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Tuberculosis is prevalent worldwide. One catastrophic manifestation of extrapulmonary tuberculosis is central nervous system (CNS) involvement, which can present as either tubercular meningitis (TBM), CNS tuberculoma, or spinal arachnoiditis. CNS tuberculosis (CNS-TB) may develop from hematogenous spread or the rupture of subependymal or meningeal tubercular foci. The condition carries the highest morbidity and mortality among all tuberculosis forms. Diagnosing CNS-TB poses challenges due to its paucibacillary nature and the limitations of conventional diagnostic methods. Clinical scoring systems exist but have flaws, emphasizing the need for a comprehensive approach, including history, examination, cerebrospinal fluid (CSF) analysis, and imaging. Though confirmatory evidence from CSF is difficult to obtain, molecular techniques like polymerase chain reaction offer valuable assistance. Epidemiological factors and extraneural infections can help identify patients with CNS-TB. CSF examination, including microscopy and culture, remains crucial. However, newer techniques like Xpert Mycobacterium tuberculosis/rifampin, loop-mediated isothermal amplification assay, and metagenomic sequencing show promise. Imaging, particularly magnetic resonance, is pivotal in detecting characteristic findings, such as basilar leptomeningeal enhancement and tuberculomas, aiding in timely and accurate diagnosis. This activity for healthcare professionals is designed to improve learners' competence in evaluating and treating CNS-TB. Participants gain a deeper understanding of the condition's pathophysiology, nuanced presentations, diagnostic approaches, and therapeutic strategies. Learners become prepared to collaborate effectively within an interprofessional team to enhance outcomes for patients with CNS-TB. Objectives: Identify the signs and symptoms indicative of central nervous system tuberculosis. Create a clinically guided diagnostic plan for an individual with suspected central nervous system tuberculosis. Implement a personalized management strategy for a patient diagnosed with central nervous system tuberculosis. Collaborate with the interprofessional team to educate, treat, and monitor patients with central nervous system tuberculosis to improve health outcomes. Access free multiple choice questions on this topic.

Mycobacterium tuberculosis is responsible for 5.9% of community-acquired central nervous system (CNS) infections worldwide.[1] Neurological or CNS tuberculosis (CNS-TB) may take 1 of 3 clinicopathological forms: Tubercular meningitis (TBM), affecting the CNS diffusely CNS tuberculoma, the focal type Spinal arachnoiditis, also called "tuberculous radiculomyelitis" (TBRM), involving only the spine [2] Of these forms, TBM predominates as it causes 70% to 80% of CNS-TB infections. TBM presents with subacute-to-chronic meningitis signs and symptoms, with disease severity commensurate with illness duration.[3] Diagnosis is fraught with challenges and is often delayed due to the varied and nonspecific presentations.[4] Besides the clinical clues, diagnostic indicators in cerebrospinal fluid (CSF) include mononuclear pleocytosis, low sugar values, and high protein concentrations. Identifying Mycobacterium tuberculosis (MTB) in CSF by staining, culture methods, and molecular analysis is confirmatory but may be challenging.[5] Advanced radiological imaging techniques are usually of great assistance in making presumptive diagnoses. Vasculitic infarcts, cranial nerve (CN) palsies, multiple neurological deficits, and hydrocephalus frequently complicate CNS-TB. A strong clinical suspicion is typically enough to start prompt antitubercular therapy. The 4-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol with adjunctive corticosteroid reduces morbidity and mortality. However, CNS-TB diagnosis and management may be complicated by drug resistance, immune reconstitution inflammatory syndrome (IRIS), and HIV coinfection. Treatment efficacy depends upon the timing. Multiple factors determine the prognosis, the most important being the TBM clinical stage at initial presentation. Untreated or unrecognized TBM may cause death within 5 to 8 weeks of disease onset. Normal Protective Barriers of the Central Nervous System

Advanced radiological imaging techniques are usually of great assistance in making presumptive diagnoses. Vasculitic infarcts, cranial nerve (CN) palsies, multiple neurological deficits, and hydrocephalus frequently complicate CNS-TB. A strong clinical suspicion is typically enough to start prompt antitubercular therapy. The 4-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol with adjunctive corticosteroid reduces morbidity and mortality. However, CNS-TB diagnosis and management may be complicated by drug resistance, immune reconstitution inflammatory syndrome (IRIS), and HIV coinfection. Treatment efficacy depends upon the timing. Multiple factors determine the prognosis, the most important being the TBM clinical stage at initial presentation. Untreated or unrecognized TBM may cause death within 5 to 8 weeks of disease onset. Normal Protective Barriers of the Central Nervous System The CNS is shielded from potentially harmful blood-borne bacteria by 2 vascular barriers: the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB). The BBB, primarily consisting of brain microvascular endothelial cells, regulates the passage of substances between the blood and CNS with tight junctions and specialized transport mechanisms. Supporting elements like pericytes and astrocytes also play crucial roles in maintaining BBB integrity. In contrast, the BCSFB is formed by choroid plexus epithelial cells and the arachnoid membrane, similarly employing tight junctions to control the exchange between blood and CSF. However, in vitro and animal models have shown that MTB can invade brain endothelial cells by rearranging cellular actin molecules. The MTB gene Rv0931c is implicated in promoting CNS infection by facilitating bacillary endothelial adhesion. MTB may also exploit the "Trojan horse" mechanism, utilizing infected macrophages and neutrophils to traverse the BBB.[6]

MTB is the organism responsible for CNS-TB. This alcohol and acid-fast bacillus may be visualized microscopically using the Ziehl-Neelsen, auramine-rhodamine, and Kinyoun stains. The etiological contribution of the other 4 Mycobacterium species in causing CNS-TB has not been established. Humans are the only known MTB hosts or reservoirs. Infection is primarily acquired through airborne aerosols from infected individuals.

Around 25% to 30% of the human population is infected with MTB. CNS-TB is reported in 1% to 2% of individuals with active tuberculosis.[7] CNS-TB accounts for 5% to 8% of extrapulmonary tuberculosis (EPTB) cases in immunocompetent hosts. Approximately 70% to 80% of CNS-TB cases present as TBM.[8] Tuberculomas are seen mostly in India and parts of Asia and may account for 20% to 30% of all intracranial space-occupying lesions.[9] An estimated 9,272 CNS-TB cases were diagnosed in the U.S. in 2016.[10] Since 2010, the incidence of tuberculosis has fallen by 2% to 3% every year, especially in 2020, probably due to the pandemic mitigation efforts, travel restrictions, or delayed or missed tuberculosis diagnoses.[11] However, the incidence of reported tuberculosis rose by 9.4% between 2020 and 2021.[12] Despite the diagnostic and treatment advances, CNS–TB still carries a mortality rate of 15% to 40%, especially in children.[13]

The 3 CNS-TB forms develop by different mechanisms. Understanding each condition's pathophysiology, explained below, is key to diagnosis. Tuberculous Meningitis CNS-TB may arise from hematogenous MTB dissemination following a primary lung infection (pulmonary tuberculosis or PTB) or late disease reactivation.[14] Meningeal or ependymal seeding results from this spread, forming multiple small granulomatous foci or tubercles (Rich foci) that may proliferate, coalesce, caseate, and rupture into the subarachnoid space before the onset of meningitis. Free bacilli produce an intense, cytokine-mediated host inflammatory response, leading to the following: Leptomeningitis, ependymitis, choroid plexitis, encephalitis, and pachymeningitis with basal and opticochiasmatic arachnoiditis (OCA) Vasculitis with endarteritis and infarcts Hydrocephalus secondary to disturbed CSF flow and absorption The extensive exudative arachnoiditis at the brain's base and the optic chiasma entraps multiple CNs in the area, including the abducens, optic, oculomotor, and trochlear. Arteritis and phlebitis result in vasculitic infarcts due to arterial vasospasm, thrombosis, or hemorrhage.[15] The disparate inflammatory response in individuals with TBM is thought to be due to human genetic polymorphisms in the leukotriene A4 hydrolase gene and toll-interleukin-1 receptor domain.[16] Inflammation can spread to the basal cisterns in many patients symptomatic for at least 3 weeks, disrupting CSF circulation and absorption and producing communicating hydrocephalus[17] Obstructive hydrocephalus occurs, though rarely, due to ependymitis-induced narrowing of the cerebral aqueduct or compression by brainstem tuberculoma in the 4th ventricle. Tuberculoma Deep-seated tubercular granulomatous foci acquired during initial bacteremia may coalesce and develop into conglomerated caseous masses called "tuberculomas" without producing meningitis. Often, tuberculomas may be present as clinically silent single or multiple lesions in patients with TBM and detected on brain imaging. Tuberculomas may form tubercular abscesses in immunosuppressed individuals. Spinal cord tuberculoma may form at any cord level through similar mechanisms or by local extension from nearby tubercular spondylitis. Spinal Arachnoiditis

Deep-seated tubercular granulomatous foci acquired during initial bacteremia may coalesce and develop into conglomerated caseous masses called "tuberculomas" without producing meningitis. Often, tuberculomas may be present as clinically silent single or multiple lesions in patients with TBM and detected on brain imaging. Tuberculomas may form tubercular abscesses in immunosuppressed individuals. Spinal cord tuberculoma may form at any cord level through similar mechanisms or by local extension from nearby tubercular spondylitis. Spinal Arachnoiditis Spinal arachnoiditis may arise as a result of previous TBM or vertebral osteomyelitis. The caseating inflammation may progress over weeks to months, leading to nerve root clumping or cord encasement (partial/total) by the thick gelatinous exudate or fibrous mass.

Histologically, the thick inflammatory meningeal exudate is granulomatous, with epithelioid macrophages, Langhans' giant cells, lymphocytes, plasma cells, and fibroblasts (see Image. Tuberculous Meningitis Histopathology). Tuberculomas are bigger encapsulated epithelioid granulomas with similar pleocytosis arranged in layers but a necrotic caseous center without pus. A tuberculous abscess has a thick wall with a liquefied pus core containing viable MTB bacilli.

The different CNS-TB forms produce various manifestations. The historical and physical features of each type are explained below. Tuberculous Meningitis Patients with TBM often present with a subacute, progressive febrile illness beginning with a prodrome of constitutional symptoms, including lassitude, malaise, night sweats, and intermittent headaches. A well-defined meningitic phase is observed in the following fortnight or more. This phase includes protracted headaches, vomiting, personality changes, confusion, and meningismus symptoms. Patients with TBM may deteriorate rapidly, developing varying degrees of confusion and coma. Seizures, multiple CN deficits, focal neurological impairments, and stroke syndromes may supervene. Children may have prominent irritability, vomiting, and focal or generalized convulsions. Individuals with untreated TBM may not survive beyond 5 to 8 weeks of illness. CN palsies are seen in 20% to 30% of patients with TBM, mostly involving CN VI.[18] OCA with blindness is a significant TBM complication.[19] Tuberculoma This CNS-TB manifestation should be included in the differential diagnosis of space-occupying lesions in young individuals. The usual symptoms include headaches, seizures, progressive neurological deficits, and papilledema with or without meningitis. Spinal Arachnoiditis Individuals with this condition present with radiculomyelopathy secondary to nerve root entrapment and cord encasement due to severe arachnoiditis at single or multiple levels. Patients may complain of radicular pain, hyperesthesia, flaccid paralysis, and urinary or stool incontinence. Cord infarction may occur due to anterior spinal arteritis and thrombosis (see Image. Pott Spine). Atypical Presentations CNS-TB may manifest in 10% to 30% of adult patients with miliary tuberculosis. The condition arises from hematogenous MTB dissemination, with immunocompromised patients being the most vulnerable. The brain parenchyma may show multiple scattered tiny granulomatous foci, which may or may not show ring enhancement.[20] TBM may also manifest as progressive cognitive dysfunction or psychosis in rare cases. The condition may likewise mimic acute encephalitis or typical pyogenic meningitis. Atypical cases may present with florid cranial polyneuropathy or hydrocephalus complications that precede meningitis signs.[21] Tuberculous Meningitis and HIV Infection

TBM may also manifest as progressive cognitive dysfunction or psychosis in rare cases. The condition may likewise mimic acute encephalitis or typical pyogenic meningitis. Atypical cases may present with florid cranial polyneuropathy or hydrocephalus complications that precede meningitis signs.[21] Tuberculous Meningitis and HIV Infection HIV coinfection does not affect CNS-TB's clinical manifestations, CSF picture, or prognosis. However, HIV-seropositive TBM may have a normal CSF, with radiographic clues holding greater importance in such cases. Cryptococcal meningitis is a close differential diagnosis and may sometimes occur concurrently. Intracerebral tuberculomas are more likely to occur in HIV patients than in the general population, often as multiloculated tubercular abscesses. CNS lymphoma or toxoplasma encephalitis closely mimics the condition. However, cisternal enhancement, basal ganglia infarction, and communicating hydrocephalus favor a CNS-TB diagnosis.[22]

Clinical Diagnosis of Tuberculous Meningitis CNS-TB is a paucibacillary disease, often eluding definitive diagnosis.[23] Conventional diagnostic techniques are insensitive and laborious.[24] Clinical scoring algorithms for definitive CNS-TB diagnosis are flawed and unreliable.[25][26] With early and precise identification being crucial for survival, diagnosis typically relies on a combination of evidence from patient history, neurological examination, CSF analysis, and radiological imaging.[27] Newer molecular techniques help confirm the presence of MTB in CSF, which is often challenging. Still, a definitive diagnosis is not always achievable, necessitating presumptive and prompt treatment initiation to mitigate delay-related risks. Investigating epidemiological factors and personal risk variables is crucial, even though such data may be limited in adults. Notably, active tuberculosis exposure can be identified in 70% to 90% of children with TBM. Identifying active extraneural infection occasionally aids in determining a presumptive diagnosis. Chest radiographs are beneficial in most pediatric TBM cases and approximately 50% of adult cases (see Image. Pulmonary Tuberculosis). Laboratory analysis may indicate mild anemia, lymphocytosis, and hyponatremia. A positive tuberculin test offers supportive evidence, notably in children, though a negative result does not rule out the diagnosis. Funduscopy may also uncover papilledema and choroid tubercles, aiding diagnosis (see Image. Tuberculoma on Funduscopy).[28] Cerebrospinal Fluid Examination and Culture A pellicle or cobweb may form during gross CSF examination, which is representative but not pathognomonic of TBM. A xanthochromic CSF indicates unusually high protein content. CSF cytological analysis typically shows the total cell count between 100 and 500/mm3 in the majority. Less than 100 cells/mm3 are present in 15% of cases. Pleocytosis may be absent in people of advanced age or with miliary tuberculosis-related CNS-TB or HIV coinfection.

A pellicle or cobweb may form during gross CSF examination, which is representative but not pathognomonic of TBM. A xanthochromic CSF indicates unusually high protein content. CSF cytological analysis typically shows the total cell count between 100 and 500/mm3 in the majority. Less than 100 cells/mm3 are present in 15% of cases. Pleocytosis may be absent in people of advanced age or with miliary tuberculosis-related CNS-TB or HIV coinfection. The CSF cell number may be 500 to 1,500 cells/mm3 in 20% of cases. A transient polymorphonuclear predominance or mixed pleocytosis may also be observed in the first week of illness. However, predominant lymphomononuclear pleocytosis is the typical CSF finding in TBM. CSF protein concentration varies from 100 to 500 mg/dl. About 25% of cases may have less than 100 mg/dl of protein, and 10% may have greater than 500 mg/dl. Values exceeding 1 g/dl is characteristic of severe adhesive spinal arachnoiditis and portends a poor prognosis. The CSF glucose level is less than 45 mg/dl in 80% of cases. However, unlike acute pyogenic meningitis, CSF glucose is never undetectable. Microbiological Tests Demonstrating MTB in the CSF smear using Ziehl-Neelsen and auramine-rhodamine staining is crucial but elusive. The detection rates range from 12.5% to 69%, showing significant variability across reports. Traditional Lowenstein-Jensen culture takes 4 to 8 weeks for growth reporting but detects MTB only in 25% to 70% of cases. Liquid culture media like Septi-Chek/Middlebrook 7H9 enhance detection rates. Detection often improves with larger sample volumes, more CSF specimens, centrifugation, and preparing thick smears from the pellicle.[29] Molecular Diagnostic Techniques The World Health Organization recommends Xpert MTB/rifampin (Xpert MTB/RIF), a polymerase chain reaction technique, to be used for molecular TBM diagnosis in CSF specimens, particularly in situations with limited sample volume.[30][31] This quick and automated cartridge-based nucleic acid amplification test targets MTB's rpob gene, enabling simultaneous detection of MTB and rifampin resistance.[32] An Xpert MTB/RIF meta-analysis demonstrated a sensitivity of 80.5% and a specificity of 97.8%.[33] Loop-mediated isothermal amplification assay is another promising, rapid, and cost-effective technique in resource-limited regions.[34]

The World Health Organization recommends Xpert MTB/rifampin (Xpert MTB/RIF), a polymerase chain reaction technique, to be used for molecular TBM diagnosis in CSF specimens, particularly in situations with limited sample volume.[30][31] This quick and automated cartridge-based nucleic acid amplification test targets MTB's rpob gene, enabling simultaneous detection of MTB and rifampin resistance.[32] An Xpert MTB/RIF meta-analysis demonstrated a sensitivity of 80.5% and a specificity of 97.8%.[33] Loop-mediated isothermal amplification assay is another promising, rapid, and cost-effective technique in resource-limited regions.[34] CSF assays for the MTB cell wall glycolipid lipoarabinomannan show sensitivity comparable to Xpert MTB/RIF, potentially aiding TBM diagnosis in patients with HIV, particularly in resource-limited settings.[35] Lipoarabinomannan detection in CSF demonstrates high TBM specificity.[36] CSF interferon-γ release assays have superior diagnostic accuracy over blood interferon-γ release assays in evaluating TBM.[37][38] Metagenomic next-generation sequencing (mNGS) has recently been shown to provide rapid and sensitive diagnostic capability in TBM.[39][40] Adding mNGS to CSF analysis may prove to be a valuable diagnostic tool when combined with traditional diagnostic methods. Adenosine Deaminase Adenosine deaminase (ADA) is an enzyme produced by T-lymphocytes that serves as an indirect measure of the host response to MTB and holds significant diagnostic value. Elevated ADA levels are observed in the CSF of 60% to 100% of individuals with TBM, with a cutoff value of 9.5 U/L used to distinguish TBM from non-TBM cases. Dynamic CSF-ADA activity monitoring may provide further diagnostic assistance.[41] One study demonstrates that ADA measurement has a sensitivity of 92.5% and a specificity of 97%, with the cutoff set to 10 U/L.[42] Imaging Neuroimaging is vital in diagnosing suspected CNS-TB cases, helping ensure a timely and correct diagnosis. Neuroimaging ideally must include the entire neuroaxis. The evaluation modalities include brain computed tomography (CT) or magnetic resonance imaging, with contrast-enhanced MRI having a superior delineating ability. Newer techniques further enhance MRI's diagnostic reliability in atypical or difficult cases (see Image. Tuberculous Meningitis on Magnetic Resonance Imaging).[43]

Neuroimaging is vital in diagnosing suspected CNS-TB cases, helping ensure a timely and correct diagnosis. Neuroimaging ideally must include the entire neuroaxis. The evaluation modalities include brain computed tomography (CT) or magnetic resonance imaging, with contrast-enhanced MRI having a superior delineating ability. Newer techniques further enhance MRI's diagnostic reliability in atypical or difficult cases (see Image. Tuberculous Meningitis on Magnetic Resonance Imaging).[43] The diagnostic triad of TBM consists of the following: Extensive basilar leptomeningeal enhancement and exudates, found in 38% to 89% Hydrocephalus, detected in 60% to 75% Cerebral infarcts, seen in 15% to 28%, followed by tuberculoma in another 27% of cases [44][45][46] TBM exudates have certain areas of predilection. Optochiasmatic arachnoiditis is almost pathognomonic of TBM.[47] The other areas include the interpeduncular fossa, perimesencephalic region, cisterna ambiens, and suprasellar and Sylvian cisterns. Exudates are best discerned on MRI fluid-attenuated inversion recovery sequences, while enhanced meninges are more visible on postcontrast spin echo MRI (see Image. Tuberculous Meningitis on MRI). On CT, intense basal cisternal enhancement may appear as a characteristic spider leg appearance (see Image. Tuberculous Meningitis on Computed Tomography).[48] Imaging features are specific (95–100%) for TBM only when interpreted in combination. However, these findings have reduced sensitivity if taken individually. TBM's basal pachymeningitis involves mostly the middle cerebral artery's M1 segment, circle of Willis, and lenticulostriate and thalamus-perforating arteries, causing a stroke.[49] The vasculitic infarcts are usually bilateral and multiple, mostly affecting the periventricular area, basal nuclei, and internal capsule. Magnetic resonance angiography helps delineate vascular narrowing in cerebral infarction territories.[50] Diffusion-weighted imaging is an advanced MRI technique that accurately identifies TBM-related cerebral vasculitis and varying stroke stages.[51]

TBM's basal pachymeningitis involves mostly the middle cerebral artery's M1 segment, circle of Willis, and lenticulostriate and thalamus-perforating arteries, causing a stroke.[49] The vasculitic infarcts are usually bilateral and multiple, mostly affecting the periventricular area, basal nuclei, and internal capsule. Magnetic resonance angiography helps delineate vascular narrowing in cerebral infarction territories.[50] Diffusion-weighted imaging is an advanced MRI technique that accurately identifies TBM-related cerebral vasculitis and varying stroke stages.[51] Tuberculomas are visible as discrete, single, or numerous ring-enhancing lesions with marked perilesional edema commonly located at the corticomedullary junction. (see Image. Brain Tuberculoma on MRI). Tuberculomas may appear differently on CT scans depending on their maturation stage, presenting as either noncaseating or solidly caseating lesions. CT may also demonstrate caseating masses with central liquefication or calcification (target sign).[52][53] MRI often shows hypointensities on T1W and hyperintensities on T2W images. Postcontrast images delineate either ring-shaped or homogeneous disc-shaped enhancement (see Image. Brain Tuberculoma on Magnetic Resonance Imaging). Tuberculomas' unique metabolite pattern on magnetic resonance spectroscopy may differentiate them from metastases and gliomas. A complete and regular peripheral hypointense ring in susceptibility-weighted imaging (SWI) favors the diagnosis of tuberculomas.[54] Tuberculous myelitis may be visible as diffuse cord swelling with an altered signal on MRI. Phase-contrast MRI is the technique of choice for identifying spinal subarachnoid space obliteration, dural thickening, paraspinal exudates, cauda equina nerve root clumps, CSF loculations, cord infarction, and syringomyelia in spinal arachnoiditis.[55][56]

Considering CNS-TB's high mortality and morbidity rates and various diagnostic challenges, empiric treatment with antituberculous therapy (ATT) and adjunctive corticosteroids may commence based on strong clinical suspicion. Patients must be closely monitored for prompt treatment of adverse drug reactions and disease-related complications. No randomized clinical trials can ascertain the most favorable drug combination, dosage, and duration for treating this condition. Various guidelines recommend different treatment regimens.[57][58][59][60] Drug susceptibility data (when available) and clinical response must always be considered regardless of the combination chosen. The optimal treatment duration is uncertain. Drug-Susceptible Central Nervous System Tuberculosis The current guidelines recommend 4 orally administered drugs: isoniazid (INH) 5 mg/kg/d, rifampicin (RMP) 10 mg/kg/d, pyrazinamide (PZA) 25 mg/kg/d, and ethambutol (ETB) 15 mg/kg/d for the first 2 months, constituting the intensive phase. The continuation phase includes INH, RMP, and ETB daily for at least 7 months. PZA and EMB may be discontinued in the maintenance phase. PZA omission in the intensive phase warrants extending treatment to 18 months. Directly observed therapy short-course, which involves thrice-weekly drug administration, is currently not the standard of care for CNS-TB in India. INH displays early bactericidal activity. RMP has excellent sterilizing activity, clearing persistent bacilli. PZA penetrates the BBB readily. ETB is a weak drug but completes the regimen for drug-susceptible tuberculosis. Drugs that may replace ETB include streptomycin, levofloxacin, and ethionamide. ETB is avoided when the patient's vision is compromised at baseline or cannot be assessed regularly. Streptomycin is contraindicated in pregnancy, kidney impairment, and hearing loss. Levofloxacin is superior to gatifloxacin or ciprofloxacin.[61] Higher RMP or levofloxacin doses are not associated with better survival.[62] OCA management continues to be a challenge. The response is usually disappointing, and pulse corticosteroids, thalidomide, and hyaluronidase have been tried with inconsistent outcomes. Neurosurgical intervention and its optimum timing are debatable. Paradoxical OCA also has a variable response.[63] Drug-Resistant Central Nervous System Tuberculosis

OCA management continues to be a challenge. The response is usually disappointing, and pulse corticosteroids, thalidomide, and hyaluronidase have been tried with inconsistent outcomes. Neurosurgical intervention and its optimum timing are debatable. Paradoxical OCA also has a variable response.[63] Drug-Resistant Central Nervous System Tuberculosis The guidelines for managing drug-resistant CNS-TB are similar to those for PTB. The key principle involves never adding a single drug to a failing regimen. Management is challenging due to the huge number of drugs with overlapping adverse drug reaction profiles. The newer agents, bedaquiline and delamanid, received accelerated approvals for PTB but not CNS-TB.[64] Tuberculomas International guidelines recommend treating tuberculomas with standard ATT for CNS-TB for 9 to 12 months.[65][66] Clinical improvement and radiological clearance are observed in 90% and 80% of patients, respectively, by 9 months. Complete resolution depends upon the lesion's initial size. Tuberculomas smaller than 2.5 cm resolve in 5 to 8 months, while 50% of lesions larger than 2.5 cm take over 12 months to disappear.[67] Additionally, guidelines recommend that every patient should receive adjunctive steroids, especially in the presence of paradoxical responses.[68] Surgical intervention is indicated in patients unresponsive to medical management or with raised intracranial pressure.[65] Spinal Arachnoiditis Spinal tuberculosis is managed similarly to other EPTB forms. Most international guidelines recommend daily therapy for 6 to 9 months, possibly extending to 24 months if the patient's response is unsatisfactory.[69] The conservative approach generally has functional outcomes similar to those of surgical treatment. Decompression surgery should be considered in individuals with progressive IRIS-unrelated neurological deficits.[70][71] Anti-Inflammatory Drugs and Supportive Therapy

Spinal tuberculosis is managed similarly to other EPTB forms. Most international guidelines recommend daily therapy for 6 to 9 months, possibly extending to 24 months if the patient's response is unsatisfactory.[69] The conservative approach generally has functional outcomes similar to those of surgical treatment. Decompression surgery should be considered in individuals with progressive IRIS-unrelated neurological deficits.[70][71] Anti-Inflammatory Drugs and Supportive Therapy The use of adjunctive steroid therapy in TBM management remains an area of ongoing debate. A recent meta-analysis identified clinical benefits when dexamethasone was combined with standard ATT regimens for treating TBM.[72] Few robust, prospective randomized control studies provide definitive data on adjunctive steroid therapy's efficacy in this setting. Thwaites et al's randomized study found that adjunctive steroid therapy provided a survival benefit but did not prevent TBM-associated disability.[73] Donovan et al's recent, large randomized study found no survival benefit to using adjunctive dexamethasone in TBM treatment in patients with HIV.[74] Steroids are generally recommended for all TBM stages, except in stage 1 (mild disease), where the clinician may use their judgment. Dexamethasone's daily dose is 0.6 mg/kg/d in children and 0.4 mg/kg/d in adults. Prednisolone is an alternative used in doses of 2 to 4 mg/kg/d in children and 2.5 mg/kg/d in adults for a minimum of 4 weeks, followed by gradual tapering over the next 4 weeks.[75] Steroids have been shown to improve survival in TBM but probably do not prevent residual neurologic deficits and severe disability.[76] Thalidomide's anti-inflammatory properties may be used to aid in recovering vision in OCA and IRIS cases.[77] Infliximab has also been shown to reduce brain inflammation in TBM with paradoxical reactions.[78] Aspirin has demonstrated a reduced 3-month stroke-related mortality rate in adults with TBM.[79] Neurocritical management of CNS-TB is also essential to interprofessional care.[80] Besides managing seizures and ischemic stroke, TBM-induced hyponatremia requires careful administration of oral salt, intravenous hypertonic saline, or, in resistant cases, fludrocortisone.[81][82] Immune Reconstitution Inflammatory Syndrome

Thalidomide's anti-inflammatory properties may be used to aid in recovering vision in OCA and IRIS cases.[77] Infliximab has also been shown to reduce brain inflammation in TBM with paradoxical reactions.[78] Aspirin has demonstrated a reduced 3-month stroke-related mortality rate in adults with TBM.[79] Neurocritical management of CNS-TB is also essential to interprofessional care.[80] Besides managing seizures and ischemic stroke, TBM-induced hyponatremia requires careful administration of oral salt, intravenous hypertonic saline, or, in resistant cases, fludrocortisone.[81][82] Immune Reconstitution Inflammatory Syndrome Clinical or radiological deterioration may occur several weeks after ATT initiation in approximately one-third of patients with CNS-TB due to an aberrant immune response.[83] Significant IRIS predictors include HIV coinfection, younger age, female sex, and shorter illness duration.[84] TB-IRIS is suspected when patients who initially improve on ATT begin demonstrating worsening symptoms, tuberculomas with increasing size or number on imaging, or OCA aggravation. No test currently exists to confirm TB-IRIS.[85][86] IRIS is believed to result from a delayed type-IV hypersensitivity reaction triggered by the significant release of mycobacterial antigens and increased tumor necrosis factor-α and CSF lymphocytes or protein levels. IRIS manifests with CN deficits due to nerve entanglement with inflammatory exudates. Conditions like communicating hydrocephalus, spinal arachnoiditis, and syringomyelia may also develop. However, the clinician's judgment is crucial in excluding other infections or potential treatment failure. HIV Coinfection Patients with HIV and TBM naive to antiretroviral therapy (ART) should begin ART 8 to 10 weeks after starting ATT. This sequence helps avert early TB-associated IRIS and its potentially fatal neurologic complications. ATT and ART coadministration in patients with HIV and CNS-TB is often complicated by numerous drug interactions and higher adverse drug reaction rates.[87] Shunt Surgery in Tuberculous Meningitis

Patients with HIV and TBM naive to antiretroviral therapy (ART) should begin ART 8 to 10 weeks after starting ATT. This sequence helps avert early TB-associated IRIS and its potentially fatal neurologic complications. ATT and ART coadministration in patients with HIV and CNS-TB is often complicated by numerous drug interactions and higher adverse drug reaction rates.[87] Shunt Surgery in Tuberculous Meningitis Communicating hydrocephalus is initially managed with corticosteroids, the carbonic anhydrase inhibitor acetazolamide, and osmotic diuretics like mannitol and glycerol. Temporary external ventricular drainage is also used for CSF drainage.[88] Endoscopic third ventriculostomy (ETV) has been reported to have a success rate of 73% to 89%.[89] ETV has fewer complications and may be more beneficial than ventriculoperitoneal shunt (VPS) placement. However, ETV is likely to fail during the illness' initial stages, in which case, VPS surgery may be performed.[90][91]. The outcome of patients treated with VPS placement depends considerably on the TBM clinical stage.[92] Vellore and modified Vellore grading systems have been validated for patients with TBM with hydrocephalus to aid in surgical decision-making and predict the success of VPS surgery and ETV. The grades vary from 1 to 4, increasing in disease severity. The modified version incorporates the Glasgow Coma Scale score. The management of patients with grade 4 TBM is still contentious.[93]

TBM presents a significant diagnostic challenge due to its broad range of potential mimics. Meticulous exclusion of other causes of chronic meningitis or meningoencephalitis is crucial, especially in immunocompromised individuals. Conditions such as fungal meningitis (particularly cryptococcal meningitis), neurobrucellosis, neurosyphilis, neuroborreliosis, and neurosarcoidosis may mimic TBM. Partially treated bacterial meningitis, neoplastic meningitis, or systemic inflammation involving the CNS should also be considered in appropriate clinical settings. Neuroradiology and neuropathology are pivotal in aiding clinicians in these diagnostic challenges. Tuberculoma has similar clinical features and radiological appearance as neurocysticercosis, cryptococcoma, CNS lymphoma, and primary or metastatic brain tumor. Focal encephalitides like herpes simplex and parameningeal infections like brain abscesses may occasionally behave similarly to CNS tuberculoma. CNS toxoplasmosis requires careful consideration in cases of HIV coinfection. Spinal arachnoiditis needs to be differentiated from an intradural spinal tuberculoma, extradural compressive myelopathy due to tuberculous spondylitis with paravertebral cold abscess, noncompressive acute transverse myelitis, and Guillain-Barre syndrome. Cytomegalovirus polyradiculopathy can confuse the picture in people with HIV.

Developments in the fields of host immune responses, pathogenesis, and tuberculosis diagnosis and treatment are happening globally.[94] Emerging techniques for rapid TBM diagnosis include measuring new biomarkers like CSF lactate, mNGS, cell-free DNA analysis, clustered regularly interspaced short palindromic repeats (CRISPR) technology for detecting low MTB levels in CSF, and peripheral blood microRNA detection using transcriptomic techniques.[95] Human genetic polymorphisms that can explain the heterogeneity of host immune response to anti-inflammatory therapies are being identified. Genomic and metabolomic studies are determining survival-predicting CSF biomarkers (αβ T-cells, natural killer cells, and pro-resolving mediators) that may be used to tailor and individualize therapy.[96][97] Advanced imaging techniques and sequences like 3-dimensional magnetization-prepared rapid gradient-echo are being studied to better delineate brain lesions. Phase-contrast MRI is another novel and sensitive technique that helps assess altered CSF flow dynamics in patients with TBM.[98] Novel promising drugs such as linezolid, bedaquiline, and pretomanid are being tested in various combinations, especially in highly drug-resistant MTB therapy.[99] Clinical trials currently examine the effectiveness of high-dose RIF and fluoroquinolones. A combination of intravenous INH, high-dose RIF, and ETB are also in the pipeline.[100] Aspirin is being investigated as an adjunctive treatment to reduce infarction incidence due to its ability to inhibit CSF thromboxane A2 and upregulate pre-resolvins.[101] Adjunctive anti-tumor necrosis factor-α, interferon-γ, and thalidomide have also been tried to modulate host immune response. Suitable strategies are likewise being designed and implemented to accomplish the End Tuberculosis Strategy's global targets.[102][103]

TBM is classified into clinical stages based on illness severity when treatment begins. These stages help prognosticate and decide on therapy.[107][108] The TBM stages are defined as follows: Stage I: The patient is alert and conscious with no focal neurological signs or hydrocephalus. Stage II: The patient is confused or irritable and has few focal signs, such as CN palsies or hemiparesis. Stage III: The patient is comatose with or without dense neurological deficit and may be in decerebrate or decorticate posturing.

CNS-TB's prognosis is dismal even after therapy. TBM's mortality ranges between 9.8% and 57%, as it is associated with distressing levels of neurologic sequelae that disproportionately afflict children.[109] Various mortality and neurological morbidity predictors have been identified, including age, symptom duration, Glasgow Coma Scale score, absence of headache, CSF protein level, arachnoiditis extent, presence of complications, and Medical Research Council staging at presentation.[110]

CNS-TB can be lethal or cause devastating complications. The initial complications arise from pachymeningitis, leading to hydrocephalus, OCA-related visual loss, focal neurological deficits, stroke, arteritis-induced hemiplegias, cerebral edema, tuberculoma- or abscess-induced seizures, and diabetes insipidus or syndrome of inappropriate antidiuretic hormone secretion. Myelitis complicates TBM in 10% of cases and is an independent predictor of poor outcomes.[111] Around 10% to 30% of patients with TBM develop long-term residual neurologic deficits, including the above complications, besides learning disabilities, dementia, endocrine syndromes, and gait disturbances.

Patients and their caregivers must be educated about medication compliance, as CNS-TB requires prolonged treatment. These individuals must be enlightened about the potential disease- and treatment-related complications. Patients and their families should be counseled for regular hospital visits, investigations, and close follow-ups to ensure disease resolution and prevent adverse drug reactions.

Pearls CNS-TB poses a diagnostic and therapeutic challenge due to its paucibacillary nature and diverse clinical manifestations. Diagnosis hinges on a combination of clinical suspicion, imaging, CSF analysis, and molecular techniques like Xpert MTB/RIF. Early and accurate diagnosis is crucial, as delayed treatment may lead to serious morbidity and mortality. Treatment involves ATT and adjunctive corticosteroids, with surgical intervention reserved for specific complications. Monitoring for paradoxical reactions and IRIS is essential during treatment. Long-term neurorehabilitation may be necessary for patients with residual neurological deficits. Interprofessional collaboration is paramount for optimizing outcomes in CNS-TB management. Other Issues A discussion of spinal tuberculosis is relevant in this section due to its overlapping neurological presentations with CNS-TB. Spinal tuberculosis, a subset of skeletal tuberculosis, manifests as spondylodiscitis or spondylitis without intervertebral disk involvement.[113] In adults, intervertebral disk involvement often results from contiguous spread from infected vertebrae. In children, hematogenous spread may lead to TB diskitis due to the area's rich vascular supply. Pott disease is characterized by osteomyelitis and arthritis and typically affects multiple vertebrae. The condition produces progressive vertebral destruction, anterior collapse, kyphotic or gibbous deformity (in thoracic vertebrae), paraspinal cold abscess formation, and spinal canal narrowing. These complications can culminate in various neurological deficits, with paraplegia being the most devastating.[114] Early-onset paraplegia may occur due to mechanical compression by tuberculous debris, bone or disk sequestrum, tuberculomas, granulomas, or abscess in extradural, intradural, or intramedullary regions, myelitis with cord edema, meningeal inflammation, and anterior spinal artery thrombosis with cord infarction. Frank infarction is rare since the smaller end-arteries are involved.[115]

Early-onset paraplegia may occur due to mechanical compression by tuberculous debris, bone or disk sequestrum, tuberculomas, granulomas, or abscess in extradural, intradural, or intramedullary regions, myelitis with cord edema, meningeal inflammation, and anterior spinal artery thrombosis with cord infarction. Frank infarction is rare since the smaller end-arteries are involved.[115] Late-onset paraplegia in severe kyphosis may result from cord transection by a transverse bony ridge or dural fibrosis with cord encasement and, occasionally, syrinx formation. Paraspinal abscesses may mechanically compress the cord depending on their location. Retropharyngeal abscesses may cause dysphagia and respiratory distress. Mediastinal lesions can track down to the trachea, esophagus, or pleural cavity. Tuberculous abscesses may present as fusiform or bulbous paravertebral swelling in the thoracic region and groin or medial thigh bulging in the lumbar area. For neuroimaging, spinal CT scans offer detailed bony information, while MRI is essential for evaluating soft tissue components (see Images. Spinal Cord Tuberculoma, Pott Spine). Spinal tuberculosis typically spares the intervertebral disc, shows vertebral endplate rarefaction and anterior vertebral wedging, and may present with paravertebral abscesses. Neuroimaging-guided needle biopsy of the involved vertebral body is the diagnostic gold standard. Pott spine treatment involves standard ATT, with the continuation phase potentially extending up to 18 months. Surgery for this condition is indicated in cases of neurological deficits, large paravertebral abscesses, and spinal instability.

CNS-TB, though rare, profoundly affects both the quantity and quality of life. Screening for active infected cases in high tuberculosis-burden settings may help prevent CNS-TB. Treatment adherence significantly influences outcomes once diagnosed. While most countries have national policies in place, embracing global evidence-based approaches to CNS-TB management is essential for ensuring optimal patient care and support.[116] CNS-TB requires comprehensive and coordinated team care to enhance patient outcomes. Each team member, including the treating clinician, infectious disease specialist, neuroradiologist, neurologist, neurosurgeon, ophthalmologist, nurse, and pharmacist, holds individual and collaborative responsibilities. Nurses are crucial for overall patient care, while pharmacists, especially infectious disease-specialized pharmacists, are vital during drug selection, medication reconciliation, dosing regimens, adjustments, and patient counseling.[117][118] Effective communication with prescribing clinicians is essential for pharmacists to modify therapy appropriately in response to patient status changes. Effective communication and collaboration within the healthcare team are essential for shared decision-making to reduce complications and expedite recovery in critically ill patients.[119] Improved infection control modalities and surveillance are necessary to screen and diagnose patients efficiently and provide interprofessional services to affected individuals. Most countries release evidence-based guidelines for managing PTB and EPTB without considering each patient's unique circumstances, geographic location, and healthcare setting. Clinical decisions must be individualized to enhance health outcomes.[120]