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CNS Tuberculosis
Introduction
Mycobacterium tuberculosis is responsible for 5.9% of community-acquired CNS infections worldwide.[1] Neurological tuberculosis (TB) or central nervous system tuberculosis (CNS-TB) may take three clinic-pathological forms: a diffuse form of tubercular meningitis (TBM), a focal form as tuberculoma, and spinal arachnoiditis also referred to as TB radiculomyelitis [TBRM].[2] Of these, TBM predominates, causing 70 to 80% of the infections. It presents as a subacute to chronic meningitis with disease severity commensurate with the duration of illness.[3]
The diagnosis is fraught with challenges and is often delayed due to the varied and non-specific presentation.[4] Besides the clinical clues, diagnostic indicators in cerebrospinal fluid (CSF) include mononuclear pleocytosis, low sugar values, and high protein concentrations. Identifying Mycobacterium tuberculosis 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. CNS-TB is frequently complicated by vasculitic infarcts, cranial nerve palsies, multiple neurological deficits, and hydrocephalus. A strong clinical suspicion is enough to start prompt anti-tubercular therapy. A 4-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol with adjunctive corticosteroid reduces morbidity and mortality. The diagnosis and management of CNS-TB may be complicated by drug resistance, immune reconstitution inflammatory syndrome, and human immunodeficiency virus (HIV) coinfection.[4]
Treatment efficacy depends upon how early it is instituted. Multiple factors determine the prognosis, the most important being the clinical stage of TBM at initial presentation. Untreated or unrecognized TBM may cause death within 5 to 8 weeks of the onset of the disease.
Etiology
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Etiology
Mycobacterium tuberculosis (MTB) is the organism responsible for CNS-TB. It is alcohol and acid-fast bacillus, stained using the Ziehl-Neelsen/Auramine-rhodamine/Kinyoun stains. The etiological contribution of the other four species of MTB-complex in causing CNS-TB is not determined. Humans are the only hosts or reservoirs known for MTB. Infection is primarily acquired through airborne aerosols from infective individuals.
Epidemiology
It has been estimated that 25 to 30% of the human population is infected with MTB. CNS-TB is reported in 1 to 2% of individuals with active TB.[6] It accounts for 5 to 8% of extra-pulmonary tuberculosis (EPTB) in immunocompetent hosts. 70 to 80% of cases of CNS-TB present as TBM.[7]
Tuberculomas are seen mostly in India and parts of Asia. They may account for 20 to 30% of all intracranial space-occupying lesions.[8] An estimated 9272 cases of CNS-TB were diagnosed in the U.S. in 2016.[9] Since 2010, TB incidence has fallen by 2 to 3% every year, especially in 2020, probably due to the pandemic mitigation efforts, travel restrictions, or delayed or missed TB diagnoses.[10]
The incidence of reported TB rose 9.4% in 2021 (2.37) compared with 2020 (2.16).[11] Despite the advances in diagnosis and management, CNS–TB still carries high mortality of 15% to 40%, especially in children.[12]
Pathophysiology
TBM
CNS-TB begins with either the hematogenous dissemination of MTB following primary lung infection or the late reactivation of TB.[13] This leads to seeding of the meninges or ependyma with multiple small granulomatous foci or tubercles (Rich focus) that may proliferate, coalesce, caseate, and finally rupture into the subarachnoid space before the onset of meningitis. This released MTB bacilli produce an intense, cytokine-mediated host inflammatory response, leading to the following.
- Leptomeningitis, ependymitis, choroid plexitis, encephalitis, and later pachymeningitis with basal and optico chiasmatic arachnoiditis.
- Vasculitis with endarteritis and infarcts
- Hydrocephalus, secondary to disturbed CSF flow and absorption
The extensive exudative arachnoiditis at the base of the brain and optic chiasma encases the multiple traversing cranial nerves, most commonly the abducens, optic, oculomotor, and trochlear. Similarly, arteritis and phlebitis result in vasculitic infarcts due to arterial vasospasm, thrombosis, or hemorrhage of the vessels.[14] It is thought that human genetic polymorphisms in the leukotriene A4 hydrolase gene and toll-interleukin-1 receptor domain may explain the disparate inflammatory response in individuals with TBM.[15]
In many patients symptomatic for three weeks or more, the inflammatory process extends to the basal cisterns, where CSF circulation and absorption are hampered, resulting in communicating hydrocephalus.[16] Obstructive hydrocephalus may rarely develop due to narrowing or obstruction of the cerebral aqueduct by ependymitis or the fourth ventricle due to brainstem tuberculoma.
Tuberculoma
Deep-seated tubercular granulomatous foci acquired during initial bacteremia may coalesce and develop into conglomerated caseous masses called tuberculomas without producing meningitis. Often, they may be present as clinically silent single or multiple lesions in patients with TBM and detected on brain imaging. In immune-suppressed individuals, these may form tubercular abscesses. Spinal cord tuberculoma may be located at any level of the cord due to similar pathogenesis or by local extension from abutting 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 clumping of nerve roots or partial/total encasement of the cord by the thick gelatinous exudate or fibrous mass.
Histopathology
Histologically, the thick inflammatory meningeal exudate is granulomatous, with epithelioid macrophages, Langhans' giant cells, lymphocytes, and plasma cells, along with fibroblasts. Tuberculomas are bigger encapsulated epithelioid granulomas with similar pleocytosis arranged in layers but a necrotic caseous center, which does not contain pus. A tuberculous abscess has a thick wall with a liquefied pus core containing viable MTB bacilli.
History and Physical
TBM
The presentation in patients with TBM is often that of subacute, progressive febrile illness beginning with a prodrome of constitutional features. These include lassitude, malaise, night sweats, and intermittent headache. The illness develops into a well-defined meningitic phase in the following fortnight or more. This phase includes protracted headache, vomiting, personality change, confusion, and symptoms of meningismus. The condition may deteriorate rapidly to varying degrees of confusion and coma. Seizures, multiple cranial nerve (CN) deficits, focal neurological deficits, and stroke syndromes may supervene.
Children may have prominent irritability and vomiting, and focal or generalized convulsions. Untreated TBM patients may not survive beyond 5 to 8 weeks of illness. CN palsies are seen in 20-30% of patients with TBM, mostly involving the sixth nerve.[17] Optico-chiasmatic arachnoiditis with blindness is a significant complication in TBM.[18]
Tuberculoma
Usually seen in young individuals, this form of CNS-TB presents like a space-occupying lesion. The usual clinical manifestations are headache, seizure, progressive neurological deficit, and papilledema with or without meningitis.
Spinal Arachnoiditis
These patients present with radiculomyelopathy secondary to entrapment of nerve roots and encasement of the cord due to severe arachnoiditis at single or multiple levels. The patient complains of radicular pain, hyperesthesia, flaccid paralysis, and urinary or stool incontinence. Cord infarction may occur due to arteritis and thrombosis of the anterior spinal artery.
Atypical Presentations
CNS-TB as a presentation of miliary tuberculosis can be seen in 10 to 30% of adult patients with miliary TB as a part of hematogenous dissemination; however, this pattern is mostly seen in immunocompromised patients. In these cases, brain parenchyma may show multiple scattered tiny granulomatous foci, which may or may not show ring enhancement.[19]
Very rarely, TBM may manifest as progressive cognitive dysfunction or as psychosis. Rarely may it mimic acute encephalitis or typical pyogenic meningitis. Atypically, the patients may present with florid complications of cranial polyneuropathy or hydrocephalus that precede the signs of meningitis.[20]
TBM and HIV Infection
Coinfection with HIV in CNS-TB does not affect the clinical manifestations, CSF picture, or prognosis. However, HIV-seropositive TBM may have a normal CSF. Therefore radiographic clues hold greater importance. Also, cryptococcal meningitis is a close differential diagnosis and may sometimes occur concurrently. Intracerebral tuberculomas are more likely to occur in HIV patients, often as multiloculated tubercular abscesses. CNS lymphoma or toxoplasma encephalitis closely mimics these lesions, but a cisternal enhancement, basal ganglia infarction, and communicating hydrocephalus favor the diagnosis of CNS-TB.[21]
Evaluation
Diagnosis of TBM
CNS-TB is a paucibacillary disease; therefore, it eludes a definite diagnosis.[22] Conventional diagnostic techniques are insensitive and laborious.[23] Specific clinical scoring algorithms have been developed for the definitive diagnosis of TBM. However, they are flawed and not reliably decisive.[24][25] Nevertheless, an early and accurate diagnosis of TBM is the cornerstone of survival. Diagnosis rests on a constellation of corroborative evidence derived from history, neurological examination, CSF, and radiological imaging.[26]
Confirmatory evidence of demonstrating MTB in CSF is challenging, so newer molecular techniques are very useful. However, diagnostic confirmation may not be possible in every case, so presumptive and early initiation of treatment should be done to prevent delay-related morbidity and mortality.
It is important to explore the epidemiological variables and various personal risk factors for acquiring infection, although this data may not always be forthcoming in adults. In children with TBM, however, exposure to active TB could be elicited in 70-90%.[17]
An extra-neural site of active infection may help make presumptive diagnoses in some cases. Chest radiographs may be valuable in most children with TBM and about 50% of adults. A laboratory workup may suggest mild anemia, lymphocytosis, and hyponatremia. A positive tuberculin test is useful as supportive evidence, especially in children; however, a negative cannot exclude the diagnosis. Fundus examination is worthwhile as it may reveal papilloedema and choroid tubercles.[27]
CSF 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 a very high protein content. CSF cytological analysis typically shows the total cell count between 100 and 500/mm^3 in the majority. In 15% of cases, <100 cells/mm^3 are present; pleocytosis may be absent in miliary TB with CNS-TB, elderly, and coinfection with HIV.
In 20% of cases, the cell number may be 500 to 1,500 cells/mm^3. Also, in the first week of illness, a transient polymorphonuclear predominance may be observed, or there may be mixed pleocytosis; however, typically, the CSF picture in TBM is that of predominant lympho-mononuclear pleocytosis.[2] Protein concentration in CSF varies from 100 to 500 mg/dl; 25% of cases may have <100 mg/dl, and 10% may have >500 mg/dl.
Value exceeding one g/dl is characteristic of severe adhesive spinal arachnoiditis and portends a poor prognosis. The glucose level in CSF is <45 mg/dl in 80% of cases; however, unlike acute pyogenic meningitis, CSF glucose is never undetectable.
Microbiological Tests
Demonstration of MTB in the CSF smear by Ziehl-Neelsen and Auramine-rhodamine staining is crucial but elusive.[28] The detection rate by smear is 12.5 to 69%, which is highly variable in various reports.[22] Traditional Lowenstein-Jensen culture takes 4 to 8 eight weeks to report growth with a detection rate of 25 to 70%. Liquid culture media (Septi-Chek/Middlebrook 7H9) help enhance the detection rate. The detection rate of MTB improves with higher sample volume, a greater number of CSF samples, centrifuging of the CSF and preparing thick smears from the pellicle.[23]
Molecular Diagnostic Techniques
Based upon the recommendations of the World Health Organization, Xpert MTB/RIF, a polymerase chain reaction (PCR) technique, is used for molecular diagnosis in CSF specimens in TBM, especially in volume constraint scenarios.[29][30] It is a quick and automated cartridge-based nucleic acid amplification test (CBNAAT). It simultaneously detects MTB and rifampin (RIF) resistance by targeting the rpob gene of MTB.[31]
A meta-analysis of Xpert MTB/RIF demonstrated sensitivity and specificity of 80.5% and 97.8%, respectively.[32] Loop-mediated isothermal amplification (LAMP) assay is another promising rapid, and cost-effective technique in resource-limited regions.[33]
The sensitivity of CSF assays for mycobacterial cell wall glycolipid lipoarabinomannan (LAM) is comparable to Xpert MTB/RIF, and it may be useful for the diagnosis of TBM in HIV-infected patients, especially in resource-poor settings.[34] CSF LAM is reported to be highly specific for the diagnosis of TBM.[35] CSF interferon-gamma release assays (IGRAs) have also been evaluated in TBM, and they exhibited a superior diagnostic accuracy compared to blood IGRAs.[36][37]
Adenosine Deaminase
Adenosine deaminase (ADA) is an enzyme produced by T-lymphocytes. It is an indirect measure of the host response to MTB and has a good diagnosis value. It is elevated in the CSF of 60 to 100% of patients with TBM. A cutoff value of 9.5 U/L in CSF is taken to differentiate TBM from non-TBM. Dynamic monitoring of CSF-ADA activity may also be helpful.[38] In another study, at a cutoff of >10U/L, ADA had a sensitivity and specificity of 92.5% and 97%, respectively.[39]
Imaging
Neuroimaging plays a vital part in the diagnostic armamentarium of suspected cases of CNS-TB and helps ensure a timely and correct diagnosis. Neuroimaging ideally must include the entire neuro-axis. The modalities for evaluation include brain CT or brain MRI of which the contrast-enhanced MRI has the superior delineating ability. Newer MRI techniques further enhance the diagnostic quality in atypical or difficult cases.[40][19]
The diagnostic triad, along with their frequency in TBM, consists of (1) Extensive basilar leptomeningeal enhancement and exudates in 38 to 89%, (2) Hydrocephalus in 60 to 75%, (3) Cerebral infarcts in 15 to 28%, followed by tuberculoma in another 27% of cases.[41][42][43]
In TBM, the exudates have certain areas of predilection. Optochiasmatic arachnoiditis is almost pathognomonic of TBM.[44] The other areas include the interpeduncular fossa, peri-mesencephalic area, the cisterna ambiens, and suprasellar and Sylvian cisterns. Exudates are best discerned on FLAIR sequences, while enhanced meninges are better visible on post-contrast spin echo MRI.[40]
On CT, intense basal cisternal enhancement may appear as a characteristic spider leg appearance.[45] Imaging features are specific (95–100%) for TBM only when read in combination; otherwise, individually, these findings lack sufficient sensitivity.[23]
The basal pachymeningitis in TBM involves mostly the middle cerebral artery (M1 segment), circle of Willis, lenticulostriate and thalamo-perforating arteries causing a stroke.[46] The vasculitic infarcts are usually bilateral and multiple and mostly affect the periventricular area, basal nuclei, and internal capsule. MR angiography helps delineate the vascular narrowing in the territories of cerebral infarctions.[47] Diffusion-weighted imaging (DWI) is an advanced technique that accurately depicts cerebral vasculitis and varying stages of stroke in TBM.[48]
Tuberculomas are visible as discrete, single, or numerous ring-enhancing lesions with marked perilesional edema. They are commonly located at the corticomedullary junction both in the brain and the spinal cord. Depending upon the pathological maturation stage, on CT, tuberculomas may have variable appearances; either as non-caseating lesions, solidly caseating lesions, or caseating masses with central liquefication or with central calcification (target sign on CT).[49][50]
On MRI, they are hypointense on T1W and appear hyperintense on T2W images. Post-contrast images delineate either ring-shaped or homogeneous disc-shaped enhancement. Tuberculomas may be differentiated from metastases and gliomas by their unique metabolite pattern on magnetic resonance spectroscopy (MRS). A complete and regular peripheral hypointense ring in susceptibility-weighted imaging (SWI) favors the diagnosis of tuberculomas.[51]
Tuberculous myelitis may be visible as diffuse cord swelling with an altered signal on MRI. The phase contrast MRI is the technique of choice for depicting obliteration of spinal subarachnoid space, dural thickening, paraspinal exudates, clumping of cauda equine nerve roots, CSF loculations, cord infarction or syringomyelia in spinal arachnoiditis.[52][53]
Treatment / Management
Considering the high mortality and morbidity rates and various diagnostic challenges in CNS-TB, empiric treatment with anti-tuberculous therapy (ATT) and adjunctive corticosteroids must be commenced based on strong clinical suspicion.[15]
In addition, it is essential to closely monitor the patient for prompt identification of adverse drug reactions and disease-related complications. There are no randomized clinical trials to ascertain the most favorable drug combination, dosage, and duration for the specific treatment of CNS-TB. Various guidelines are available that outline different treatment regimens.[54][55][56][57] (A1)
Whatever regimen is used, it should be tailored to the drug susceptibility data (when available) and clinical response. The optimal duration of treatment is uncertain.
Drug-susceptible CNS-TB
The current guidelines use four 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 first two months (intensive phase) followed by three drugs (INH, RMP, ETB) daily for a minimum of 7 months in the continuation phase. Directly observed therapy short-course, which involves intermittent administration of drugs (thrice weekly), is currently not followed for CNS-TB in India.[57]
INH displays early bactericidal activity, and RMP has excellent sterilizing activity (clearing persisters). PZA penetrates the blood-brain barrier readily, and ETB, a weak drug, completes the regimen for drug-susceptible TB. In the maintenance phase, PZA and EMB may be discontinued. If PZA is omitted in the intensive phase, treatment should be extended to 18 months. Other drugs which may substitute ETB include streptomycin (SM), levofloxacin, or ethionamide. ETB is also avoided when the vision is compromised or cannot be assessed regularly. SM is avoided during pregnancy, kidney impairment, or hearing loss. Levofloxacin is superior to gatifloxacin or ciprofloxacin.[56][58] (A1)
Higher doses of RMP or levofloxacin are not associated with better survival.[59] Management of opticochiasmatic arachnoiditis (OCA) continues to be a challenge. The response is usually disappointing, so 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.[60]
Drug-resistant CNS TB
Management of drug-resistant CNS-TB derives the guidelines from those of pulmonary TB. The key principle involves never adding a single drug to the failing regimen. Management is challenging due to the huge number of drugs with overlapping adverse drug reaction profiles. The newer agents, bedaquiline (BDQ) and delamanid, have received accelerated approvals for pulmonary TB but have not yet been approved for treating CNS-TB.[15][61]
Tuberculomas
International guidelines recommend treating tuberculomas with standard ATT for CNS-TB for 9-12 months.[62][63] Clinical improvement and radiological clearance are observed in 90% and 80% of patients, respectively, by nine months. Complete resolution depends upon the initial size; those <2.5 cm resolve in 5–8 months, while 50% of >2.5 cm take over 12 months to disappear.[64] (B2)
Additionally, every patient should receive adjunctive steroids as per guidelines, especially unequivocally for those that develop paradoxical responses.[65] Surgical intervention is indicated in patients who show no response to medical management or have raised intracranial pressure.[62](B3)
Spinal Arachnoiditis
Spinal TB is managed on the lines of other extrapulmonary TB. Most international guidelines recommend daily therapy for 6-9 months. However, the treatment is extended for more prolonged periods, sometimes up to 24 months in clinical practice, as the response may not be satisfactory.[66] The conservative approach generally has similar functional outcomes as surgical treatment. Decompression surgery should be considered in patients with progressive neurological deficits unrelated to IRIS.[67][68]
Anti-inflammatory Drugs and Supportive Therapy
Adjunctive steroid therapy benefits all patients with TBM, even those with HIV infection. Steroids are generally recommended for all stages of TBM, although in stage 1 with mild disease, the clinician may use his judgment. The daily dose of dexamethasone is 0.6 mg/kg/d and 0.4 mg/kg/d in children and adults, respectively. Prednisolone is the other alternative drug, used in doses of 2 to 4 mg/kg/d and 2.5 mg/kg/d in children and adults, respectively. This dosage is given for a minimum of 4 weeks, followed by gradual tapering over the next four weeks.[69] Though steroids have been shown to improve survival in TBM, they probably do not prevent residual neurologic deficits and severe disability.[70][71] (A1)
Due to its anti-inflammatory action, thalidomide may aid in the recovery of vision in OCA and cases of IRIS.[72] Similarly, infliximab has been shown to reduce brain inflammation in TBM with paradoxical reactions.[73] Aspirin has been shown to reduce the 3-month mortality rate in adult patients with TBM.[74] Neurocritical management of patients with CNS-TB is also essential to interprofessional care.[75] Besides managing seizures and ischaemic stroke, hyponatremia in TBM requires careful administration of oral salt, intravenous (IV) hypertonic saline, or fludrocortisone (in resistant cases).[76][77](A1)
Immune Reconstitution Inflammatory Syndrome (IRIS)
In approximately one-third of patients with CNS-TB, clinical or radiological worsening may occur several weeks after initiation of ATT due to an aberrant immune response.[78] Significant predictors of IRIS include simultaneous HIV infection, younger age, female gender, and a shorter length of illness.[79]
TB-IRIS is suspected when patients who initially improved on ATT develop deterioration of symptomatology, increase in size or number of tuberculous lesions on imaging (in case of tuberculomas), or aggravation of OCA while continuing on ATT. There is no confirmatory test to diagnose TB- IRIS.[80][81]
IRIS is thought to represent a delayed type-IV hypersensitivity response to the substantial release of mycobacterial antigens and an increase in TNFα, and an increase in CSF lymphocytes or protein. During IRIS, cranial nerve deficits may emerge due to entanglement in the inflammatory exudates, and similarly communicating hydrocephalus, spinal arachnoiditis, and syringomyelia may start to manifest. However, the clinician's judgment is imperative in ruling out any alternate infection or possible treatment failure.
HIV Coinfection
Antiretroviral therapy (ART) naïve, HIV-infected patients with TBM should receive the ART after a delay of 8-10 weeks of ATT initiation. This is essential to avert early TB-associated IRIS, increasing the risk of potentially fatal neurologic complications. Among HIV-infected patients with CNS-TB, co-administration of ATT and ART is often complicated by numerous drug interactions and higher adverse drug reactions.[82]
Shunt Surgery in TBM
In the initial stages, communicating hydrocephalus is treated with corticosteroids, the carbonic anhydrase inhibitor acetazolamide, and osmotic diuretics like mannitol, glycerol, and CSF drainage through temporary external ventricular drainage.[83] Endoscopic third ventriculostomy (ETV) has been reported to have a success rate of 73 to 89%.[84]
ETV may be beneficial over VP shunt due to lesser long-term complications. However, it is likely to fail during the initial stage of the illness; therefore, a ventriculoperitoneal (VP) shunt needs to be placed.[85][86]. The outcome of patients treated with VP shunt depends considerably on the clinical stage of TBM.[87] (A1)
Vellore and modified Vellore grading have been validated for patients with TBM with hydrocephalous to aid in surgical decision-making and predict the success of shunt 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 in grade 4 is still contentious.[88]
Differential Diagnosis
TBM is a great mimic, and the list of differential diagnoses is vast.[26] Therefore one has to carefully rule out other causes of chronic meningitis/meningoencephalitis, particularly in the setting of immunosuppression. Fungal meningitis, especially cryptococcal meningitis, is a major consideration. Other conditions like neurobrucellosis, neurosyphilis, neuroborreliosis, and neurosarcoidosis may be confused with TBM. Besides, one has to keep in mind partially treated bacterial meningitis and neoplastic meningitis or systemic inflammation involving CNS in appropriate clinical settings. Here is where neuroradiology and neuropathology come to the clinician’s aid.[4]
Tuberculoma shares its clinical features and radiological appearance with neurocysticercosis, cryptococcoma, CNS lymphoma, and primary or metastatic brain tumor. Occasionally focal encephalitis, such as herpes simplex, and parameningeal infection, such as brain abscess, may behave similarly to tuberculoma. CNS toxoplasmosis requires careful consideration in cases of HIV infection.
Spinal arachnoiditis needs to be differentiated into an intradural spinal tuberculoma, extradural compressive myelopathy due to tuberculous spondylitis with paravertebral cold abscess, a non-compressive acute transverse myelitis, and Guillain-Barre syndrome. Cytomegalovirus polyradiculopathy can confuse the picture in HIV-infected patients.[15]
Pertinent Studies and Ongoing Trials
Many latest developments in the fields of host immune responses and pathogenesis, better diagnostic modalities, and treatment of TB are happening globally.[89] Emerging diagnostic techniques to improve the rapid diagnosis of TBM include new biomarkers such as CSF lactate, metagenomic next-generation sequencing, cell-free DNA analysis, CRISPR technology to detect low levels of MTB in CSF, and peripheral blood microRNA detection using transcriptomic techniques.[90]
Human genetic polymorphisms are being identified that could explain the heterogeneity of host immune response to anti-inflammatory therapies. Studies on genomics and metabolomics are identifying survival-predicting biomarkers in CSF (αβ T cells, NK cells, and pro-resolving mediators) that may be used to tailor and individualize therapy.[91][92][5]
Advanced imaging techniques and sequences like 3-D magnetization-prepared rapid gradient-echo (MP-RAGE) are being studied to delineate brain lesions better. Phase-contrast MRI is another novel and sensitive technique to assess altered CSF flow dynamics in patients with TBM.[93]
Novel promising drugs such as linezolid, bedaquiline, and pretomanid are being tested in various combinations, especially in highly drug-resistant forms.[94] Clinical trials are examining the effectiveness of high-dose RIF and fluoroquinolones. A combination of intravenous INH, high-dose RIF, and ETB are also in the pipeline.[95]
Aspirin is being investigated as an adjunctive treatment to reduce infarction incidence because it could inhibit CSF thromboxane A2 and upregulate pre-resolvins.[96] Similarly, adjunctive anti-TNF-α, interferon-γ, or thalidomide have been tried to modulate host immune response.[63]
Suitable strategies are also being designed and implemented to accomplish the targets of the End Tuberculosis Strategy on a global level.[97][98]
Toxicity and Adverse Effect Management
ATT is generally well tolerated; however, close follow-up is needed to monitor any adverse drug reactions (ADRs). ADR occurrence in the context of ATT is expected as multiple drugs are combined for a prolonged duration.[99]
Besides gastrointestinal intolerance and fatigue, all the drugs have specific side effects. Factors such as confection with HIV, drug-resistant TB, and steroid prescription raise the complexity further. INH, RMP, and PZA are all hepatotoxic. In addition, INH can cause peripheral neuropathy, which can be prevented by supplementing pyridoxine. Very rarely, INH can cause lupus-like syndrome, pellagra, and psychosis. RMP discolors the urine and may cause rash, influenza-like syndrome, and thrombocytopenia.
ETB causes dose-dependent optic neuritis and peripheral neuropathy. PZA causes various cutaneous reactions, asymptomatic hyperuricemia, and occasionally gouty arthritis. SM is associated with ototoxicity, vertigo, and pain at the injection site. The novel drug BDQ is associated with QT prolongation in electrocardiograms. All patients on ATT should have liver monitoring during the initial eight weeks of treatment. An asymptomatic rise in hepatic transaminases is expected at the beginning of treatment. In the event of transaminase levels exceeding 3 to 5 times the upper limit of normal or serum bilirubin of >2.5 mg/L, ATT needs to be modified to replace hepatotoxic drugs with second or third-line drugs.[100][101]
Staging
Patients of TBM are categorized into clinical stages according to the degree of illness at which treatment is initiated. These stages help to prognosticate and decide on therapy.[102][103] These are defined as
- Stage I: The patient is alert and conscious but has no focal neurological signs or hydrocephalus
- Stage II: The patient is confused/ irritable or has few focal signs, such as CN palsies or hemiparesis
- Stage III: Comatose with or without dense neurological deficit/ decerebrate or decorticate posturing
Prognosis
Despite therapy, the prognosis of CNS-TB is dismal. The mortality ranges between 9.8 to 57% for TBM.[104] It is associated with distressing levels of neurologic sequelae that disproportionately afflict children. Various predictors of mortality and neurological morbidity have been identified.[105]
The clinical outcome depends upon the age, clinical stage, and duration of symptoms before admission of elevated CSF protein, the extent of arachnoiditis, as well as the presence of complications.[95]
Complications
CNS-TB can be lethal or cause devastating complications. The initial complications are a result of pachymeningitis leading to hydrocephalus and multiple cranial nerve palsies, including deafness, opticochiasmatic arachnoiditis resulting in visual loss, focal neurological deficits, stroke, and hemiplegia due to arteritis, cerebral edema, and seizures due to intracranial tuberculoma/tuberculous abscesses 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.[106]
From 10 to 30% of patients with TBM are left with long-term residual neurologic deficits.[95] These complications include persisting neurological deficits, as listed above, along with learning disabilities and dementia, endocrine syndromes due to hypothalamic and pituitary involvement, and gait disturbance due to spinal arachnoiditis.
Postoperative and Rehabilitation Care
TBM is a severely disabling condition; therefore, besides optimum medical management, it requires intensive rehabilitation to minimize disability and speed up recovery. The comprehensive rehabilitation program should be initiated while the patient is in the hospital or the intensive care unit and continue well into their homes after discharge. It should involve multimodal sensory stimulation to improve the functional recovery of the brain, scheduled posturing and positioning to prevent immobilization-related issues, passive and active range of motion to maintain muscle power, and chest physical therapy to prevent hypostatic pneumonia and aspiration. Long-term rehabilitation should be offered to all patients with residual neurological sequelae.[107]
Consultations
- Infectious disease specialist
- Neuroradiologist
- Neurologist
- Neurosurgeon
- Ophthalmologist
- Physiotherapist
Deterrence and Patient Education
The patient and relatives must be educated about medication compliance as CNS-TB requires prolonged treatment. They need to be enlightened about the potential disease-related complications and side effects of treatment, including symptoms of liver injury. They should be counseled for regular hospital visits, investigations, and close follow-ups to ensure that there are no ADRs and that the disease is resolved.
Pearls and Other Issues
It is pertinent to discuss spinal TB in this section due to certain overlapping neurological presentations. Spinal TB is part of skeletal tuberculosis and may occur as spondylodiscitis or spondylitis without disc involvement.[108]
In adults, intervertebral disc involvement occurs secondary to the spread from the contiguously infected vertebra. In children, the disc may be involved hematogenously due to a rich blood supply leading to TB discitis. Pott's disease consists of osteomyelitis and arthritis, typically involving more than one vertebra. It comprises progressive vertebral destruction leading to gradual anterior collapse and kyphotic or gibbous deformity (thoracic vertebrae), paraspinal cold abscess formation, and spinal canal narrowing culminating in multiple neurologic deficits, the most devastating being paraplegia.[109]
Early-onset paraplegia may occur due to mechanical compression by tuberculous debris, bone or disk sequestrum, tuberculomas or granulomas or abscess in extradural, intradural, or intramedullary regions, myelitis with cord edema, meningeal inflammation and anterior spinal artery thrombosis leading to cord infarction. However, since the smaller end-arteries are involved, frank infarction is rare.[110]
Late-onset paraplegia could occur due to transection of the cord by a transverse bony ridge in severe kyphosis or dural fibrosis and cord encasement and, infrequently, the formation of a syrinx. The paraspinal abscess may cause mechanical compression depending on its location. In the cervical region, it may present as a retropharyngeal abscess causing dysphagia and respiratory distress; in the mediastinum, it may track down and enter the trachea, esophagus, or pleural cavity. In the thoracic region, it may manifest as fusiform or bulbous paravertebral swelling. In the lumbar area, it may appear as swelling in the groin or the medial aspect of the thigh.
CT of the spine provides bony detail, while MRI is required to evaluate the soft tissue component. Points in favor of TB spine are the relative sparing of the intervertebral disc, rarefaction of the vertebral endplates, anterior vertebral wedging, and paravertebral abscesses. Neuroimaging-guided needle biopsy from the involved vertebral body is the gold standard for diagnosis. Patients with Pott's spine are managed with standard ATT, although the continuation phase may need to extend up to 18 months. Surgery for Pott's disease is indicated when patients present with neurologic deficits, large paravertebral abscesses, and spinal instability.[26]
Enhancing Healthcare Team Outcomes
CNS-TB is a rare form of tuberculosis but has a devastating impact on the quantity and quality of life. Screening for active infected cases in the community in the high TB burden settings may also prevent CNS-TB. Once diagnosed, treatment adherence is a significant predictor of treatment outcomes. Most countries have national policies in place, but global evidence-based approaches to CNS-TB care need to be fully adopted for optimal patient care and support.[111]
CNS-TB involves holistic and integrated team care to improve patient outcomes. Each team member, including the treating clinician, infectious disease specialist, neuroradiologist, neurologist, neurosurgeon and ophthalmologist, nurse, and pharmacist, has their individual and collaborative responsibility. The nurse is essential for overall patient care, and the pharmacist is critical for dispensing and ensuring compliance with treatment.[112][113] Pharmacists, particularly infectious disease specialty pharmacists, can play an important role in drug selection, medication reconciliation, dosing regimens and adjustments, and patient counseling. They must be able to communicate with the prescribing clinician when changes in the patient's status warrant therapeutic modification.
The entire team must communicate and collaborate for shared decision-making to minimize complications and hasten recovery in these critically ill patients.[114] In addition, improved modalities of infection control and surveillance are required to effectively screen and diagnose patients and also to deliver interprofessional services to diagnosed cases.[112]
To summarise, evidence-based guidelines for managing pulmonary and extrapulmonary TB are released by most countries. However, they often cannot consider the unique and compelling circumstances of every patient, region, and healthcare setting. Therefore, clinical decisions have to be individualized on case to case basis.[115]
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