eMedicine Specialties > Neurology > Neurological Infections

Tuberculous Meningitis: Differential Diagnoses & Workup

Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
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Updated: Dec 4, 2008

Differential Diagnoses

Other Problems to Be Considered

Tuberculous meningitis (TBM) must be differentiated from other forms of acute and subacute meningitis, viral infections, and cerebral abscess. The radiological differential diagnosis includes cryptococcal meningitis, cytomegalovirus encephalitis, sarcoidosis, meningeal metastases, and lymphoma.

Diagnostic confusion often exists between TBM and other meningoencephalitides. In one study, 5 features were independently predictive of the diagnosis of TBM (P <.007), including (1) prodromal stage lasting 7 days or longer, (2) optic atrophy upon fundal examination, (3) focal deficit, (4) abnormal movements, and (5) CSF leukocytes comprising less than 50% polymorphs. 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 continues to be an important disease and should be considered in the differential diagnosis in any patient presenting with fever and a change in sensorium.

• Infections
  • Fungal - Cryptococcus, 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
  • Viral - Herpes, mumps, retrovirus (HIV type 1, human T-lymphotropic virus type 1), enterovirus infection (in hypogammaglobulinemics)
• Acute hemorrhagic leukoencephalopathy
• Behçet disease
• Chemical meningitis
• Chronic benign lymphocytic meningitis
• Neoplastic - Metastatic, lymphoma
• Systemic lupus erythematosus
• Vascular - Multiple emboli, subacute bacterial endocarditis, sinus thrombosis
• Vasculitis - Isolated CNS angiitis, systemic giant cell arteritis, Wegener granulomatosis, polyarteritis nodosa, noninfectious granulomatosis, lymphomatoid granulomatosis
• Vogt-Koyanagi-Harada syndrome

Workup

Laboratory Studies

• Complete blood cell count
• Erythrocyte sedimentation rate
• Electrolytes: Mild-to-moderate hyponatremia is present in roughly 45% of patients, in some cases constituting a true SIADH.
• Serum glucose level
• BUN and creatinine levels
• Serology for syphilis
• Complementation test or its equivalent for fungal infections
• Urinalysis
• CSF analysis (also see Procedures)
  • Cell counts, differential count, cytology
  • Glucose level, with a simultaneous blood glucose level
  • Protein level
  • Acid-fast stain, Gram stain, appropriate bacteriologic culture and sensitivity, India ink stain
  • Cryptococcal antigen and herpes antigen testing
  • Culture for M tuberculosis (50-80% of known cases of TBM yield positive results)
  • Polymerase chain reaction (PCR): Results imply that PCR can provide a rapid and reliable diagnosis of TBM, although false-negative results potentially occur in samples containing very few organisms (<2 colony forming units per mL).
  • Syphilis serology
• Tuberculin test: Negative results from the purified protein derivative test do not rule out TB; if the 5-tuberculin test skin test result is negative, repeat the test with 250-tuberculin test. Note that this test is often nonreactive in persons with TBM.
  • Despite its many limitations, tuberculin skin testing, by necessity, remains in widespread use. The CDC, the American Thoracic Society, and the Infectious Disease Society of America have updated the guidelines, and they are quite useful in practice.¹⁴
  • These guidelines stress that in general, one should not obtain a tuberculin skin test unless treatment would be offered in the event of a positive test result. Cutoff points for induration (5, 10, or 15 mm) for determining a positive test result vary based on the pretest category into which the patient falls. While this approach might decrease the specificity of the test, it increases the sensitivity for capturing those at highest risk for developing the disease in the short term.

Imaging Studies

• Chest radiography posteroanterior and lateral views may reveal hilar lymphadenopathy, simple pneumonia, infiltrate, fibronodular infiltrate/cavitation, and/or pleural effusion/pleural scar.
• CT scanning and MRI of the brain reveal hydrocephalus, basilar meningeal thickening, infarcts, edema, and tuberculomas (see Media file 2).
  • The characteristic CT finding is a nodular, enhancing lesion with a central hypodense lesion.¹⁵ Contrast enhancement is essential. Early stages are characterized by low-density or isodense lesions, often with edema out of proportion to the mass effect and little encapsulation. At a later stage, well-encapsulated tuberculomas appear as isodense or hyperdense lesions with peripheral ring enhancement.
  • Srikanth et al concluded that CT features of TBM in elderly patients were few, atypical, and noncontributory for diagnosis, probably because of age-related immune senescence.¹⁶ Hence, strong clinical suspicion and correlation with laboratory findings is necessary for early diagnosis.
  • Although CT scanning and MRI lack specificity, they help in monitoring complications that require neurosurgery.
  • MRI and CT scanning are critical for the diagnosis of TBRM, revealing loculation and obliteration of the subarachnoid space along with linear intradural enhancement.
  • For tuberculous spinal meningitis, MRI shows that the subarachnoid space is obliterated, with focal or diffusely increased intramedullary signal on T2-weighted images and variable degrees of edema and mass effect.
    • With gadolinium, contrast enhancement is often seen surrounding the spinal cord and the roots. The nerve roots may appear clumped and show contrast enhancement, secondary to inflammation and edema, depending on the degree of involvement.
    • Rarely, tuberculomas occur in the spinal cord, and they may occur on the surface of the cord, as dural lesions, or deep inside in an intramedullary location.
    • Less frequently, intramedullary tuberculous abscesses have been reported.
  • Tuberculous spondylitis neuroimaging invariably reveals bone destruction and fragmentation with involvement of the disk space and calcified paravertebral mass.
    • MRI has an accuracy of 94% in vertebral osteomyelitis. It reveals hypointense T1-weighted areas in the vertebral bodies, alternating with areas of hyperintense T2-weighted signal in the disk spaces and the paravertebral soft tissue. Infected bone and disk often reveal contrast enhancement.
    • CT scanning is superior to MRI in detecting psoas abscess calcification that, when present, strongly raises the suspicion of a tuberculous etiology. Epidural deposits are best shown by MRI, which reveals a soft-tissue mass that is isointense to hypointense compared with the spinal cord on T1-weighted images and hyperintense on proton-density and T2-weighted images and has variable degrees of contrast enhancement.
    • Tuberculous myelitis and radiculomyelitis are predominantly diseases of the thoracic spinal cord. Most spinal cord lesions appear hyperintense on T2-weighted images and isointense or hypointense on T1-weighted images. MRI findings in patients with spinal cord TB have both diagnostic and prognostic significance. Cord atrophy or cavitation and the presence of syrinx on MRIs may be associated with a poor outcome.¹
• Perform magnetic resonance angiography and venography if indicated.
  • Findings on conventional 4-vessel angiography and magnetic resonance angiography most typically have included evidence of hydrocephalus, narrowing of the arteries at the base of the brain, and narrowed or occluded small and medium-sized arteries.
  • Imaging studies, both CT scanning and MRI, are performed with and without enhancement, as long as the renal function of the patient is not compromised.
  • Basal cisterns often enhance strikingly, corresponding to the thick exudate that is observed pathologically. The quadrigeminal cistern, interpeduncular fossa, ambient cistern, and chiasmatic region are particularly involved, owing to associated arachnoiditis. Meningeal enhancement is more common in HIV-infected patients.
  • Contrast enhancement further delineates focal parenchymal and space-occupying lesions, with or without associated hydrocephalus.
• Skull radiography may reveal evidence of increased intracranial tension in children, in the form of sutural diastasis. During follow-up of patients with TBM, intracranial calcification may be evident.
  • Calcification occurs in 2 main sites, (1) more commonly in the basal meninges and, (2) to a lesser extent, within brain substance.
  • Calcification is generally in the sellar region, either as a single lesion or as a cluster of small calcifications. These calcifications sometimes harbor tubercle bacilli, which may be responsible for a relapse of the disease.

Other Tests

• The diagnosis of TBM cannot be made or excluded on the basis of clinical findings. Tuberculin testing is of limited value. Variable natural history and accompanying clinical features of TBM hinder the diagnosis. Ziehl-Neelsen staining lacks sensitivity, and culture results are often too late to aid clinical judgment. Semiautomated radiometric culture systems, such as the Bactec 460, and automated continuously monitored systems have reduced culture times. Newer methods involving amplification of bacterial DNA by PCR and comparable systems have not been assessed completely and may not be suitable for laboratories in developing countries with limited resources. The duration of chemotherapy for TBM is unclear, and the benefits of adjuvant corticosteroids remain in doubt. Death may occur as a result of missed diagnoses and delayed treatment.
• In one study, EEG findings were abnormal in 24 patients. The EEG abnormalities included diffuse theta-to-delta slowing in 22 patients, intermittent rhythmic delta activity in the frontal region in 15 patients, right-to-left asymmetry in 5 patients, and epileptiform discharges in 4 patients. At the end of 3 months, 5 patients had died, while recovery was poor in 13 patients, partial in 3, and complete in 11. EEG findings correlated with severity of meningitis and degree of coma; outcome at 3 months was assessed using the Barthel index score.
• In the same study, brainstem auditory evoked potential abnormalities were observed in more than 50% of patients with TBM. Motor and somatosensory evoked potentials may be helpful in objective documentation of respective motor and sensory functions in patients with TBM and altered sensorium.
• A dot-immunobinding assay (Dot-Iba) has been standardized to measure circulating antimycobacterial antibodies in CSF specimens for the rapid laboratory diagnosis of TBM.¹⁷
  • Specific CSF immunoglobulin G antibody to M tuberculosis from a patient with culture-proven TBM was isolated and coupled with activated cyanogen bromide-Sepharose 4B. A 14-kd antigen present in the culture filtrates of M tuberculosis was isolated by immunosorbent affinity chromatography and used in the Dot-Iba to quantitate specific antimycobacterial antibodies. The Dot-Iba gave positive results in all 5 patients with culture-proven TBM; no false-positive results were obtained from CSF specimens from patients with partially treated pyogenic meningitis.
  • In the opinion of Sumi et al, the Dot-Iba developed in their laboratory is a simple, rapid, and specific method and, more importantly, is suited for the routine application in laboratories with limited resources. This is not yet available for routine use, and proof of its utility requires further studies.
• Use of neurochemical markers has been investigated in patients with aseptic meningitis or TBM.
  • CSF levels of amino acids, nitrite (a metabolite of nitric oxide), vitamin B-12, and homocysteine were quantitated in both groups of patients.
  • Levels of excitatory amino acids aspartic acid and glutamic acid, GABA, glycine, and tryptophan all were increased significantly in both groups, whereas levels of taurine were decreased and levels of phenylalanine were increased only in patients with TBM.
  • Levels of nitrite and its precursor arginine were significantly higher in patients with TBM, whereas they were unchanged in patients with aseptic meningitis.
  • Levels of homocysteine were increased significantly, and levels of vitamin B-12 decreased only in patients with TBM, whereas these levels were unchanged in patients with aseptic meningitis. This indicates that patients with TBM are particularly prone to vitamin B-12 deficiency, resulting in increased levels of homocysteine and free radicals, showing the importance of these biological markers in the development and design of therapeutic approaches.

Procedures

• For more information about CSF studies, see Lab Studies.
• Spinal tap carries some risk of herniation of the medulla in any instance when intracranial pressure is increased (eg, TBM), but if meningitis is suspected, the procedure must be performed regardless of the risk, using suitable precautions and obtaining informed consent before the procedure.
  • Use manometrics to check CSF pressure. Typically, the pressure is higher than normal.
  • Inspect the CSF visually and note its gross appearance. It typically is clear or slightly turbid. If the CSF is left to stand, a fine clot resembling a pellicle or cobweb may form. This faintly visible "spider's web clot" is due to the very high level of protein in the CSF (ie, 1-8 g/L, or 1000-8000 mg/dL) typical of this condition.
  • Hemorrhagic CSF also has been recorded in proven cases of TBM; this is attributed to fibrinoid degeneration of vessels resulting in hemorrhage (Smith, 1947).
  • Abnormalities in the CSF depend on a tuberculin reaction within the subarachnoid space. Acellular CSF has been reported in elderly patients and patients who are HIV positive.
  • CSF typically has an elevated protein level, marked hypoglycorrhachia, and a pleocytosis, initially polymorphs then lymphocytes.
    • In adults, mean the WBC count averages around 223 cells/µL (range, 0-4000 cells/µL), while the proportion with neutrophilic pleocytosis (>50% neutrophils) averages 27% (range, 15-55%) and the proportion with normal cell count averages 6% (range, 5-15%). In children, these numbers are 200 cells/µL (range, 5-950 cells/µL), 21% (range, 15-30%), and 3% (range, 1-5%), respectively.
    • The mean protein level in adults averages 224 mg/dL (range, 20-1000 mg/dL), and in children it is 219 mg/dL (range, 50-1300 mg/dL). The proportion with normal a protein content averages 6% (range, 0-15%) for adults and 16% (range, 10-30%) for children. The proportion with depressed glucose levels ( <45 mg/dL or 40% of serum glucose) averages 72% (range, 50-85%) for adults and 77% (range, 65-85%) for children.
  • A positive smear result is present in an average of 25% (range, 5-85%) of adults and only 3% (range, 0-6%) of children, whereas the numbers with a positive CSF culture average 61% (range, 40-85%) and 58% (range, 35-85%) for adults and children, respectively. Failure to respond to treatment should prompt a search for fungal infections or malignancy.
  • For patients with HIV and/or immunosuppression, while the mean WBC count in the CSF is 230 cells/µL, as many as 16% of HIV-infected patients may have acellular CSF, compared with 3-6% of HIV-negative patients. Patients whose CSF samples are acellular may show pleocytosis if a spinal tap is repeated 24-48 hours later. The proportion who have neutrophilic pleocytosis of the CSF (>50% neutrophils) is 42% (range, 30-55%). While HIV-infected patients generally have a mean protein level of 125 mg/dL (range, 50-200 mg/dL), as many as 43% of these patients may have a normal CSF protein content. The proportion who have depressed CSF glucose levels (<45 mg/dL or 40% of serum glucose) averages around 69% (range, 50-85%). The number who have a positive CSF culture results averages 23%.
• Within a few days after commencement of anti-TB therapy, the initial mononuclear pleocytosis may change briefly in some patients to one of polymorphonuclear predominance, which may be associated with clinical deterioration, coma, or even death. This therapeutic paradox has been regarded by some authors as virtually pathognomonic of TBM. This syndrome is probably the result of an uncommon hypersensitivity reaction to the massive release of tuberculoproteins into the subarachnoid space.
• When CSF analysis offers no clues and the diagnosis remains elusive, a brain biopsy may be warranted under appropriate circumstances. This carries significant risks, however, including epidural hematoma and hydrocephalus.

Histologic Findings

The Ziehl-Neelsen stain uses the properties of the cell wall to form a complex that prevents decolorization by acid or alcohol. Fluorochrome tissue stains also can be helpful in the diagnosis of TBM (see Image 3).

Hematogenous spread leads to perivascular microscopic foci that form tubercles. These characteristically are associated with central caseation and epithelioid and giant cells. Gradually they enlarge to form numerous small macroscopic tuberculomas, which then may coalesce. In essence, tuberculomas are conglomerate caseous foci within the substance of the brain that develop from deep-seated tubercles (see Image 4).

Clinically silent single or multiple enhancing granulomata are observed in a significant minority of cases of TBM and in some cases of miliary TB without meningitis (Stevens, 1978).

Staging

• In 1948, the British Medical Research Council developed a method for staging the severity of the disease.
  • Stage I describes the early nonspecific symptoms and signs, including apathy, irritability, headache, malaise, fever, anorexia, nausea, and vomiting, without any alterations in the level of consciousness.
  • Stage II describes altered consciousness without coma or delirium but with minor focal neurological signs. Symptoms and signs of meningism and meningitis are present, in addition to focal neurological deficits, isolated CN palsies, and abnormal involuntary movements.
  • Stage III describes an advanced state with stupor or coma, severe neurological deficits, seizures, posturing, and/or abnormal movements.
  • Prognosis is related directly to the clinical stage at diagnosis.

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