History
Tuberculous meningitis (TBM) is often difficult to diagnose, as it presents subacutely and often without classic signs of meningitis.
Inquire about the patient’s medical and social history, including recent contact with patients with tuberculosis (TB). Elicit any known history of a positive result on the purified protein derivative (PPD) test, especially a recent conversion.
Determine if the patient has a history of immunosuppression from a known disease (especially HIV) or from drug therapy.
Check if the patient has a negative history for bacillus Calmette-Guérin (BCG) vaccination. BCG vaccination is known to be effective at preventing TB and TBM in children in particular. [61] Walker et al reported that BCG vaccination is partially protective against TB meningitis; therefore, a history of BCG vaccination or the presence of a BCG vaccination scar affords some degree of reassurance when considering a diagnosis of TBM (grade C). [19] In patients in whom TBM is suspected clinically, the diagnosis must be rigorously investigated, and a history of BCG vaccination does not rule out the diagnosis (grade C).
In an immunocompetent individual, TBM typically presents as an acute-to-subacute illness characterized by a prodrome of fever, headache, malaise, weight loss, drowsiness, and confusion over a period of approximately 2–3 weeks (although the duration of presenting symptoms may vary from 1 day to 9 months, with 55% presenting by 2 weeks). Only some patients have classic meningitis signs and symptoms initially, such as nuchal rigidity. The headache tends to progress over 1–2 weeks, after which vomiting and altered mental status occur, and finally obtundation, coma, and death if untreated. [57]
During the prodrome, patients often have a concurrent infection of the upper respiratory tract. As a result, TBM should be suspected in at-risk patients with respiratory tract signs and symptoms if fever and irritability or lethargy seem out of proportion to the respiratory pathology itself, or if they persist after the respiratory symptoms have improved. Fever and headache can be absent in 25% of patients, and malaise can be absent in as many as 60% of patients. Headache and mental status changes are much more common in elderly persons.
As TBM may result in strokes and seizures, a sudden onset of focal neurologic deficits, including monoplegia, hemiplegia, aphasia, and cranial nerve deficits may occur, particularly if the disease is more advanced at presentation. Tremor and, less commonly, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than in adults. Myoclonus and cerebellar dysfunction have also occurred.
Visual symptoms include visual impairment or blindness and, occasionally, abrupt onset of painful ophthalmoplegia. Ocular tuberculosis presents as a form of granulomatous uveitis. Delayed or wrong diagnosis may result in blindness. [20]
The occurrence of syndrome of inappropriate diuretic hormone secretion (SIADH) as well as Cerebral Salt Wasting occurs in > 50% of TBM patients. [59]
Children may present with cough, fever, vomiting (with or without diarrhea), poor feeding, weight loss, and irritability. [57]
Tuberculous spinal meningitis
Tuberculous spinal meningitis may manifest as an acute, subacute, or chronic form. The clinical picture in primary spinal meningitis is often characterized by myelopathy, with progressive ascending paralysis, eventually resulting in basilar (cranial) meningitis and associated sequelae. In some cases with acute onset, in addition to variable constitutional symptoms, patients develop acute paraplegia with sensory deficits and urinary retention. The clinical picture often mimics transverse myelitis or Guillain-Barré syndrome. The subacute form generally presents as myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia. A less virulent chronic form may mimic slowly progressive spinal cord compression or nonspecific arachnoiditis.
Tuberculous spondylitis
Tuberculous spondylitis is also known as Pott's disease or spinal caries. In endemic areas (eg, Asia and Africa), this condition still accounts for 30%–50% of all cases of compressive myelopathy resulting in paraplegia. Spinal TB also accounts for approximately 50% of all bone and joint TB cases. It usually presentes subacutely or chronically, with symptoms such as back pain, fever, radicular pain, and variable neurological deficits (eg, motor and sensory disturbances, changes in bowel and bladder function). In the lumbar region, tuberculous spondylitis may result in a psoas abscess that often calcifies. Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may occur if untreated.
Serous tuberculous meningitis and tuberculous encephalopathy
Two rare forms of TBM are serous: TB meningitis and TB encephalopathy. Serous TB meningitis is characterized by signs and symptoms of a mild meningitis with spontaneous recovery. TB encephalopathy usually occurs in young children with progressive primary TB; the presentation is that of reduced levels of consciousness with few focal signs and minimal meningism. Diffuse edema and white matter pallor with demyelination are found upon pathologic examination. The pathogenesis is uncertain but is presumed to be immune mediated. Diagnosis is important because anecdotal reports suggest a good response to corticosteroids.
Tuberculous radiculomyelitis
Tuberculous radiculomyelitis (TBRM) is a rare complication of TBM.
Physical Examination
Perform careful general, systemic, and neurologic examinations, looking especially for lymphadenopathy, papilledema, and tuberculomas during funduscopy, and meningismus. Look also for a bacille Calmette-Guerin (BCG) vaccination scar, as it is partially protective against tuberculous meningitis (TBM) (but does not necessarily rule out the diagnosis). [19]
Visual findings
Fundus examination may reveal papilledema, often related to increased intracranial pressure, and occasionally a retinal tuberculoma or a small grayish-white choroidal nodule, highly suggestive of TB. These lesions are believed to be more common in miliary TB than in other forms of TB. In children, fundus examination may reveal pallor of the disc. Examination may elicit visual impairment and/or cranial nerve palsies (III, IV, VI).
Neurological exam
Nuchal rigidity is variable, and often absent.
Depending on the stage of TBM on presentation, patients may have altered mental status, ranging from confusion to coma.
Cranial neuropathies are more common than in bacterial meningits, as TBM has a predilection for the skull base. The most common cranial nerves affect, in order of decreasing frequency, are, VI>III>IV>VII. [57] Less commonly, CNs II, VIII, X, XI, and XII are affected.
Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis.
Movement disorders, most commonly tremor, may be seen.
In children, where hydrocephalus is more common, signs of increased intracranial pressure may predominate, such as decreased level of consciousness, abducens nerve palsies, and bulging anterior fontanelle. [57]
Complications
Complications of tuberculous meningitis (TBM) include:
-
Hydrocephalus
-
Cranial nerve palsies
-
Visual impairment and blindness
-
Stroke (ischemic or hemorrhagic)
-
Seizures and epilepsy
-
Spinal TB
-
Tuberculous radiculomyelitis (TBRM)
-
Hyponatremia (eg, SIADH, CSWS)
-
Arachnoiditis
-
Tuberculoma formation
-
Permanent neurological disability
-
Death
Staging
The British Medical Research Council TBM grade has been in wide use since the 1940s, and since then was updated to include the GCS score. [58]
-
Stage I describes the early nonspecific symptoms and signs including apathy, irritability, headache, malaise, fever, anorexia, nausea, and vomiting, without any alteration in the level of consciousness (GCS 15).
-
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 (GCS 15 with focal deficits, or GCS 11–14 without focal deficits).
-
Stage III describes an advanced state with stupor or coma, dense neurological deficits, seizures, posturing, and/or abnormal movements (GCS < /= 10).
Prognosis is strongly associated with the clinical stage at diagnosis.
Uniform Tuberculous Meningitis Research Case Definition Criteria
The Uniform Tuberculous Meningitis Research Case Definition Criteria, described in an article by Marais et al in Lancet, [62] provides thorough, diagnostic criteria for TBM.
Table of TBM Criteria. (Open Table in a new window)
| 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. | |
Abbreviations: AFB, acid-fast bacilli; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; IGRA, interferon-γ release assay; MRI, magnetic resonance imaging; NAAT, nucleic acid amplification test; TB, tuberculosis; TBM, tuberculous meningitis; TST, tuberculin skin test; US, ultrasound.
-
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.
-
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).
-
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.
-
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. | |
What would you like to print?
- 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
- Show All
- Treatment
- Medication
- Media Gallery
- Tables
- References
