Diagnostic Considerations
Unlike many forms of bacterial meningitis, tuberculous meningitis (TBM) is often difficult to diagnose, as initial symptoms are generally subacute and often nonspecific (although occasionally may present more acutely), and neck stiffness is typically not present in the early course of the illness. [51, 57] The duration of presenting symptoms may vary from 1 day to 9 months (on average, 2 weeks), and the prodrome is usually nonspecific, including headache, vomiting, photophobia, and fever. Meningismus may also occur. Unlike most of forms of bacterial meningitis, TBM is more likely to cause neurological deficits, including altered mental status, personality changes, and, as the lesions may result in neurovascular compression, cranial nerve deficits and infarcts. [51]
The clinician should have a high index of clinical suspicion if a patient presents with a clinical picture of subacute meningitis or encephalitis (particularly if > 5 days) in high-risk groups or in endemic areas. There is frequently diagnostic uncertainty when differentiating TBM from other meningoencephalitides, such as partially treated meningitis. TBM must be differentiated not only from other forms of acute and subacute meningitis but also from conditions such as viral infections and cerebral abscesses. High-risk groups include patients from endemic areas (eg, from Africa or Asia), those with HIV infection or alcohol or drug abuse, homeless persons, people in correctional facilities, residents of long-term care facilities, and malnourished patients.
Diagnostic confusion often exists between TBM and other meningoencephalitides, in particular partially treated meningitis. Acid-fast bacilli are seen in only approximately 25% of cerebrospinal fluid (CSF) smears. CSF culture is time-consuming and may not yield positive results. Recent advances have sought to improve smear sensitivity, such as by nucleic acid amplification tests. [59]
In one study, 5 features independently predicted the diagnosis of TBM:
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Prodromal stage lasting 7 days or longer
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Optic atrophy on fundal examination
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Focal deficit
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Abnormal movements
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CSF leukocytes comprising < 50% polymorphonuclear leukocytes
Validation of these criteria on another set of 128 patients revealed a sensitivity of 98.4% if at least one feature was present and a specificity of 98.3% if 3 or more were present. This simple rule is useful for physicians working in regions where TB is prevalent.
TBM must be differentiated not only from other forms of acute and subacute meningitis but also from conditions such as viral infections and cerebral abscess. The radiological differential diagnosis, which should take into account HIV status, includes cryptococcal meningitis, cytomegalovirus encephalitis, sarcoidosis, meningeal metastases, and lymphoma.
TB of any form is a notifiable disease in the United States. Mandatory notification of the appropriate health department is the responsibility of the physician who makes the diagnosis.
TBM should be considered in the differential diagnosis in any high-risk patient presenting with fever and a change in sensorium. Other problems to be considered include:
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Infections: Fungal (cryptococcal, histoplasmosis, actinomycetic, nocardiasis, Arachnia infection, candidiasis, coccidiosis); spirochetal (Lyme disease, syphilis, leptospirosis); bacterial (partially treated bacterial meningitis, brain abscess, listeriosis, Neisseria species infection, tularemia); brucellosis; parasitic (cysticercosis, acanthamebiasis, angiostrongylosis, toxoplasmosis, trypanosomiasis); and viral (herpes, mumps, retrovirus, enterovirus [in hypogammaglobulinemics])
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Acute hemorrhagic leukoencephalopathy
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Behçet disease
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Chemical meningitis
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Chronic benign lymphocytic meningitis
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Neoplastic: metastatic, lymphoma
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Systemic lupus erythematosus
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Vascular: Multiple emboli, subacute bacterial endocarditis, sinus thrombosis
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Vasculitis: Isolated central nervous system (CNS) angiitis, systemic giant cell arteritis, Wegener granulomatosis, polyarteritis nodosa, noninfectious granulomatosis, lymphomatoid granulomatosis
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Vogt-Koyanagi-Harada syndrome
Differential Diagnoses
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SLE vasculitis
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Tuberculoma is the round gray mass in the left corpus callosum. The red meninges on the right are consistent with irritation and probable meningeal reaction to tuberculosis. Courtesy of Robert Schelper, MD, Associate Professor of Pathology, State University of New York Upstate Medical University.
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MRI of the brain in a patient with TBM and concurrent AIDS (with 8 CD4 cells/mL). The patient's history includes previous interstitial pneumonia, pericarditis, adnexitis, and a positive result on the Mantoux test. His recent history includes fever, headache, strabismus, diplopia, and cough. Laboratory studies revealed hyponatremia. CSF findings strongly suggested a diagnosis of tuberculous meningitis, and culture results were positive for Mycobacterium tuberculosis. The MRI shows the presence of exudates, in and over the sellar seat, with parasellar extension to the left, with irregular margins, marked heterogenous enhancement, and compression of the optic chiasm and third ventricle. Presence of nodular areas with marked enhancement of basal cisterns is an expression of basilar leptomeningeal involvement. This patient died after 2 months of inadequate antituberculosis therapy (due to poor compliance). Courtesy of Salvatore Marra, AIDS Imaging (http://members.xoom.it/Aidsimaging).
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Fluorochrome for tuberculosis. Fluorescent staining procedures are used with auramine O or auramine-rhodamine as the primary fluorochrome dye. After decolorization with an acid-alcohol preparation, the smear is counterstained with acridine orange or thiazine red and scanned at a lower magnification with a 25X dry objective fluorescent microscope. Acid-fast bacilli appear as yellow-green fluorescent thin rods against a dark background. Courtesy of Robert Schelper, MD, Associate Professor of Pathology, State University of New York Upstate Medical University.
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Hematoxylin and eosin stain showing caseation in tuberculosis. Courtesy of Robert Schelper, MD, Associate Professor of Pathology, State University of New York Upstate Medical University.
Tables
| Clinical criteria (maximum category score = 6) | |
| Symptom duration of > 5 d | 4 |
| Systemic symptoms suggestive of TB (≥ 1): weight loss/(poor weight gain in children), night sweats, or persistent cough > 2 wk | 2 |
| History of recent close contact with an individual with pulmonary TB or a positive TST/IGRA in a child aged < 10 y | 2 |
| Focal neurological deficit (excluding cranial nerve palsies) | 1 |
| Cranial nerve palsy | 1 |
| Altered consciousness | 1 |
| CSF criteria (maximum category score = 4) | |
| Clear appearance | 1 |
| Cells: 10–500/µL | 1 |
| Lymphocytic predominance (> 50%) | 1 |
| Protein concentration > 1 g/L | 1 |
| CSF to plasma glucose ratio of < 50% or an absolute CSF glucose concentration < 2.2 mmol/L | 1 |
| Cerebral imaging criteria (maximum category score = 6) | |
| Hydrocephalus (CT and/or MRI) | 1 |
| Basal meningeal enhancement (CT and/or MRI) | 2 |
| Tuberculoma (CT and/or MRI) | 2 |
| Infarct (CT and/or MRI) | 1 |
| Precontrast basal hyperdensity (CT) | 2 |
| Evidence of tuberculosis elsewhere (maximum category score = 4) | |
| Chest radiograph suggestive of active TB (excludes miliary TB) | 2 |
| Chest radiograph suggestive of miliary TB | 4 |
| CT/MRI/US evidence for TB outside the CNS | 2 |
| AFB identified or Mycobacterium tuberculosis cultured from another source (ie, sputum, lymph node, gastric washing, urine, blood culture) | 4 |
| Positive commercial M. tuberculosis NAAT from extraneural specimen | 4 |
| Exclusion of alternative diagnoses: An alternative diagnosis must be confirmed microbiologically, serologically, or histopathologically. | |
| Definite TBM: AFB seen on CSF microscopy, positive CSF M. tuberculosis culture, or positive CSF M. tuberculosis commercial NAAT in the setting of symptoms/signs suggestive of meningitis; or AFB seen in the context of histological changes consistent with TB brain or spinal cord together with suggestive symptoms/signs and CSF changes, or visible meningitis (on autopsy). | |
| Probable TBM: total score of ≥ 12 when neuroimaging available or total score of ≥10 when neuroimaging unavailable. At least 2 points should either come from CSF or cerebral imaging criteria. | |
| Possible TBM: total score of 6–11 when neuroimaging available, or total score of 6–9 when neuroimaging unavailable. | |
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- Overview
- Presentation
- DDx
- Workup
- Approach Considerations
- Serum and Urine Chemistry Studies
- Tuberculin Skin Testing
- Lumbar Puncture
- Dot-Immunobinding Assay
- Chest Radiography
- Brain and Spinal Imaging
- Angiography
- Electroencephalography
- Brainstem Auditory Evoked Response Testing
- Use of Neurochemical Markers
- Histologic Findings
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