosis of the profound venous system, basal meningeal contrast enhance‐

and the RNA HIV

*6.3.1. Tuberculoma*

space-occupying lesions especially cerebral toxoplasmosis and lymphoma [19].In such cases

Nontuberculous mycobacteria induce CNS lesions especially in AIDS patients with advanced stages of immunodepression. Sporadic cases triggered by M. avium, M. kanssasi, M. fortui‐ tum, M gordonae, M. genavense and M. terrae were reported [105,106]. As a rule CNS infec‐ tionswithnon-tuberculousmycobacteriaaretheresultofMACinfection.Nevertheless infection with MAC shows no predilection for the CNS as it frequently colonises the respiratory and gastrointestinal tract. Disseminated infections occur as a result of a severe immune dysfunc‐

tionisalsopossible [107].Howeveracase studyreportedbyFletcherdisclosedacerebralabscess with a double etiology involving M tbc and MAC in an AIDS patient with a CD+4 count of 140

intheabsenceofasystemicinfection[109].MostMACneurologicmanifestations inHIVinfected patients are cerebral abscesses and meningoencephalitis. Localized mass lesions (including singleormultipleabscesses) containalargenumberofmycobacteriaintheabsenceofthe typical granulomatous structure. These findings are frequently accompanied by pleocytosis and an occasionally high protein level on CSF examination. The diagnosis should be confirmed by a histological exam (in cerebral localized forms) or by using minimum 2 hemocultures (in disseminated forms). MAC was also isolated in the CSF in disseminated forms. NeuroIRIS-

MAC associated manifestations were sporadically reported in HIV patients [110].

The treatment of NTB in HIV patients should be combined, controlled and individualized. **1.** The antituberculous and antiretroviral medication must be *combined* according to the synergistic drug interactions; the doses in the combined scheme must be adjusted to

**2.** The drug regimen must be *controlled* for adherence, drug interactions, toxicities, clinical

**3.** Treatment must be *individualized* and adapted to other co-morbidities, associated therapies

The main antituberculous and antiretroviral classes, their corresponding representative drugs, pharmacologicalinteractions, adverse reactions andtreatment efficacyare shownintable 3.The NTB treatment principles in HIV patients are presented in accordance with the European AIDS Clinical Society guidelines, CDC and American Thoracic Society recomandations [111-113].

[57]. Under 10 cells/ mm3

[108]. Higher values of the CD4+ count were also found in cases of MAC–related IRIS

the neurological dissemina‐

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 309

**7. Infections with non-tuberculous mycobacteria in HIV patients**

PCR techniques could increase the diagnostic yield [101,102].

tion at a CD4 count under 60 cells/mm3

**8. The treatment of NTB in HIV patients**

prevent treatment resistance.

response and treatment resistance

and hypersensitivity reactions of the patient

cells/mm3

**Figure 3.** Cranio-cerebral *MRI,* showing left pontine tuberculoma in a 16 year-old patient previously diagnosed and undergoing treated for lymph node TB for the past 2 months and recently diagnosed with HIV infection.The patient also associated HBV and CMV infection and oral candidiosis.On admission the patient was in coma. The laboratory data displayed a CD4 count of 24 cells/mm3 and RNA HIV 1064973copies/ml. Final diagnosis was NeuroIRIS TB (tuber‐ culoma).The CSF disclosed no changes.The clinical evolution was favourable. *A:* coronal T1 weighted image demon‐ strating left pontine paramedian nodular lesion of 4 mm surrounded by perilesional edema (discrete hyposignal). *B:* coronal section T1 postcontrast shows hypersignal; C- coronal section T2 and D- axial FLAIR section show intense con‐ trast uptake and no diffusion restriction.

#### *6.3.2.Tuberculous abscess*

The tuberculous abscess represents a purulent collection delineated by a capsule with a granulomatous structure. This is a rare finding in immunocompetent patients as well as in the early stages of AIDS but common in severe immunodeficiency states with CD4+T cell count under 100/mm3 [96]. The tuberculous abscess results from the liquefaction of tuberculomas [13] or from the necrotic evolution of granulomas in the setting of severe immunodeficiency [98].The necrotic centre is invaded by mycobacteria. The CSF is unchanged. The evolution is more acute than tuberculomas with neurologic deficit, fever and headaches [96, 99-100]. The CT/MRI aspect resembles the images in caseous tuberculomas but the lesion is larger (>3cm), multilobulated, surrounded by a thick capsule and ring enhancement. The perilesional edema and the mass effect are the most important features. The histological and bacteriological exam the cerebral biopsy confirm the diagnosis. The differential diagnosis includes other intracranial space-occupying lesions especially cerebral toxoplasmosis and lymphoma [19].In such cases PCR techniques could increase the diagnostic yield [101,102].
