CNS TB refers to the clinical and pathological spectrum of TBM, spinal TB arachnoiditis and tuberculoma. The epidemiology of CNS TB varies by regional TB prevalence. In areas of high TB prevalence, CNS TB occurs more commonly among children and young adults, whereas TBM predominates and occurs more commonly in adults as reactivation disease in low-prevalence settings. In one retrospective Canadian series, 75% of CNS TB disease was adult TBM.190–192
TBM is the most severe and rapidly progressive form of TB, meaning suspected cases must be treated as a medical emergency. Young children (less than 5 years) and people with HIV are at greatest risk of TBM. Although classically, TBM is described as a slow progressive meningitis syndrome, 50% of people with TBM are ill for less than 2 weeks before diagnosis.193 TBM may have a prodrome of headache, malaise, fever and personality changes, followed by meningismus, cranial nerve palsies and confusion.194
Prior to the development of anti-TB therapy, TBM was universally fatal. Despite major advances in diagnosis and treatment, global mortality estimates for TBM remain high (20-40%), with up to 50% of survivors suffering permanent neurologic deficits and long-term disability.194–197 Unfavorable outcomes in TBM correlate with older age, immunosuppression, presence of hydrocephalus and/or vasculitis and more advanced clinical stage at time of presentation.193,198,199 Prognostic models have been developed for the prediction of unfavorable outcomes among adults (greater than 14 years of age) with TBM.198,200
Neurologic imaging in TBM can support the diagnosis; inform prognosis; and identify a need for neurosurgical intervention. Basal meningeal enhancement on contrast-enhanced CT has high specificity for TBM (greater than 90% in adults and children), further increased by additional findings of infarcts and hydrocephalus that may become more apparent in later-stage disease.194,201 Gadolinium-enhanced MRI of the brain provides improved identification of early disease by visualization of localized leptomeningeal disease, characterization of ischemia and early infarction and superior evaluation of cranial nerve and brain stem involvement, compared with CT. However, both CT and MRI lack diagnostic sensitivity. Typical findings may be less prominent or absent in 15-30% of children, those with early disease, and those with advanced HIV.202,203
Lumbar puncture should be performed when feasible as the preferred diagnostic test for TBM. Early in the disease, cerebrospinal fluid (CSF) measurements are often normal. With disease progression, opening pressure becomes elevated, with low glucose levels (less than 2.5 mmol per L), elevated protein (greater than or equal to 0.5 g per L) and a moderate pleocytosis with lymphocyte/mononuclear cell predominance (100-500 total white cells per mL).204 Identification of M. tuberculosis in CSF is the standard for definite diagnosis of TBM (Table 1). However, the paucibacillary nature of TBM limits the diagnostic yield of microbial tests. Large volume sampling (7 to 15 mL, 3 serial samples), concentration of samples, experienced laboratory-technician review and the inclusion of more gene targets in NAATs can maximize diagnostic yield.23,205–207 Based on the insensitivity of CSF microscopy and diagnostic delay of culture-based methods, NAAT testing should be performed if adequate volume of CSF is available to assist with rapid diagnosis.208,209 Among commercially available NAATs, GeneXpert ULTRA has the best-available evidence supporting high sensitivity and should be used when possible.32
3.5.2. TBM treatment
Clinical suspicion of TBM should be based upon presence of epidemiological risk factors and clinical features for TB, as well as relative suspicion of alternate diagnosis. Treatment started during early-stage TBM disease may decrease mortality to less than 10%.206,210–212
Good practice statement
In cases with high suspicion of TB meningitis, we suggest initiating empiric therapy immediately while awaiting diagnostic results, to reduce mortality and prevent complications.
An optimal anti-TB therapy regimen for TBM remains uncertain. Current guidelines from the American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America, National Institute for Health and Care Excellence, American Academy of Pediatrics and World Health Organization (WHO) recommend standard dose RMP and INH with pyrazinamide (PZA) during initial two-month intensive phase, with lack of consensus on the best fourth agent.213–218
Based on relatively low CNS penetration of RMP, a series of clinical trials have evaluated the clinical and pharmacokinetic outcomes of higher dose (“intensified”) RMP as part of intensive-phase regimens for TBM (in these studies high dose RMP was not given throughout full duration of treatment). Although published studies have not identified an optimal dose or conclusively demonstrated clinical benefit, there are now compelling and consistent findings for both RMP CNS-concentration response correlation and safety studies supporting use of higher-dose RMP regimens.219–226
We conditionally recommend using higher doses of rifampin (greater than 15 mg/kg/day orally, up to a maximum dose of 35 mg/kg/day orally or 20 mg/kg/day IV) along with standard dose isoniazid, pyrazinamide and ethambutol during the intensive phase treatment for drug-susceptible TB meningitis (poor evidence).
In the absence of clinical trial data regarding the optimal fourth drug in a TBM regimen, the American Pediatric Association and the WHO advise the use of streptomycin or ethionamide in place of ethambutol (EMB), based on low CNS penetration of EMB and difficulty monitoring EMB toxicity in children.227 Although fluoroquinolones have a favorable CNS-penetration profile, clinical trials evaluating their use as a fourth agent for TBM in adults and children have not shown benefit outside of drug-resistant disease and raise concern about adverse effects.228–231 Second-line drugs with favorable CNS-penetration profiles (linezolid, ethionamide) lack adequate quality clinical data to support standard use at this time.232,233,234,235,219
We conditionally recommend against using fluoroquinolone for TB meningitis unless there is a concern about drug resistance (poor evidence).
No clinical trials have directly assessed duration of anti-TB treatment for CNS TB. A review of TBM observational studies did not find increased relapse among those treated for 6 months.236 However, given concerns about variable CNS drug penetration and potential for significant harm from relapsed disease if undertreated, current American, British and WHO guidelines continue to recommend a minimum of nine months and up to 12 months of anti-TB therapy for all forms of drug-susceptible CNS-TB.190,214,217,237,238 Based on poor evidence for extended duration of therapy, if issues with anti-TB therapy tolerance occur, then continuation beyond 6 months should be reevaluated in consultation with an expert in TB.
We conditionally recommend, given the severity of disease and risk of morbidity with inadequate treatment of central nervous system TB, extending treatment to 9-12 months for drug-susceptible disease (poor evidence).
In addition to anti-TB therapy, measures to mitigate elevated intracranial pressure and prevent hydrocephalus and infarction are important. Adjunctive steroids have been shown to reduce short-term mortality of TBM but have not been demonstrated to reduce disabling neurologic defects or longer-term survival. 194,197,239,240 ( Table 2 Corticosteroid Dosing).
We strongly recommend that all individuals presenting with TB meningitis receive a course of corticosteroids guided by disease severity (good evidence).
Several small controlled trials using aspirin (ASA), in addition to anti-TB therapy and corticosteroids, for TBM in both adults and children have suggested potential benefit (reduction of new infarctions and decrease in 60-day mortality) without added harm. Studied ASA regimens ranged from 81 to 1000 mg per day for the initial 1-2 months of treatment.241,242 Given the preliminary nature of these findings, recommendation for the addition of ASA to TBM treatment cannot be made at this time but may change with results from pending studies in both adults and children.243,244
Several large clinical studies evaluating TBM treatment are currently underway (INTENSE-TBM, HARVEST, and TBM-KIDS) and guideline recommendations will be refined as data from the trials become available.219–221
3.5.3. Tuberculoma and spinal TB arachnoiditis
Both tuberculoma and spinal TB arachnoiditis may occur with TBM. Spinal disease (often clinically occult) has been reported in up to 76% of TBM cases and brain tuberculomas in approximately 10% of TBM cases, with even higher prevalence in people with HIV.195,242,245 When presenting in isolation, symptoms are more typically subacute and neurologic in nature relating to mass effect (headache and/or focal neurologic signs of hemiplegia, nerve root compression and spinal cord syndromes), in contrast to the more acute infectious and inflammatory presentation of TBM.191,212
Contrast-enhanced CT and gadolinium-enhanced MRI can demonstrate solitary or multiple ring-enhancing lesions suggestive of tuberculoma in the brain and spinal cord. MRI offers improved visualization of spinal TB arachnoiditis and associated epidural space infection, myelitis, spondylitis and nerve root involvement.201 When possible, a tissue/microbiologic diagnosis should be pursued prior to treatment initiation (Table 1). If empiric therapy is commenced, it is important to note that paradoxical clinical (30%) and radiographic (65%) worsening during the first 6 months of effective therapy is common and confounds assessment of treatment response. Follow-up neuroimaging should be used primarily to evaluate for alternate diagnoses and complications, and be interpreted in concert with clinical and microbiological information.246
3.5.4. Tuberculoma treatment
There are no controlled trials evaluating optimal management of either tuberculoma or TB arachnoiditis. Recommendations for treatment duration and adjunctive corticosteroids are extrapolated from observational and clinical trial data for TBM.246
Good practice statement
In cases of drug-susceptible tuberculoma and spinal arachnoiditis, 9-12 months of standard anti-TB therapy is suggested, given the severity of disease and risk of morbidity with inadequate treatment.
Extrapolating from other inflammatory parenchymal CNS diseases (ie, cancer) and limited observational data, corticosteroids may have a limited role for symptom relief in the context of tuberculomas with vasogenic edema-associated neurologic symptoms.190
We conditionally recommend against universal use of adjunctive corticosteroids in cases of central nervous system tuberculoma without meningitis (poor evidence).
The Tuberculosis Meningitis International Research Consortium has compiled a collection of peer-reviewed, open-access expert reviews to address the rapidly evolving field of CNS-TB diagnosis and management (https://wellcomeopenresearch.org/collections/tbmeningitis). A comprehensive review of the management of complications associated with CNS-TB has also recently been by published by Donovan et al.247
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