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HIV-Associated Central Nervous System Tuberculosis Gabriel Chamie, MD, MPH1
Carina Marquez, MD1
1 HIV/AIDS Division, Department of Medicine, San Francisco General
Hospital, University of California, San Francisco, California
Anne Luetkemeyer, MD1 Address for correspondence Gabriel Chamie, MD, MPH, Division of HIV/AIDS, San Francisco General Hospital, Box 0874, San Francisco, CA 94143-0874 (e-mail: [email protected]).
Abstract Keywords
► human immunodeficiency virus ► central nervous system ► tuberculosis ► tuberculosis meningitis
Central nervous system tuberculosis (CNS TB) represents one of the most devastating manifestations of TB. HIV dramatically increases the risk of TB disease, including CNS TB. Early recognition and treatment of CNS TB, and TB meningitis in particular, is of critical importance to reducing disability and death associated with CNS TB. The diagnosis and treatment of HIV-associated CNS TB presents particular challenges for clinicians due to the increased risk of other CNS infections and malignancies, atypical cerebrospinal fluid characteristics, drug-drug interactions, timing of antiretroviral therapy and immune reconstitution inflammatory syndrome, and the increased risk of poor clinical outcomes in HIV-infected compared with HIV-uninfected CNS TB patients. The authors review recent updates and highlight challenges specific to CNS TB in the HIV-infected patient.
Tuberculosis (TB) is a leading cause of death among human immunodeficiency virus- (HIV-) infected persons worldwide, and HIV dramatically increases the risk of TB disease, including central nervous system (CNS) TB.1–3 CNS TB represents one of the most devastating manifestations of TB, and may present as TB meningitis, tuberculoma, abscess, or more rarely encephalitis or radiculomyelitis. Early diagnosis and treatment of CNS TB, and TB meningitis in particular, is critical to minimizing disability and preventing death.4 Recognizing CNS TB in HIVinfected patients, especially those with advanced immune suppression, is particularly challenging due to the elevated risk of other CNS opportunistic infections and malignancies that may present similarly or along with CNS TB. Management in HIV coinfection is complicated by HIV–TB drug–drug interactions, overlapping drug toxicities, the question of when to start antiretroviral therapy (ART) during TB treatment, immune reconstitution inflammatory syndrome (IRIS), and worse outcomes as compared with HIV-uninfected CNS TB patients. We review recent updates and highlight challenges specific to CNS TB in the HIV-infected patient.
Pathogenesis The elevated risk of TB disease in HIV-infected persons is due in part to impairment of T-cell-mediated immunity, with TB
Issue Theme HIV Neurology; Guest Editors, Serena Spudich, MD, MA, and Ana-Claire Meyer, MD, MSHS
risk increasing as CD4 T cells decline.5,6 In HIV disease, granuloma formation and Mycobacterium tuberculosis (MTB) containment by the immune system are impaired, resulting in an increased risk of dissemination and extrapulmonary TB either during reactivation TB or primary progression after TB infection. CNS TB occurs with hematogenous dissemination of TB bacilli, resulting in a cortical or meningeal focus of infection (a “Rich” focus). This focus may undergo subsequent caseation with discharge of TB bacilli into the subarachnoid space causing meningitis.7
Manifestations of CNS TB in the HIV-Infected Patient TB Meningitis TB meningitis (TBM) represents 1% of TB disease.8 HIV-infected TB patients are at elevated risk of TBM compared with HIVuninfected TB patients.1,9 In a study predating the availability of combination ART, 10% of HIV-infected TB cases had TBM, compared with 2% without HIV infection.1 Children account for at least 10 to 15% of new TB cases and they are particularly vulnerable to rapid primary progression of disease and disseminated disease.10,11 The risk of TBM and death in children is increased by young age (< 3 y) and HIV infection.10,12,13
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1372347. ISSN 0271-8235.
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Semin Neurol 2014;34:103–116.
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The clinical presentation of TBM can be categorized into three phases. In the prodromal phase, symptoms are typically nonspecific. Adults may experience malaise, anorexia, weight loss, personality changes, and/or low-grade fever lasting approximately 1 to 3 weeks. In the meningitic phase, unlike in acute bacterial meningitis, nuchal rigidity is often absent, and worsening headache, nausea and vomiting, confusion, and cranial nerve palsies develop. With advanced disease (the paralytic phase), hemiplegia, paraplegia, seizures, and/or coma ensue; without treatment, death typically occurs 6 to 8 weeks after initial symptom onset. HIV infection generally does not alter the presentation of TBM.1,9,14,15 One small series reported an increased rate of CNS mass lesions in HIV-infected versus uninfected TBM patients.14 However, in HIV-infected patients, the challenge of diagnosing TBM is further complicated by the possibility of opportunistic intracranial infections and malignancies that need to be excluded. This differential diagnosis can be daunting and includes other subacute meningitides, most notably cryptococcal meningitis, as well as fungal meningitis due to Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, or Aspergillus fumigatus, neurosyphilis, viral etiologies (herpes simplex virus [HSV] and cytomegalovirus [CMV] encephalitis), bacterial etiologies (partially treated bacterial meningitis, bacterial infections with a parameningeal focus, such as epidural abscesses, and CNS brucellosis) and malignancy (leptomeningeal carcinomatosis). Further complicating TBM diagnosis in HIV-infected persons is the possibility of more than one CNS process occurring at the time of TBM diagnosis, particularly at low CD4 cell counts. Clinical and epidemiologic factors to differentiate other causes of subacute meningitis from TBM are shown in ►Table 1. The presence of extrameningeal TB should be looked for in any TBM suspect using microscopy and mycobacterial culture of appropriate extrameningeal specimens including sputum, as up to 50% of TBM patients may have culture positive sputum.16 However, the absence of pulmonary TB (PTB) does not exclude TBM, and the presence of PTB does not exclude other causes of meningitis in HIV-infected patients.17,18 For example, among the subset of PTB cases diagnosed with meningitis in a randomized controlled trial of the timing of antiretroviral therapy in HIV-associated TB disease (the SAPiT trial), cryptococcal meningitis occurred more commonly than TBM.17 Serum and CSF cryptococcal antigen tests have excellent sensitivity and specificity for cryptococcemia and cryptococcal meningitis, respectively, and should be used to rapidly distinguish cryptococcal from TB meningitis.19 In resource-limited settings where cryptococcal antigen tests may not be available, distinguishing these two types of meningitis may be particularly challenging. The development of rapid, point-of-care cryptococcal antigen tests offer a promising solution to this challenge in settings with limited laboratory capacity.20
CNS Tuberculoma CNS tuberculomas are aggregated granulomatous TB foci that may occur throughout the CNS, including the cerebrum, cerebellum, spinal cord, and the subarachnoid, subdural, or Seminars in Neurology
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epidural spaces.21 Clinical presentation is variable and may range from an asymptomatic mass lesion noted on imaging to symptoms attributable to a space-occupying lesion, such as headache, seizures, and hemiplegia (from cerebral tuberculoma) with or without fever, and signs and symptoms of elevated intracranial pressure due to hydrocephalus from mechanical obstruction of CSF pathways. Patients with spinal cord tuberculoma may present with lower extremity weakness, paresthesias, bowel and bladder dysfunction, and a sensory level.22 There is limited published literature contrasting the clinical and radiographic presentation of CNS tuberculoma by HIV status. In one small study of four HIV-infected versus five HIVuninfected patients with tuberculoma, all of the HIV-infected cases presented with fever and headache without seizure and had hypodense lesions on head computed tomography (CT) scan, whereas four of five HIV-uninfected cases presented with seizure and none had hypodense lesions seen on CT.23 The differential diagnosis for cerebral tuberculomas in HIV-infected patients includes other etiologies of CNS mass lesions, most commonly toxoplasmosis and lymphoma, as well as bacterial abscesses (due to Staphylococcus and Streptococcus, as well as Rhodococcus, Nocardia, and Listeria), cryptococcoma, Aspergillus abscess, reactivation Chagas disease and inflammatory progressive multifocal leukoencephalopathy (PML) during immune reconstitution (which may present with surrounding edema and mass effect) (►Table 2). Tuberculomas of the spinal cord causing myelopathy may mimic other causes of myelopathy in HIV, including viral myelopathy caused by HSV, CMV and varicella zoster, as well as AIDS vacuolar myelopathy and spinal infection by Schistosoma mansoni or Schistosoma haematobium in the right epidemiologic setting.22,24
CNS TB Abscess CNS TB abscesses are a less common form of space-occupying CNS TB lesion than tuberculoma.25 Abscess formation is thought to be due to caseous necrosis and liquefaction of tuberculomas.26 CNS TB abscesses are typically larger (> 3 cm), multiloculated and progress more rapidly than tuberculomas, but their clinical presentation and differential diagnosis is otherwise similar to CNS tuberculoma.21,27 Based on case series, CNS TB abscesses may occur more frequently in HIV-infected than in HIV-uninfected patients28,29; however, there are no published data directly comparing the clinical presentation and outcome of TB abscess in HIV-infected versus uninfected patients.
Diagnosis Diagnosing CNS TB is a challenge due to the nonspecific presenting signs and symptoms early in the course of disease and insensitive diagnostic tests. CNS TB in AIDS patients may be mistaken for or occur along with other HIV-associated conditions, resulting in delayed treatment and a missed opportunity for preventing disability and death. Clinical diagnostic rules for TBM have been developed, with one diagnostic rule having a sensitivity ranging from 86 to 98%,
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Opening pressure: Frequently elevated WBC: Normal or elevated- with lymphocytic predominance Glucose: Decreased or normal Protein: Normal or elevated In HIV-infected patients CSF can be normal (26% of patients in case-series presented with normal CSF)80 or < 10 lymphocytes/μL.81
Typically CD4 T cells < 100 cells/μL Clinical features: Usually subacute, characterized by headache, fever, altered mental status, seizures. Focal deficits and cranial neuropathies less common.
Variable CD4 T cell counts, but more common if CD4 < 250 cells/μL Epidemiology: Endemic in southwestern United States and Northwestern Mexico. Clinical presentation: Headache, altered mental status, fever, nausea, vomiting. Meningismus in 50% of cases. Focal neurologic deficit may be less common. Commonly associated with diffuse pulmonary disease in HIV-infected patients.
CD4 T-cell counts 10,000 cells/mm. Lymphocytic predominance is typical. Eosinophils rare, but when present, highly suggestive of the diagnosis. Glucose: Decreased or normal CSF protein: Elevated, > 150 mg/dL
Opening pressure: Elevated (>25 cm H20) in 50% of cases WBC: Usually elevated with 10–500 cells/μL with lymphocytic predominance (> 50%), can be mixed neutrophil and lymphocytes initially Glucose: Decreased, ratio of CSF to plasma glucose 0.5. Protein: Elevated (>1 g/L) HIV–infected patients can have atypical CSF profiles (especially at CD4 T-cell counts < 50), with lower CSF cell counts, lower-normal CSF protein, and higher glucose levels.
CD4 T cell variable, most commonly < 200 cells/μL Clinical Features: Nonspecific prodrome of malaise, weight loss, lowgrade fever, and gradual onset of headache. Clinical symptoms of disease progression typically involve worsening headache, confusion, cranial nerve palsies, and ultimately coma and death if untreated. Nuchal rigidity is often absent in early stages of disease.
TB Meningitis76,77
CSF profile
Differentiating epidemiologic & clinical features
Disease
Table 1 Differential diagnosis for subacute meningitis in HIV-infected patients
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Opening pressure: Normal Lymphocytes: Usually increased RBC: Normal or increased Glucose: Normal Protein: Usually high
Variable CD4 T-cell counts Clinical features: Vary widely, and include fever, headache, neck stiffness, vomiting, disorientation, memory loss, dysphasia, personality change, seizures, visual hallucinations. Encephalopathy can develop subacutely over several weeks.
HSV meningoencephalitis93–95
Temporal lobe enhancement most common. Intracranial hemorrhage possible.
Wide variety of findings. May show enhancement of the meninges, cranial nerves. Cerebral gummas seen in tertiary syphilis; show areas of enhancement and surrounding edema adjacent to the meninges.
Leptomeningeal enhancement and/ or mass lesion(s)
Imaging
CSF HSV PCR
Serum RPR: Titer > 1:32 associated with increased risk of neurosyphilis CSF VDRL: Specific, not sensitive False-negatives 30–70%. CSF-FTA-ABS: Sensitive, but not specific
CSF culture is gold standard. Blastomycosis urine or CSF antigen. Sensitivity for urine antigen 92.9% and 79.3% for all forms of blastomycoses. Cross-reactivity with histoplasmosis and paracoccidioides high.90
lower sensitivity than urine antigen.
Diagnostic tests
HIV-Associated CNS Tuberculosis
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Opening pressure: Normal WBC: Elevated, >5 cells/μL, lymphocytic predominance. Usually 10– 100 cells/μL. Can be hard to distinguish from HIV-associated pleocytosis alone. Glucose: Normal or low Protein: Elevated, but lower < 100 mg/dL CSF profile influenced by CD4 T-cell count, and HIV viral load, and antiretroviral use.
Variable CD4 T-cell counts, increased risk CD4 350 cells/μL Clinical features: Prodromal symptoms can occur days or headache, confusion, nausea vomiting. Cranial neuropathies, particularly optic, facial, or auditory nerves common. Can occur concurrently with primary syphilis—presence of chancre.
Neurosyphilis91,92
Opening pressure: Normal WBC: Elevated, usually lymphocytic predominance, can have neutrophilic predominance. Glucose: Normal to low Protein: Elevated
CSF profile
CD4 T-cell variable, more common in < 200 cells/μL Epidemiology: Endemic in the southcentral, southeastern, and midwestern United States, and has been described in Africa Clinical presentation: Often preceded by pulmonary disease. Symptoms include fever, headache, altered mental status, and occasionally seizures. Relatively uncommon in HIV, but in one study 40% of AIDS patients with blastomycosis had CNS involvement.13
and Mississippi River valleys. Clinical presentation: Subacute presentation, time from symptom onset to diagnosis can be months to years. Fever, malaise, headache, altered mental status can be seen. 10– 30% will exhibit focal neurologic deficits.
Differentiating epidemiologic & clinical features
Blastomycosis 88,89
Disease
Table 1 (Continued)
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Opening pressure: Normal WBC: Normal or increased, neutrophilic predominance Glucose: Normal (may be decreased in ventriculitis) Protein: Normal or increased
Opening pressure: Normal WBC: 10–200 (mononuclear cells) Glucose: Normal or decreased Protein: Normal or Increased
Opening pressure: Elevated to normal WBC: Mildly elevated, lymphocytic predominance Glucose: Decreased or normal Protein: Elevated
CD4 T cell counts < 50 cells/μL Rare manifestation of CMV disease in HIV-infected patients Clinical features: Altered mental status, seizures, fever. Progressive encephalopathy can be accompanied by brainstem symptoms and seizures. Previous or concurrent CMV retinitis common.
Variable CD4 T cell counts Epidemiology: Contact with unpasteurized milk and cheese or farm animals. Endemic areas include Mediterranean basin, Central and South America, and the Indian subcontinent. Clinical features: Headache, altered mental status, cranial neuropathies, agitation. Behavioral and neuropsychiatric changes can be seen.
Variable CD4 T-cell counts Epidemiology: Associated with breast, lung, gastrointestinal cancers, melanoma, lymphoma, and leukemia. Clinical features: Symptoms emerge over days to weeks. Symptoms are usually multifocal. Most common symptoms: Headache, vomiting, leg weakness, altered mental status, cerebellar dysfunction, and cranial nerve palsies.
Variable CD4 T-cell counts Clinical features: Headache, altered mental status, nuchal rigidity. Associated with intracranial or epidural abscess.
CMV encephalitis and ventriculitis 94,95
Neurobrucellosis97,98
Leptomeningeal carcinomatosis99
Parameningeal focus of bacterial infection
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Leptomeningeal enhancement, epidural or intracranial abscess.
Linear and nodular leptomeningeal enhancement, thickening and enhancement of cranial nerves, hydrocephalus.
Radiographic findings vary from normal, leptomeningeal white matter lesions, or vasculitides.
Imaging can be normal, < 50% with leptomeningeal or periventricular enhancement. Demyelination can result in diffuse white matter abnormalities, and a characteristic pattern of ependymitis.
Imaging
CSF culture (may be negative) Identification and culture of abscess.
Positive CSF cytology gold standard—however often negative in over 20% of infections.
CSF culture Serologic: Serum agglutination or ELISA
CSF CMV PCR (90% > sensitive and specific) Presence of CMV retinitis raises risk for CMV encephalitis.96
Diagnostic tests
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Abbreviations: ADA, adenosine deaminase; AFB, acid-fast bacilli; AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FTA-ABS, fluorescent treponemal antibody-absorbed; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction; RBC, red blood cell; RPR, rapid plasma reagin; TB, tuberculosis; VDRL, Venereal Disease Research Laboratory; WBC, white blood cell count.
Opening pressure: Elevated to normal WBC: Elevated, neutrophil predominance Glucose: Decreased Protein: Elevated
CSF profile
Differentiating epidemiologic & clinical features
Disease
Table 1 (Continued)
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Single or multiple Single lesions more likely to be CNS lymphoma than toxoplasmosis
CD4 T cells < 50 cells/μL Common space-occupying lesions among patients with AIDS. Constitutional symptoms, confusion, lethargy, focal neurologic deficit, seizures
Primary CNS lymphoma106,108–110
Frequent
Frequent
Possible
Possible
Mass effect
Enhancement: Irregular, patchy, or diffuse enhancement. Appearance similar to toxoplasmosis
Enhancement: Yes, >90% ring have enhancement
Enhancement: Yes On MRI, abscesses more likely to have hyperintense center compared with tuberculomas. Tend to be larger than tuberculomas > 3 cm On MRI, large lipid/acetate peak helps differentiated from pyogenic abscess.
Enhancement: Yes Noncaseating lesions: Usually show nodular homogenous enhancement. MRI appearance is usually hypointense on T1weighted images and hyperintense on T2- weighted images. Caseating lesions: Show rim enhancement. On MRI appears hypointense on T1-weighted images and isointense to hypointense on T2-weighted images, and is accompanied by rim enhancement. Typical size is 4 cm more likely to be lymphoma than toxoplasmosis.
Commonly involves the parietal, frontal, thalamus, or basal ganglia. Frequently at corticomedullary junction. Brain stem involvement uncommon.
Adults: Majority supratentorial. Frontal and parietal lobes most common. Children: More likely infratentorial than in adults
Location
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Usually multiple. If single lesion is seen on CT, then MRI is recommended.
CD4 T cells < 100 cells/μL Common space-occupying lesions among patients with AIDS. Fever, headache, altered mental status, focal neurologic deficits, seizures
More likely to be solitary compared with tuberculomas
Single or multiple
Toxoplasmosis102,104–107
Variable CD4 T-cell counts Can be asymptomatic and occur without meningitis. Clinical presentation: Focal symptoms, headache, confusion, focal neurologic deficits, seizures
Multiple or single lesions
Variable CD4 T-cell counts Can present with fever, constitutional symptoms, headache, confusion, focal neurologic deficits
100–104
Clinical features
Brain biopsy (gold standard) CSF Epstein-Barr virus PCR
Brain biopsy Serum Toxoplasma IgG CSF Toxoplasma PCR Clinical and radiographic improvement to empiric treatment
Brain biopsy CSF AFB culture may be positive.
Brain biopsy CSF AFB Culture rarely positive if no meningitis
Diagnostic tests
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TB Abscess100–104
Tuberculoma
Disease
Table 2 Differential diagnosis for central nervous system mass lesions in HIV-infected patients
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CD4 T cells < 100 cells/μL Fever, altered mental status, seizures, headache
Variable CD4 T-cell counts Fever, altered mental status, seizures, headache
CD4 T cells < 200 cells/μL, but more common if CD4 T cells < 50 cells/μL Rapidly progressive, focal neurologic deficits including hemiparesis, ataxia, aphasia. Usually occurs within 12 weeks of starting antiretroviral therapy.
CD4 T cell-counts variable, but reactivation more common if CD4 T cells < 200 cells/μL Suspect in patients from endemic regions: Central or South America. Headache, neurologic deficits, and fever are common. Can also see altered mental status and seizures.
Cryptococcoma104,111,112
Bacterial Abscess101
PML104,113,114
Chagoma115,116 Single or multiple
Single or multiple
Usually single
Single or multiple
Multiple or single lesions
Possible
Rare
Possible
Possible
Mass effect
Commonly enhance
Enhancement: Occasionally, with IRIS 25% of lesions show enhancement Typically PML lesions without IRIS do not enhance.
Enhancement: Yes MRI: T1 hypointense and T2 hyperintense, well defined smooth or lobulated ring enhancement.
Enhancement: Varies, can see nodular enhancement. Often reside in perivascular spaces.
Imaging
White matter and supratentorial involvement common.
Commonly involves the subcortical white matter, cerebellum, or brainstem.
Variable
Commonly involves the basal ganglia, thalamus, cerebellum
Location
Serologic studies can identify past infection Gold standard: Direct visualization of the trypomastigote on thick smear of CSF
History of PML CSF JC Virus PCR
Brain biopsy CSF culture may be positive
Brain biopsy Serum and/or CSF Cryptococcal antigen
Diagnostic tests
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Abbreviations: AFB, acid-fast bacilli; AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IRIS, immune reconstitution inflammatory syndrome; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; PCR, polymerase chain reaction.
Clinical features
Disease
Table 2 (Continued)
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and specificity from 68 to 88% in several different settings, but the sensitivity of these rules is diminished in HIV-infected patients, primarily due to cryptococcal meningitis patients screening positive by these rules.30,31 Differentiating TBM from cryptococcal meningitis is a particular challenge in resource-limited settings without routine access to cryptococcal antigen tests. A high index of suspicion is needed and TB treatment should be started once CNS TB is suspected. Anti-TB treatment will not jeopardize the sensitivity of the early diagnostic evaluation, including MTB culture, and treatment should not be withheld for diagnostic purposes. The cerebrospinal fluid (CSF) analysis in TBM is characterized by increased white cells (mixture of neutrophils and lymphocytes with a shift to lymphocyte predominance), elevated protein (100–500 mg/dL), decreased glucose with a typical ratio of CSF:plasma glucose of < 0.5, and often an elevated opening pressure of > 25 cm H20. However, atypical CSF findings are more common in HIV-associated TBM, including lower CSF protein, higher glucose levels, and lower CSF cell counts than in non-HIV-associated TBM.1,32,33 These atypical findings occur more commonly at CD4 T cell counts < 50 cells/μL.34 The absence of a CSF pleocytosis (< 5 cells/ mL) makes diagnosis especially challenging and has been described in up to 25 to 33% of HIV-infected TBM cases with CD4 T cell counts < 50 cells/μL.32,34 HIV-associated TBM patients may also present with normal CSF protein levels, and even completely normal CSF findings have been reported.14,35 CSF microscopy with Ziehl-Neelsson (ZN) staining for acidfast bacilli (AFB) is the test used most often worldwide for TB evaluation, but generally has poor sensitivity (roughly 10– 20%) in TBM and cannot be relied upon to rule out TBM. The sensitivity of microscopy varies depending on the CSF volume obtained, the skill of the technician, and the time spent reading a slide.16 In a small study from China of 29 patients with TBM, sensitivity of ZN staining was dramatically improved due to the detection of intracellular AFB using cytospin slides and pretreatment with a detergent (Triton X-100) on low volume (0.5 mL) CSF samples.36 These findings merit further study in a larger study population. Mycobacterium tuberculosis culture remains the gold standard test for TBM, and for phenotypic drug-susceptibility testing. However, even this gold standard is quite limited, as CSF MTB culture is slow, insufficiently sensitive (roughly 60– 70%) and often not available in resource-limited settings.37 Nucleic acid amplification tests (NAAT) can provide substantial improvements in sensitivity and specificity compared with microscopy and culture, but reported sensitivities vary widely (56–94%) and appear to be substantially lower in commercial assays compared with in-house assays, although comparison can be difficult.16,38 The Xpert MTB/RIF assay, a rapid, fully automated polymerase chain reaction- (PCR-) based assay (Cepheid, Sunnyvale, CA) has been endorsed by the World Health Organization (WHO) for TB diagnosis in resource-limited settings,39 but its use has primarily been studied on sputum specimens for pulmonary TB diagnosis.40,41 Several small studies have evaluated the Xpert MTB/RIF assay on CSF specimens for TBM diagnosis with Seminars in Neurology
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sensitivities ranging between 29–86%.42,43 In a South African study of 204 patients with meningeal-like illness, 87% of whom had HIV infection, the Xpert assay performed on CSF had a sensitivity of 62% and specificity of 95%; of note, sensitivity was markedly increased if CSF was centrifuged prior to testing (82% vs. 47%).44 At this juncture, NAAT-based testing is a useful diagnostic tool but still is not sufficiently sensitive to rule out TB. Other diagnostic tests for TBM include CSF adenosine deaminase (ADA) assays, interferon-gamma release assays (IGRAs) in both whole blood and CSF, and CSF lipoarabinomannan (LAM), which have been recently reviewed in depth elsewhere.16 In HIV-associated TBM, the sensitivity of CSF ADA is diminished compared with HIV-uninfected TBM cases, and CSF ADA is elevated in other infections, limiting its routine use for TBM diagnosis.45,46 Routine use of these tests in resource-limited settings is unlikely in the near future, due to limitations in diagnostic characteristics, laboratory infrastructure, and cost. For radiographic assessment of TBM, magnetic resonance imaging (MRI) is preferable to CT, as MRI better characterizes the typical findings of TBM, including brainstem involvement, leptomeningeal enhancement, and evidence of vascular and cranial nerve involvement.47,48 However, these radiographic findings are not specific to TBM, and may not be sufficient to exclude other coinfections in advanced HIV disease. CNS tuberculoma and TB abscess may be suspected based on brain or spinal cord imaging. The presence of CNS mass lesions in HIV-infected patients with TBM is not specific for tuberculoma; indeed, in one series of HIV/TBM cases, all of the brain masses identified were due to toxoplasmosis (confirmed on autopsy) in marked contrast to HIV-uninfected TBM cases.33 Brain or spinal cord biopsy can confirm the diagnosis of tuberculoma or abscess. AFB microscopy is insensitive in tuberculoma, but may have higher yield in CNS abscess.21 In cases of suspected CNS tuberculoma at CD4 T-cell counts < 200 cells/μL, testing for serum toxoplasma IgG, CSF toxoplasma PCR, and serum and CSF cryptococcal antigen can aid in ruling out other diagnoses. In patients with CNS lesions exhibiting mass effect, the decision to perform a lumbar puncture must be weighed against the risk of brainstem herniation. When available, CT scan is recommended prior to lumbar puncture in HIV-infected patients to identify patients with mass lesions at potential increased risk for herniation.49 Response to toxoplasmosis treatment can also aid in differentiating CNS toxoplasmosis from isolated CNS tuberculoma.
Treatment The treatment of drug-sensitive TB meningitis is standard four-drug therapy with isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin for 2 months, followed by 7 to 10 months of isoniazid and rifampin. Corticosteroids given during the first 6 to 8 weeks of TBM treatment have been shown in several randomized controlled trials (RCT) to reduce mortality in adults and children with TBM.4,50 In a double-blind, placebo-controlled RCT of TBM
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patients > 14 years of age, a subgroup analysis of 98 HIVinfected patients found no significant reduction in mortality in participants given dexamethasone versus placebo.4 The lack of a significant mortality reduction in this subgroup may be explained by several factors: median CD4 T-cell count was low (66 cells/μL), antiretroviral therapy was not given during therapy, and the number of HIV-infected patients enrolled was insufficient to find a significant difference in mortality in this subgroup analysis. However, corticosteroids were safe among the HIV-infected participants, and based on the overall reduction in mortality observed, corticosteroids should be administered in the treatment of HIV-associated TBM despite a lack of sufficient evidence in HIV-associated TBM, pending further study.50 Aspirin has been inconsistently shown to reduce mortality as an adjunct to TBM treatment in some trials; more data are needed to evaluate the role of aspirin in TBM.51,52 There are no RCTs establishing optimal TB treatment duration, but U.S. guidelines recommend 9 to 12 months to avoid TBM relapse.53 CNS tuberculomas and TB abscesses should also be treated for 9 to 12 months with the same anti-TB regimen as TBM. CNS TB abscesses are often resistant to antibiotic therapy and may require surgical excision for cure.29 Rifampin is essential for achieving optimal outcomes in drug-sensitive TBM, and significantly higher mortality rates have been reported in patients with rifampin monoresistance, as well as multidrug resistant (MDR) TBM.54,55 In addition, the fluoroquinolones moxifloxacin and levofloxacin both have in vitro activity against MTB and excellent CSF penetration,56,57 as does ethionamide.58 To evaluate optimized regimens with high CSF penetration, an open-label phase II RCT comparing high-dose, intravenous rifampin versus standard rifampin given with isoniazid and pyrazinamide for 2 weeks, with additional randomization to one of three arms: high-dose oral moxifloxacin versus low-dose oral moxifloxacin versus ethambutol, was conducted among 60 TBM patients > 14 years of age in Indonesia.59 The high-dose intravenous rifampin group had significantly higher plasma maximum concentrations and 6-hour, geometric mean area under the timeconcentration curve (AUC) measures, and higher CSF maximum concentrations than the standard dose rifampin group, without a significant increase in adverse events. Mortality was substantially lower with high-dose rifampin (35%) than standard-dose rifampin (65%). Only seven HIV-infected participants were enrolled. A nonrandomized Indian study also evaluated higher dose rifampin and quinolones, using levofloxacin, high-dose rifampin (900 mg), double-dose isoniazid (1200 mg), pyrazinamide, and ethionamide for 7 days in 65 HIV patients undergoing TBM treatment.60 Seven days of the experimental regimen was associated with an absolute mortality reduction of 21% at 12 months, compared with local historical controls. Of note, ART use was similar in the experimental (39%) and historical control (43%) arms. Future studies in HIV-infected TBM patients, as well as a larger ongoing trial comparing high-dose oral rifampin and levofloxacin to standard treatment International Standard Randomized Controlled Trial Number (ISRCTN) 61649292 will provide further information on this approach.61
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Two challenges unique to HIV-associated TBM are drug interactions during cotreatment of HIV and TB, and the timing of ART therapy initiation in TBM patients. The most significant drug interactions in HIV-TB treatment occur between rifamycins and ART. Rifampin is a potent inducer of the cytochrome p450 isoenzyme, and it substantially reduces levels of boosted protease inhibitors (PIs); the two should not be coadministered. The nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz can be safely given with rifampin, and is the treatment of choice, along with two nucleoside reverse transcriptase inhibitors (NRTIs), for HIV-associated TB.62 For patients receiving a PI-based regimen, rifabutin may be used at 150 mg daily. Prior guidelines had recommended 150 mg every other day, but more recent data suggest that every other day dosing results in suboptimal rifabutin levels.62 The integrase inhibitor raltegravir has been shown to be safe and effective in achieving virologic suppression compared with efavirenz, during rifampin-containing TB treatment in a phase II trial.63 Doubling the dose of raltegravir from 400 mg twice daily to 800 mg twice daily may result in a reduced likelihood of developing integrase inhibitor resistance. One small phase I study of HIV-uninfected participants given the integrase inhibitor dolutegravir along with rifampin for 14 days, suggests that dolutegravir may be an additional option with rifampin, but further study is needed.64 Comprehensive guidance to drug–drug interactions between TB and HIV treatment is provided elsewhere.65 Several RCTs have shown that immediate initiation (< 2 wk after TB treatment initiation) of ART in HIV-associated pulmonary TB results in significantly reduced mortality compared with early ART (< 8 wk) initiation in patients with CD4 T cell counts
HIV-Associated Central Nervous System Tuberculosis Gabriel Chamie, MD, MPH1
Carina Marquez, MD1
1 HIV/AIDS Division, Department of Medicine, San Francisco General
Hospital, University of California, San Francisco, California
Anne Luetkemeyer, MD1 Address for correspondence Gabriel Chamie, MD, MPH, Division of HIV/AIDS, San Francisco General Hospital, Box 0874, San Francisco, CA 94143-0874 (e-mail: [email protected]).
Abstract Keywords
► human immunodeficiency virus ► central nervous system ► tuberculosis ► tuberculosis meningitis
Central nervous system tuberculosis (CNS TB) represents one of the most devastating manifestations of TB. HIV dramatically increases the risk of TB disease, including CNS TB. Early recognition and treatment of CNS TB, and TB meningitis in particular, is of critical importance to reducing disability and death associated with CNS TB. The diagnosis and treatment of HIV-associated CNS TB presents particular challenges for clinicians due to the increased risk of other CNS infections and malignancies, atypical cerebrospinal fluid characteristics, drug-drug interactions, timing of antiretroviral therapy and immune reconstitution inflammatory syndrome, and the increased risk of poor clinical outcomes in HIV-infected compared with HIV-uninfected CNS TB patients. The authors review recent updates and highlight challenges specific to CNS TB in the HIV-infected patient.
Tuberculosis (TB) is a leading cause of death among human immunodeficiency virus- (HIV-) infected persons worldwide, and HIV dramatically increases the risk of TB disease, including central nervous system (CNS) TB.1–3 CNS TB represents one of the most devastating manifestations of TB, and may present as TB meningitis, tuberculoma, abscess, or more rarely encephalitis or radiculomyelitis. Early diagnosis and treatment of CNS TB, and TB meningitis in particular, is critical to minimizing disability and preventing death.4 Recognizing CNS TB in HIVinfected patients, especially those with advanced immune suppression, is particularly challenging due to the elevated risk of other CNS opportunistic infections and malignancies that may present similarly or along with CNS TB. Management in HIV coinfection is complicated by HIV–TB drug–drug interactions, overlapping drug toxicities, the question of when to start antiretroviral therapy (ART) during TB treatment, immune reconstitution inflammatory syndrome (IRIS), and worse outcomes as compared with HIV-uninfected CNS TB patients. We review recent updates and highlight challenges specific to CNS TB in the HIV-infected patient.
Pathogenesis The elevated risk of TB disease in HIV-infected persons is due in part to impairment of T-cell-mediated immunity, with TB
Issue Theme HIV Neurology; Guest Editors, Serena Spudich, MD, MA, and Ana-Claire Meyer, MD, MSHS
risk increasing as CD4 T cells decline.5,6 In HIV disease, granuloma formation and Mycobacterium tuberculosis (MTB) containment by the immune system are impaired, resulting in an increased risk of dissemination and extrapulmonary TB either during reactivation TB or primary progression after TB infection. CNS TB occurs with hematogenous dissemination of TB bacilli, resulting in a cortical or meningeal focus of infection (a “Rich” focus). This focus may undergo subsequent caseation with discharge of TB bacilli into the subarachnoid space causing meningitis.7
Manifestations of CNS TB in the HIV-Infected Patient TB Meningitis TB meningitis (TBM) represents 1% of TB disease.8 HIV-infected TB patients are at elevated risk of TBM compared with HIVuninfected TB patients.1,9 In a study predating the availability of combination ART, 10% of HIV-infected TB cases had TBM, compared with 2% without HIV infection.1 Children account for at least 10 to 15% of new TB cases and they are particularly vulnerable to rapid primary progression of disease and disseminated disease.10,11 The risk of TBM and death in children is increased by young age (< 3 y) and HIV infection.10,12,13
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1372347. ISSN 0271-8235.
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Semin Neurol 2014;34:103–116.
HIV-Associated CNS Tuberculosis
Chamie et al.
The clinical presentation of TBM can be categorized into three phases. In the prodromal phase, symptoms are typically nonspecific. Adults may experience malaise, anorexia, weight loss, personality changes, and/or low-grade fever lasting approximately 1 to 3 weeks. In the meningitic phase, unlike in acute bacterial meningitis, nuchal rigidity is often absent, and worsening headache, nausea and vomiting, confusion, and cranial nerve palsies develop. With advanced disease (the paralytic phase), hemiplegia, paraplegia, seizures, and/or coma ensue; without treatment, death typically occurs 6 to 8 weeks after initial symptom onset. HIV infection generally does not alter the presentation of TBM.1,9,14,15 One small series reported an increased rate of CNS mass lesions in HIV-infected versus uninfected TBM patients.14 However, in HIV-infected patients, the challenge of diagnosing TBM is further complicated by the possibility of opportunistic intracranial infections and malignancies that need to be excluded. This differential diagnosis can be daunting and includes other subacute meningitides, most notably cryptococcal meningitis, as well as fungal meningitis due to Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, or Aspergillus fumigatus, neurosyphilis, viral etiologies (herpes simplex virus [HSV] and cytomegalovirus [CMV] encephalitis), bacterial etiologies (partially treated bacterial meningitis, bacterial infections with a parameningeal focus, such as epidural abscesses, and CNS brucellosis) and malignancy (leptomeningeal carcinomatosis). Further complicating TBM diagnosis in HIV-infected persons is the possibility of more than one CNS process occurring at the time of TBM diagnosis, particularly at low CD4 cell counts. Clinical and epidemiologic factors to differentiate other causes of subacute meningitis from TBM are shown in ►Table 1. The presence of extrameningeal TB should be looked for in any TBM suspect using microscopy and mycobacterial culture of appropriate extrameningeal specimens including sputum, as up to 50% of TBM patients may have culture positive sputum.16 However, the absence of pulmonary TB (PTB) does not exclude TBM, and the presence of PTB does not exclude other causes of meningitis in HIV-infected patients.17,18 For example, among the subset of PTB cases diagnosed with meningitis in a randomized controlled trial of the timing of antiretroviral therapy in HIV-associated TB disease (the SAPiT trial), cryptococcal meningitis occurred more commonly than TBM.17 Serum and CSF cryptococcal antigen tests have excellent sensitivity and specificity for cryptococcemia and cryptococcal meningitis, respectively, and should be used to rapidly distinguish cryptococcal from TB meningitis.19 In resource-limited settings where cryptococcal antigen tests may not be available, distinguishing these two types of meningitis may be particularly challenging. The development of rapid, point-of-care cryptococcal antigen tests offer a promising solution to this challenge in settings with limited laboratory capacity.20
CNS Tuberculoma CNS tuberculomas are aggregated granulomatous TB foci that may occur throughout the CNS, including the cerebrum, cerebellum, spinal cord, and the subarachnoid, subdural, or Seminars in Neurology
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epidural spaces.21 Clinical presentation is variable and may range from an asymptomatic mass lesion noted on imaging to symptoms attributable to a space-occupying lesion, such as headache, seizures, and hemiplegia (from cerebral tuberculoma) with or without fever, and signs and symptoms of elevated intracranial pressure due to hydrocephalus from mechanical obstruction of CSF pathways. Patients with spinal cord tuberculoma may present with lower extremity weakness, paresthesias, bowel and bladder dysfunction, and a sensory level.22 There is limited published literature contrasting the clinical and radiographic presentation of CNS tuberculoma by HIV status. In one small study of four HIV-infected versus five HIVuninfected patients with tuberculoma, all of the HIV-infected cases presented with fever and headache without seizure and had hypodense lesions on head computed tomography (CT) scan, whereas four of five HIV-uninfected cases presented with seizure and none had hypodense lesions seen on CT.23 The differential diagnosis for cerebral tuberculomas in HIV-infected patients includes other etiologies of CNS mass lesions, most commonly toxoplasmosis and lymphoma, as well as bacterial abscesses (due to Staphylococcus and Streptococcus, as well as Rhodococcus, Nocardia, and Listeria), cryptococcoma, Aspergillus abscess, reactivation Chagas disease and inflammatory progressive multifocal leukoencephalopathy (PML) during immune reconstitution (which may present with surrounding edema and mass effect) (►Table 2). Tuberculomas of the spinal cord causing myelopathy may mimic other causes of myelopathy in HIV, including viral myelopathy caused by HSV, CMV and varicella zoster, as well as AIDS vacuolar myelopathy and spinal infection by Schistosoma mansoni or Schistosoma haematobium in the right epidemiologic setting.22,24
CNS TB Abscess CNS TB abscesses are a less common form of space-occupying CNS TB lesion than tuberculoma.25 Abscess formation is thought to be due to caseous necrosis and liquefaction of tuberculomas.26 CNS TB abscesses are typically larger (> 3 cm), multiloculated and progress more rapidly than tuberculomas, but their clinical presentation and differential diagnosis is otherwise similar to CNS tuberculoma.21,27 Based on case series, CNS TB abscesses may occur more frequently in HIV-infected than in HIV-uninfected patients28,29; however, there are no published data directly comparing the clinical presentation and outcome of TB abscess in HIV-infected versus uninfected patients.
Diagnosis Diagnosing CNS TB is a challenge due to the nonspecific presenting signs and symptoms early in the course of disease and insensitive diagnostic tests. CNS TB in AIDS patients may be mistaken for or occur along with other HIV-associated conditions, resulting in delayed treatment and a missed opportunity for preventing disability and death. Clinical diagnostic rules for TBM have been developed, with one diagnostic rule having a sensitivity ranging from 86 to 98%,
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104
Opening pressure: Frequently elevated WBC: Normal or elevated- with lymphocytic predominance Glucose: Decreased or normal Protein: Normal or elevated In HIV-infected patients CSF can be normal (26% of patients in case-series presented with normal CSF)80 or < 10 lymphocytes/μL.81
Typically CD4 T cells < 100 cells/μL Clinical features: Usually subacute, characterized by headache, fever, altered mental status, seizures. Focal deficits and cranial neuropathies less common.
Variable CD4 T cell counts, but more common if CD4 < 250 cells/μL Epidemiology: Endemic in southwestern United States and Northwestern Mexico. Clinical presentation: Headache, altered mental status, fever, nausea, vomiting. Meningismus in 50% of cases. Focal neurologic deficit may be less common. Commonly associated with diffuse pulmonary disease in HIV-infected patients.
CD4 T-cell counts 10,000 cells/mm. Lymphocytic predominance is typical. Eosinophils rare, but when present, highly suggestive of the diagnosis. Glucose: Decreased or normal CSF protein: Elevated, > 150 mg/dL
Opening pressure: Elevated (>25 cm H20) in 50% of cases WBC: Usually elevated with 10–500 cells/μL with lymphocytic predominance (> 50%), can be mixed neutrophil and lymphocytes initially Glucose: Decreased, ratio of CSF to plasma glucose 0.5. Protein: Elevated (>1 g/L) HIV–infected patients can have atypical CSF profiles (especially at CD4 T-cell counts < 50), with lower CSF cell counts, lower-normal CSF protein, and higher glucose levels.
CD4 T cell variable, most commonly < 200 cells/μL Clinical Features: Nonspecific prodrome of malaise, weight loss, lowgrade fever, and gradual onset of headache. Clinical symptoms of disease progression typically involve worsening headache, confusion, cranial nerve palsies, and ultimately coma and death if untreated. Nuchal rigidity is often absent in early stages of disease.
TB Meningitis76,77
CSF profile
Differentiating epidemiologic & clinical features
Disease
Table 1 Differential diagnosis for subacute meningitis in HIV-infected patients
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Opening pressure: Normal Lymphocytes: Usually increased RBC: Normal or increased Glucose: Normal Protein: Usually high
Variable CD4 T-cell counts Clinical features: Vary widely, and include fever, headache, neck stiffness, vomiting, disorientation, memory loss, dysphasia, personality change, seizures, visual hallucinations. Encephalopathy can develop subacutely over several weeks.
HSV meningoencephalitis93–95
Temporal lobe enhancement most common. Intracranial hemorrhage possible.
Wide variety of findings. May show enhancement of the meninges, cranial nerves. Cerebral gummas seen in tertiary syphilis; show areas of enhancement and surrounding edema adjacent to the meninges.
Leptomeningeal enhancement and/ or mass lesion(s)
Imaging
CSF HSV PCR
Serum RPR: Titer > 1:32 associated with increased risk of neurosyphilis CSF VDRL: Specific, not sensitive False-negatives 30–70%. CSF-FTA-ABS: Sensitive, but not specific
CSF culture is gold standard. Blastomycosis urine or CSF antigen. Sensitivity for urine antigen 92.9% and 79.3% for all forms of blastomycoses. Cross-reactivity with histoplasmosis and paracoccidioides high.90
lower sensitivity than urine antigen.
Diagnostic tests
HIV-Associated CNS Tuberculosis
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Opening pressure: Normal WBC: Elevated, >5 cells/μL, lymphocytic predominance. Usually 10– 100 cells/μL. Can be hard to distinguish from HIV-associated pleocytosis alone. Glucose: Normal or low Protein: Elevated, but lower < 100 mg/dL CSF profile influenced by CD4 T-cell count, and HIV viral load, and antiretroviral use.
Variable CD4 T-cell counts, increased risk CD4 350 cells/μL Clinical features: Prodromal symptoms can occur days or headache, confusion, nausea vomiting. Cranial neuropathies, particularly optic, facial, or auditory nerves common. Can occur concurrently with primary syphilis—presence of chancre.
Neurosyphilis91,92
Opening pressure: Normal WBC: Elevated, usually lymphocytic predominance, can have neutrophilic predominance. Glucose: Normal to low Protein: Elevated
CSF profile
CD4 T-cell variable, more common in < 200 cells/μL Epidemiology: Endemic in the southcentral, southeastern, and midwestern United States, and has been described in Africa Clinical presentation: Often preceded by pulmonary disease. Symptoms include fever, headache, altered mental status, and occasionally seizures. Relatively uncommon in HIV, but in one study 40% of AIDS patients with blastomycosis had CNS involvement.13
and Mississippi River valleys. Clinical presentation: Subacute presentation, time from symptom onset to diagnosis can be months to years. Fever, malaise, headache, altered mental status can be seen. 10– 30% will exhibit focal neurologic deficits.
Differentiating epidemiologic & clinical features
Blastomycosis 88,89
Disease
Table 1 (Continued)
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Opening pressure: Normal WBC: Normal or increased, neutrophilic predominance Glucose: Normal (may be decreased in ventriculitis) Protein: Normal or increased
Opening pressure: Normal WBC: 10–200 (mononuclear cells) Glucose: Normal or decreased Protein: Normal or Increased
Opening pressure: Elevated to normal WBC: Mildly elevated, lymphocytic predominance Glucose: Decreased or normal Protein: Elevated
CD4 T cell counts < 50 cells/μL Rare manifestation of CMV disease in HIV-infected patients Clinical features: Altered mental status, seizures, fever. Progressive encephalopathy can be accompanied by brainstem symptoms and seizures. Previous or concurrent CMV retinitis common.
Variable CD4 T cell counts Epidemiology: Contact with unpasteurized milk and cheese or farm animals. Endemic areas include Mediterranean basin, Central and South America, and the Indian subcontinent. Clinical features: Headache, altered mental status, cranial neuropathies, agitation. Behavioral and neuropsychiatric changes can be seen.
Variable CD4 T-cell counts Epidemiology: Associated with breast, lung, gastrointestinal cancers, melanoma, lymphoma, and leukemia. Clinical features: Symptoms emerge over days to weeks. Symptoms are usually multifocal. Most common symptoms: Headache, vomiting, leg weakness, altered mental status, cerebellar dysfunction, and cranial nerve palsies.
Variable CD4 T-cell counts Clinical features: Headache, altered mental status, nuchal rigidity. Associated with intracranial or epidural abscess.
CMV encephalitis and ventriculitis 94,95
Neurobrucellosis97,98
Leptomeningeal carcinomatosis99
Parameningeal focus of bacterial infection
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Leptomeningeal enhancement, epidural or intracranial abscess.
Linear and nodular leptomeningeal enhancement, thickening and enhancement of cranial nerves, hydrocephalus.
Radiographic findings vary from normal, leptomeningeal white matter lesions, or vasculitides.
Imaging can be normal, < 50% with leptomeningeal or periventricular enhancement. Demyelination can result in diffuse white matter abnormalities, and a characteristic pattern of ependymitis.
Imaging
CSF culture (may be negative) Identification and culture of abscess.
Positive CSF cytology gold standard—however often negative in over 20% of infections.
CSF culture Serologic: Serum agglutination or ELISA
CSF CMV PCR (90% > sensitive and specific) Presence of CMV retinitis raises risk for CMV encephalitis.96
Diagnostic tests
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Abbreviations: ADA, adenosine deaminase; AFB, acid-fast bacilli; AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FTA-ABS, fluorescent treponemal antibody-absorbed; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; NAAT, nucleic acid amplification test; PCR, polymerase chain reaction; RBC, red blood cell; RPR, rapid plasma reagin; TB, tuberculosis; VDRL, Venereal Disease Research Laboratory; WBC, white blood cell count.
Opening pressure: Elevated to normal WBC: Elevated, neutrophil predominance Glucose: Decreased Protein: Elevated
CSF profile
Differentiating epidemiologic & clinical features
Disease
Table 1 (Continued)
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Single or multiple Single lesions more likely to be CNS lymphoma than toxoplasmosis
CD4 T cells < 50 cells/μL Common space-occupying lesions among patients with AIDS. Constitutional symptoms, confusion, lethargy, focal neurologic deficit, seizures
Primary CNS lymphoma106,108–110
Frequent
Frequent
Possible
Possible
Mass effect
Enhancement: Irregular, patchy, or diffuse enhancement. Appearance similar to toxoplasmosis
Enhancement: Yes, >90% ring have enhancement
Enhancement: Yes On MRI, abscesses more likely to have hyperintense center compared with tuberculomas. Tend to be larger than tuberculomas > 3 cm On MRI, large lipid/acetate peak helps differentiated from pyogenic abscess.
Enhancement: Yes Noncaseating lesions: Usually show nodular homogenous enhancement. MRI appearance is usually hypointense on T1weighted images and hyperintense on T2- weighted images. Caseating lesions: Show rim enhancement. On MRI appears hypointense on T1-weighted images and isointense to hypointense on T2-weighted images, and is accompanied by rim enhancement. Typical size is 4 cm more likely to be lymphoma than toxoplasmosis.
Commonly involves the parietal, frontal, thalamus, or basal ganglia. Frequently at corticomedullary junction. Brain stem involvement uncommon.
Adults: Majority supratentorial. Frontal and parietal lobes most common. Children: More likely infratentorial than in adults
Location
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Usually multiple. If single lesion is seen on CT, then MRI is recommended.
CD4 T cells < 100 cells/μL Common space-occupying lesions among patients with AIDS. Fever, headache, altered mental status, focal neurologic deficits, seizures
More likely to be solitary compared with tuberculomas
Single or multiple
Toxoplasmosis102,104–107
Variable CD4 T-cell counts Can be asymptomatic and occur without meningitis. Clinical presentation: Focal symptoms, headache, confusion, focal neurologic deficits, seizures
Multiple or single lesions
Variable CD4 T-cell counts Can present with fever, constitutional symptoms, headache, confusion, focal neurologic deficits
100–104
Clinical features
Brain biopsy (gold standard) CSF Epstein-Barr virus PCR
Brain biopsy Serum Toxoplasma IgG CSF Toxoplasma PCR Clinical and radiographic improvement to empiric treatment
Brain biopsy CSF AFB culture may be positive.
Brain biopsy CSF AFB Culture rarely positive if no meningitis
Diagnostic tests
HIV-Associated CNS Tuberculosis
TB Abscess100–104
Tuberculoma
Disease
Table 2 Differential diagnosis for central nervous system mass lesions in HIV-infected patients
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CD4 T cells < 100 cells/μL Fever, altered mental status, seizures, headache
Variable CD4 T-cell counts Fever, altered mental status, seizures, headache
CD4 T cells < 200 cells/μL, but more common if CD4 T cells < 50 cells/μL Rapidly progressive, focal neurologic deficits including hemiparesis, ataxia, aphasia. Usually occurs within 12 weeks of starting antiretroviral therapy.
CD4 T cell-counts variable, but reactivation more common if CD4 T cells < 200 cells/μL Suspect in patients from endemic regions: Central or South America. Headache, neurologic deficits, and fever are common. Can also see altered mental status and seizures.
Cryptococcoma104,111,112
Bacterial Abscess101
PML104,113,114
Chagoma115,116 Single or multiple
Single or multiple
Usually single
Single or multiple
Multiple or single lesions
Possible
Rare
Possible
Possible
Mass effect
Commonly enhance
Enhancement: Occasionally, with IRIS 25% of lesions show enhancement Typically PML lesions without IRIS do not enhance.
Enhancement: Yes MRI: T1 hypointense and T2 hyperintense, well defined smooth or lobulated ring enhancement.
Enhancement: Varies, can see nodular enhancement. Often reside in perivascular spaces.
Imaging
White matter and supratentorial involvement common.
Commonly involves the subcortical white matter, cerebellum, or brainstem.
Variable
Commonly involves the basal ganglia, thalamus, cerebellum
Location
Serologic studies can identify past infection Gold standard: Direct visualization of the trypomastigote on thick smear of CSF
History of PML CSF JC Virus PCR
Brain biopsy CSF culture may be positive
Brain biopsy Serum and/or CSF Cryptococcal antigen
Diagnostic tests
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Abbreviations: AFB, acid-fast bacilli; AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; IRIS, immune reconstitution inflammatory syndrome; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; PCR, polymerase chain reaction.
Clinical features
Disease
Table 2 (Continued)
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and specificity from 68 to 88% in several different settings, but the sensitivity of these rules is diminished in HIV-infected patients, primarily due to cryptococcal meningitis patients screening positive by these rules.30,31 Differentiating TBM from cryptococcal meningitis is a particular challenge in resource-limited settings without routine access to cryptococcal antigen tests. A high index of suspicion is needed and TB treatment should be started once CNS TB is suspected. Anti-TB treatment will not jeopardize the sensitivity of the early diagnostic evaluation, including MTB culture, and treatment should not be withheld for diagnostic purposes. The cerebrospinal fluid (CSF) analysis in TBM is characterized by increased white cells (mixture of neutrophils and lymphocytes with a shift to lymphocyte predominance), elevated protein (100–500 mg/dL), decreased glucose with a typical ratio of CSF:plasma glucose of < 0.5, and often an elevated opening pressure of > 25 cm H20. However, atypical CSF findings are more common in HIV-associated TBM, including lower CSF protein, higher glucose levels, and lower CSF cell counts than in non-HIV-associated TBM.1,32,33 These atypical findings occur more commonly at CD4 T cell counts < 50 cells/μL.34 The absence of a CSF pleocytosis (< 5 cells/ mL) makes diagnosis especially challenging and has been described in up to 25 to 33% of HIV-infected TBM cases with CD4 T cell counts < 50 cells/μL.32,34 HIV-associated TBM patients may also present with normal CSF protein levels, and even completely normal CSF findings have been reported.14,35 CSF microscopy with Ziehl-Neelsson (ZN) staining for acidfast bacilli (AFB) is the test used most often worldwide for TB evaluation, but generally has poor sensitivity (roughly 10– 20%) in TBM and cannot be relied upon to rule out TBM. The sensitivity of microscopy varies depending on the CSF volume obtained, the skill of the technician, and the time spent reading a slide.16 In a small study from China of 29 patients with TBM, sensitivity of ZN staining was dramatically improved due to the detection of intracellular AFB using cytospin slides and pretreatment with a detergent (Triton X-100) on low volume (0.5 mL) CSF samples.36 These findings merit further study in a larger study population. Mycobacterium tuberculosis culture remains the gold standard test for TBM, and for phenotypic drug-susceptibility testing. However, even this gold standard is quite limited, as CSF MTB culture is slow, insufficiently sensitive (roughly 60– 70%) and often not available in resource-limited settings.37 Nucleic acid amplification tests (NAAT) can provide substantial improvements in sensitivity and specificity compared with microscopy and culture, but reported sensitivities vary widely (56–94%) and appear to be substantially lower in commercial assays compared with in-house assays, although comparison can be difficult.16,38 The Xpert MTB/RIF assay, a rapid, fully automated polymerase chain reaction- (PCR-) based assay (Cepheid, Sunnyvale, CA) has been endorsed by the World Health Organization (WHO) for TB diagnosis in resource-limited settings,39 but its use has primarily been studied on sputum specimens for pulmonary TB diagnosis.40,41 Several small studies have evaluated the Xpert MTB/RIF assay on CSF specimens for TBM diagnosis with Seminars in Neurology
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sensitivities ranging between 29–86%.42,43 In a South African study of 204 patients with meningeal-like illness, 87% of whom had HIV infection, the Xpert assay performed on CSF had a sensitivity of 62% and specificity of 95%; of note, sensitivity was markedly increased if CSF was centrifuged prior to testing (82% vs. 47%).44 At this juncture, NAAT-based testing is a useful diagnostic tool but still is not sufficiently sensitive to rule out TB. Other diagnostic tests for TBM include CSF adenosine deaminase (ADA) assays, interferon-gamma release assays (IGRAs) in both whole blood and CSF, and CSF lipoarabinomannan (LAM), which have been recently reviewed in depth elsewhere.16 In HIV-associated TBM, the sensitivity of CSF ADA is diminished compared with HIV-uninfected TBM cases, and CSF ADA is elevated in other infections, limiting its routine use for TBM diagnosis.45,46 Routine use of these tests in resource-limited settings is unlikely in the near future, due to limitations in diagnostic characteristics, laboratory infrastructure, and cost. For radiographic assessment of TBM, magnetic resonance imaging (MRI) is preferable to CT, as MRI better characterizes the typical findings of TBM, including brainstem involvement, leptomeningeal enhancement, and evidence of vascular and cranial nerve involvement.47,48 However, these radiographic findings are not specific to TBM, and may not be sufficient to exclude other coinfections in advanced HIV disease. CNS tuberculoma and TB abscess may be suspected based on brain or spinal cord imaging. The presence of CNS mass lesions in HIV-infected patients with TBM is not specific for tuberculoma; indeed, in one series of HIV/TBM cases, all of the brain masses identified were due to toxoplasmosis (confirmed on autopsy) in marked contrast to HIV-uninfected TBM cases.33 Brain or spinal cord biopsy can confirm the diagnosis of tuberculoma or abscess. AFB microscopy is insensitive in tuberculoma, but may have higher yield in CNS abscess.21 In cases of suspected CNS tuberculoma at CD4 T-cell counts < 200 cells/μL, testing for serum toxoplasma IgG, CSF toxoplasma PCR, and serum and CSF cryptococcal antigen can aid in ruling out other diagnoses. In patients with CNS lesions exhibiting mass effect, the decision to perform a lumbar puncture must be weighed against the risk of brainstem herniation. When available, CT scan is recommended prior to lumbar puncture in HIV-infected patients to identify patients with mass lesions at potential increased risk for herniation.49 Response to toxoplasmosis treatment can also aid in differentiating CNS toxoplasmosis from isolated CNS tuberculoma.
Treatment The treatment of drug-sensitive TB meningitis is standard four-drug therapy with isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin for 2 months, followed by 7 to 10 months of isoniazid and rifampin. Corticosteroids given during the first 6 to 8 weeks of TBM treatment have been shown in several randomized controlled trials (RCT) to reduce mortality in adults and children with TBM.4,50 In a double-blind, placebo-controlled RCT of TBM
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patients > 14 years of age, a subgroup analysis of 98 HIVinfected patients found no significant reduction in mortality in participants given dexamethasone versus placebo.4 The lack of a significant mortality reduction in this subgroup may be explained by several factors: median CD4 T-cell count was low (66 cells/μL), antiretroviral therapy was not given during therapy, and the number of HIV-infected patients enrolled was insufficient to find a significant difference in mortality in this subgroup analysis. However, corticosteroids were safe among the HIV-infected participants, and based on the overall reduction in mortality observed, corticosteroids should be administered in the treatment of HIV-associated TBM despite a lack of sufficient evidence in HIV-associated TBM, pending further study.50 Aspirin has been inconsistently shown to reduce mortality as an adjunct to TBM treatment in some trials; more data are needed to evaluate the role of aspirin in TBM.51,52 There are no RCTs establishing optimal TB treatment duration, but U.S. guidelines recommend 9 to 12 months to avoid TBM relapse.53 CNS tuberculomas and TB abscesses should also be treated for 9 to 12 months with the same anti-TB regimen as TBM. CNS TB abscesses are often resistant to antibiotic therapy and may require surgical excision for cure.29 Rifampin is essential for achieving optimal outcomes in drug-sensitive TBM, and significantly higher mortality rates have been reported in patients with rifampin monoresistance, as well as multidrug resistant (MDR) TBM.54,55 In addition, the fluoroquinolones moxifloxacin and levofloxacin both have in vitro activity against MTB and excellent CSF penetration,56,57 as does ethionamide.58 To evaluate optimized regimens with high CSF penetration, an open-label phase II RCT comparing high-dose, intravenous rifampin versus standard rifampin given with isoniazid and pyrazinamide for 2 weeks, with additional randomization to one of three arms: high-dose oral moxifloxacin versus low-dose oral moxifloxacin versus ethambutol, was conducted among 60 TBM patients > 14 years of age in Indonesia.59 The high-dose intravenous rifampin group had significantly higher plasma maximum concentrations and 6-hour, geometric mean area under the timeconcentration curve (AUC) measures, and higher CSF maximum concentrations than the standard dose rifampin group, without a significant increase in adverse events. Mortality was substantially lower with high-dose rifampin (35%) than standard-dose rifampin (65%). Only seven HIV-infected participants were enrolled. A nonrandomized Indian study also evaluated higher dose rifampin and quinolones, using levofloxacin, high-dose rifampin (900 mg), double-dose isoniazid (1200 mg), pyrazinamide, and ethionamide for 7 days in 65 HIV patients undergoing TBM treatment.60 Seven days of the experimental regimen was associated with an absolute mortality reduction of 21% at 12 months, compared with local historical controls. Of note, ART use was similar in the experimental (39%) and historical control (43%) arms. Future studies in HIV-infected TBM patients, as well as a larger ongoing trial comparing high-dose oral rifampin and levofloxacin to standard treatment International Standard Randomized Controlled Trial Number (ISRCTN) 61649292 will provide further information on this approach.61
Chamie et al.
Two challenges unique to HIV-associated TBM are drug interactions during cotreatment of HIV and TB, and the timing of ART therapy initiation in TBM patients. The most significant drug interactions in HIV-TB treatment occur between rifamycins and ART. Rifampin is a potent inducer of the cytochrome p450 isoenzyme, and it substantially reduces levels of boosted protease inhibitors (PIs); the two should not be coadministered. The nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz can be safely given with rifampin, and is the treatment of choice, along with two nucleoside reverse transcriptase inhibitors (NRTIs), for HIV-associated TB.62 For patients receiving a PI-based regimen, rifabutin may be used at 150 mg daily. Prior guidelines had recommended 150 mg every other day, but more recent data suggest that every other day dosing results in suboptimal rifabutin levels.62 The integrase inhibitor raltegravir has been shown to be safe and effective in achieving virologic suppression compared with efavirenz, during rifampin-containing TB treatment in a phase II trial.63 Doubling the dose of raltegravir from 400 mg twice daily to 800 mg twice daily may result in a reduced likelihood of developing integrase inhibitor resistance. One small phase I study of HIV-uninfected participants given the integrase inhibitor dolutegravir along with rifampin for 14 days, suggests that dolutegravir may be an additional option with rifampin, but further study is needed.64 Comprehensive guidance to drug–drug interactions between TB and HIV treatment is provided elsewhere.65 Several RCTs have shown that immediate initiation (< 2 wk after TB treatment initiation) of ART in HIV-associated pulmonary TB results in significantly reduced mortality compared with early ART (< 8 wk) initiation in patients with CD4 T cell counts
