Extrapulmonary tuberculosis
CNS and Skeletal TB
Dr. S.N.H.Nimesha
Senior Registrar in pulmonology
CNS Tuberculosis
● Clinical CNS TB occurs in 1 to 2% of all patients with active TB
● Around 8% of all extrapulmonary cases
● But the diagnosis can be challenging with sub acute and atypical Presentations.
● The monitoring of the disease difficult with no proper markers.
● The disease trajectory may be complicated with immunological phenomenon
● Need long term treatment and associated complications
CNS Tuberculosis
Main disease presentations
1. Tuberculous meningitis
2. Tuberculoma
3. Spinal arachnoiditis ( TB radiculomyelitis )
Pathogensis
● During the bacterial that follows primary infection or late reactivation TB bacilli
may seed to the brain, meninges or adjacent bone forming tb foci ( Rich foci)
● This can eventually leads to CNS disease
● They may rupture in to sucarachnoid space causing meningitis
● Can cause deep cerebral access or tuberculoma
Tuberculous meningitis
● Develops most commonly as a complication of progressive primary
infection in infants and young children
● As chronic reactivation bacillemia in adults with immune deficiency.
(aging, alcoholism, malnutrition, malignancy, HIV infection or drugs)
● The presentation may be subacute ,subtle or atypical
● Mortality is around 15 %-40%.
● 25% ends up with long term disability.
Clinical manifestations
● Headache
● Fever
● Vomiting
● Altered sensorium
How does it differs from the bacterial meningitis
Subacute presentation
Presence of neurological symptoms
Presentation with cranial nerve palsies ( III and VI )
Atypical manifestations
● Patients may present with atypical features that mimic other neurologic
conditions.
● Acute, rapidly progressive meningitic syndrome suggesting pyogenic
meningitis, or with slowly progressive dementia over months characterized by
personality change, social withdrawal, loss of libido, and memory deficits.
● Less commonly, patients may present with an encephalitic course manifested
by stupor, coma, and convulsions without overt signs of meningitis
Stages of the TB meningitis
Patients with tuberculous meningitis typically progress through three phases
Prodromal phase
● Lasts one to three weeks
● Characterized by the insidious onset of malaise, lassitude, headache, low-grade fever, and personality change.
Meningitic phase
● More pronounced neurologic features, such as meningismus, protracted headache, vomiting, lethargy, confusion, and
varying degrees of cranial nerve and long-tract signs.
Paralytic phase
● With disease progression confusion gives way to stupor and coma, seizures, and often hemiparesis.
● For the majority of untreated patients, death ensues within five to eight weeks of the onset of illness.
Complications
Stroke
Seizures
Hydrocephalus
Hyponatremia
Vision loss
Transverse myelitis
Hydrocephalus inthe lateral ventricles
Basal exudate in MRI
Patients with HIV
● HIV infection is an important risk factor for tuberculous
● The presentation of TB meningitis is similar to that of non HIV infected patient.
● However, concurrent TB outside the CNS and lung occurs more commonly.
● Initiation of antiretroviral therapy in patients with HIV infection and no prior
CNS symptoms may precipitate onset of new symptoms, reflecting
progression of underlying TB infection as a manifestation of immune
reconstitution inflammatory syndrome.
Lung and brain involvement of miliary TB
Tuberculoma
▪ Deep-seated tubercular granulomatous foci acquired during initial bacteremia may coalesce
and develop into conglomerated caseous masses
▪ They occur most commonly in the brain and may also occur in the spinal cord
▪ They are often clinically silent and may reach considerable size in the absence of meningeal
inflammation
▪ In immune-suppressed individuals, these may form tubercular abscesses
▪ Tuberculomas may develop during adequate antituberculous therapy; this may be a result of the
immune response against dying M. tuberculosis organisms
Spinal arachnoiditis
▪ Present with radiculomyelopathy secondary to entrapment of nerve roots and
encasement of the cord due to severe arachnoiditis at single or multiple levels
▪ Present with radicular pain, hyperesthesia, flaccid paralysis, and urinary or
stool incontinence
▪ Cord infarction may occur due to arteritis and thrombosis of the anterior spinal
artery
Diagnosis of CNS tuberculosis
● Can be challenging due to atypical and subtle presentation
● Tests are not absolute and has many differentials.
● Tests has suboptimal sensitivity and specificity.
A presumptive diagnosis of tuberculous meningitis may be made in the setting of
relevant clinical and epidemiologic factors and typical CSF findings (lymphocytic
pleocytosis, elevated protein concentration, and low glucose concentration).
Diagnosis
● Routine blood counts and chemistries are relatively nonspecific.
● Hyponatremia may be observed in the context of inappropriate antidiuretic
hormone or cerebral salt wasting
● CXR abnormalities may be seen in up to half of patients with CNS TB.
● The tuberculin skin test (TST) or an interferon-gamma release assay (IGRA)
is frequently positive.
● But they can be negative in immunosuppressed patients.
The diagnosis may be definitively established in the setting of cerebrospinal fluid
(CSF) with positive smear for acid-fast bacilli (AFB), CSF culture positive for M.
tuberculosis, or CSF with positive nucleic acid amplification test (NAAT)
CSF examination
● LP opening pressure should be measured.
● CSF is sent for,
Full report- total cell count with white blood cell differential, protein
concentration, and glucose concentration
NAAT
AFB smear and culture
Cryptococcal antigen ( HIV patients )
CSF Full report
1. WBC typically between 100- 500 cells with lymphocyte predominance
2. Protein is typically between 100- 500 mg/dl
3. If Protein concentration is >10 g/dl → suspect CSF block
4. Glucose concentration is low → <45mg/dl.
Acid-fast bacilli smear and culture
The sensitivity of acid-fast staining for diagnosis of tuberculous meningitis is 30 to 60 %.
The diagnostic yield is increased with volume of CSF (up to 10 to 15 mL) and number of
CSF specimens (up to four)
AFB smears and cultures may be positive even days after treatment has been initiated.
Organisms can be demonstrated most readily in a smear of the clot or sediment.
If no clot forms, addition of 2 mL of 95% alcohol induces a heavy protein precipitate that
carries bacilli to the bottom of the tube upon centrifugation.
Nucleic acid amplification test
● Has rapid turn over with high specificity
● Test may be positive several months after treatment as well
● Xpert MTB/RIF or Xpert MTB Ultra can be used
● GeneXpert MTB/RIF has sensitivity of 20- 60 %
● GeneXpert MTB Ultra Sensitivity is 44-77 %
CSF ADA testing
High ADA level can aid in the diagnosis
Yet bacterial meningitis also can give rise to the same rise and the interpretation
has to be done in the clinical context
Radiographic imaging
Computed tomography (CT)
Magnetic resonance imaging (MRI)
● MRI is superior To CT
● Classic image findings include basilar extrudate, hydrocephalus,
periventricular infractions and tuberculomas
● Tuberculoma present as a ring enchancing lesion with perileisional oedema
● Tuberculoma can be single or multiple
● The presence of ring enhancing lesions is not definitely a tuberculoma
Differential for ring enchancing lesions
● Cryptococcal meningitis
● Toxoplasmosis
● Metastasis
● Lymphoma
● Sarcoidosis
Treatment for TB meningitis
● Prompt administration of antituberculous therapy, together with
glucocorticoids.
● For patients with hydrocephalus, surgical consultation is warranted.
● Empiric treatment should not be delayed, given the high mortality and
complication rate of untreated infection
In general, treatment of CNS TB consists of an initial intensive phase (four
drugs administered for two months) followed by a prolonged continuation
phase (usually two drugs administered for an additional 7 to 10 months), for
a total treatment duration of 9 to 12 months
Intensive phase
For empiric treatment- four-drug regimen consists of isoniazid, rifampin, pyrazinamide,
ethambutol
Isoniazid, rifampin, and pyrazinamide are bactericidal and penetrate inflamed meninges
Isoniazid, pyrazinamide have excellent CNS penetration and is more active against rapidly
dividing organisms
Rifampin is active against both rapidly dividing organisms and semi-dormant organisms, despite
its relatively poor CNS penetration
Pyrazinamide is highly active against intracellular mycobacteria
Ethambutol has relatively poor cerebral spinal fluid (CNS) penetration
Streptomycin is considered to have weak bactericidal properties. But Poor CNS penetration even
with inflamed Meninges
Other options include levofloxacin, ethionamide, and streptomycin, which have
better CNS penetration than ethambutol.
The WHO 2010 guidelines favored use streptomycin over ethambutol as a fourth
drug
however, a subsequent WHO 2022 statement favored use of ethambutol as a
fourth drug in adults
Continuation phase
Continuation phase consists of isoniazid and rifampin (given daily), continued for 7
to 10 months
The optimal duration of treatment is uncertain
An extended period of treatment is administered because tuberculous meningitis
is associated with high rates of disability and deaths
Antiretroviral therapy
Patients with HIV infection are treated with the same antituberculous therapy as
patients without HIV infection
Patients on antituberculous therapy, administration of antiretroviral therapy (ART)
requires careful attention to potential interactions, particularly with rifamycins.
CDC/ATS/IDSA guidelines recommending that initiation of ART should be delayed
for the first eight weeks of antituberculous therapy, regardless of CD4 count
Initiation of ART may be complicated by the immune reconstitution inflammatory
syndrome (IRIS), which can manifest as progression of TB disease or clinical
deterioration in patients previously improving on antituberculous therapy.
Glucocorticoids
● WHO which recommends six to eight weeks of adjunctive glucocorticoid
therapy for patients with tuberculous meningitis.
● Glucocorticoids given to patients with and without HIV infection.
● Dexamethasone or prednisolone can be given.
● After six to eight weeks, glucocorticoids should be tapered off.
● This helps to reduce the inflammation in brain
● Corticosteroids significantly improve survival rates
Patients >14 years of age
1. Dexamethasone 0.3 to 0.4 mg/kg/day intravenously (IV) for 2 weeks
2. Then 0.2 mg/kg/day IV week 3
3. Then 0.1 mg/kg/day IV week 4
4. Then 4 mg per day orally and taper 1 mg off the daily dose each week
5. Total duration approximately eight weeks.
In conscious patients, oral prednisolone 0.5 mg/kg (up to 40 mg/day) may be
given for four weeks and then tapered over the following four weeks
Treatment of tuberculoma
▪ Treatment of tuberculoma consists of anti-tuberculous therapy
▪ For tuberculomas duration is usually extended, intensive phase for 3 months
and continuation phase for 18 months
▪ But adjunctive glucocorticoids are not usually prescribed for Tuberculomas
▪ Surgical consultation is warranted for patients with obstructive hydrocephalus
or brainstem compression
▪ Intracranial tuberculoma may persist following comprehensive anti-tuberculous
therapy
▪ In some cases they may persist for several years
▪ Persistent tuberculoma does not represent active disease
▪ Experts believe that persistent tuberculoma does not represent treatment failure
and prolonged anti-tuberculous therapy in an otherwise asymptomatic patient is
not needed
▪ No trials have evaluated whether patients with tuberculoma benefit from
adjunctive glucocorticoids.
Treatment of transverse myelitis
Consists of anti TB treatment with steroids
Paradoxical worsening
● After initiation of antituberculous therapy, paradoxical worsening of
clinical manifestations or progression of CNS lesions with initial
improvement.
● Among patients with HIV infection, paradoxical worsening typically occurs
after initiation of ART and is known as IRIS.
● The risk of IRIS is increased in patients with an initial CD4 count below
100/microL and in patients with a rapid fall in viral load and rise in CD4 count.
● Manifestations of CNS disease progression in the setting of IRIS include
meningitis, intracranial tuberculoma, brain abscess, radiculomyelitis, and
spinal epidural abscess
● Diagnosis of IRIS is one of exclusion.
● Patients should be evaluated with radiographic imaging and CSF examination
if feasible.
● CSF examination may demonstrate neutrophilic predominance
● Treatment is steroids with continuation of ATT
Follow up in CNS tuberculosis
Clinical symptoms follow up plays a major role
Follow up imaging also recommended. But the improvement may be differs
among cases and may takes some time for improvement
Some like tuberculoma, may not improve
Might develop complications during the course of illness and need additional
treatment.
Skeletal tuberculosis
Of all TB cases, 1%–3% show skeletal system involvement and 30% are HIV
coinfected.
Distribution of skeletal TB is majorly in the spine, followed by the hip, knee, and
foot/ankle
It is the third most common Extra pulmonary TB
Pathology
● During primary M. tuberculosis infection, bacillemia may lead to seeding of
organisms in bone and/or synovial tissue.
● In most cases, small foci of infection are confined by local adaptive immune
processes, and infection is subclinical.
● Following primary infection, reactivating foci are usually contained by the cellular
immune response.
● CD4 and CD8 lymphocytes play important roles, as does interferon-gamma.
● The likelihood of reactivation of infection with progression to clinically apparent
disease increases when local immune defenses fail, as in the setting of malnutrition,
advancing age, HIV infection, or advanced kidney disease
● Active TB disease can develop immediately or after decades of latent
infection.
● In highly endemic regions, musculoskeletal TB usually manifests clinically in
the year following primary lung infection and therefore occurs more frequently
in relatively young patients
● Outside highly endemic areas, musculoskeletal TB is more commonly
associated with late reactivation of infection and occurs mainly in adults.
● Rarely, bones and joints are involved in contiguous spread of TB from another
site.
Types of skeletal tuberculosis
1. Spondylitis (Pott disease)
2. Arthritis
3. Osteomyelitis
Spondylitis (Pott disease)
● Most commonly affects the lower thoracic and upper lumbar region.
● Involvement of the cervical and upper thoracic region is less common.
● Progression of infection generally begins with inflammation of the anterior aspect of
intervertebral joints.
● typically, it spreads behind the anterior ligament to involve the adjacent vertebral body.
● Once two adjacent vertebrae are involved, infection enters the adjoining intervertebral disc space.
● This tends to occur later in Pott disease than in bacterial vertebral
● Osteomyelitis and may have the radiographic appearance of relative disc sparing.
● Eventually, the avascular disc tissue dies with vertebral narrowing and subsequent vertebral
collapse.
● Gibbus deformity, a form of structural kyphosis, distorts spinal canal anatomy.
● Local pain is the most common and Associate with muscle spasm and rigidity.
Arthritis
Tuberculous arthritis can occur in virtually any joint, but it tends to occur in the hip
or the knee
Usually, it is monoarticular.
Hip involvement is the most common.
TB arthritis - infectious
Clinical manifestations include
● Swelling, pain, and/or loss of joint function that progresses over weeks to
months.
The joint is generally "cold"
Constitutional symptoms, fever, and weight loss occur in only about 30 percent of
cases
Patients who present late in the course of disease often have evidence of joint
destruction including local deformity and restricted range of motion.
Advanced disease can have draining sinuses.
Granulomatous changes typically accompany synovial proliferation in tuberculous
arthritis, with joint effusion and erosion of cartilage.
The consequences are slowly progressive destruction, disorganization of joint
architecture, and potential deformity
Types of bone involvement – Infectious
1. Caseous exudative type - bone destruction, local swelling, abscess formation,
sinus formation, and constitutional symptoms. It occurs most often in children.
2. Granular type- More insidious and less destructive than the caseous
exudative type, and abscess formation is less common. It occurs most often
in adults.
Inflammatory (Poncet disease)
Acute symmetric polyarthritis involving large and small joints associated with active
extrapulmonary, pulmonary, or miliary TB.
There is inflammation of the involved joints but no objective evidence of active TB
Poncet disease is relatively rare, and the pathogenesis is unclear.
It is probably immune mediated.
HIV coinfection is also a risk factor.
The arthritis generally resolves within a few weeks of initiation of anti-TB therapy, with no
residual joint destruction
Prosthetic joint infection
Rarely, M. tuberculosis can cause infection at the site of a prosthetic joints.
Diagnosis has been described at the time of initial arthroplasty as well as
subsequent to hardware placement.
Osteomyelitis
Tuberculous osteomyelitis can occur in virtually any bone, including the ribs, skull,
tubular bones of the hands and feet (dactylitis), wrist, phalanx, pelvis, and long
bones.
The onset is often insidious but, in rare cases, the onset may be acute or
subacute.
Typically, osteomyelitis occurs at a single site.
However, rarely bony involvement can be multifocal.
Can present as cold abscesses.
DIAGNOSIS
Diagnosis is challenging especially since there is no evidence of active chest
disease in the majority cases.
The diagnosis of musculoskeletal TB is established by microscopy and culture of
infected material.
Tissue may be obtained by needle aspiration and/or biopsy for culture.
Drug susceptibility testing of isolates is essential.
Synovial fluid findings are usually nonspecific; the white cell count can be high or
low, with preponderance of either neutrophils or lymphocytes.
The Xpert MTB/RIF can simultaneously identify M. tuberculosis and rifampin
resistance.
GeneXpert and Xpert Ultra shows sensitivity of 79 and 91 percent, respectively.
Radiology in bone TB
Radiological tests also helps in the diagnosis
MRI is the modality of choice
Need to look pulmonary involvement in all patients
Radiography in Pott disease
1. First observed in the anterior aspect of a vertebral body, with demineralization of the end plate and
loss of definition of the bony margin
2. Subsequently, the opposing vertebra becomes involved
3. As infection progresses, the disc is also involved and disc space narrowing occurs
4. Finally anterior wedging and angulation
In some patients, spinal TB presents with osteolytic lesions in the absence of disc space
involvement; these lesions may occur at multiple sites
TREATMENT
General approach — Treatment of musculoskeletal TB consists of antimicrobial
therapy.
In some cases, surgical intervention is also warranted.
Pain relief takes a special place in the management
Duration of treatment
▪ Duration of treatment usually 9-12 months
▪ Intensive phase 2 months
▪ Continuation phase 7-10 months
▪ Longer duration of therapy (9 to 12 months) is warranted for patients on regimens that do
not include rifampin and/or for patients with extensive or advanced disease, particularly if it
is difficult to assess the response to therapy
Drug-resistant infection – Data are limited on the optimal drug regimen and
duration for treatment of musculoskeletal infection due to drug-resistant M.
tuberculosis.
Data on shorter-course regimens employing bedaquiline and/or linezolid for
musculoskeletal tuberculosis are limited.
Indications for surgery
●Patients with spinal disease and advanced neurological deficits
●Patients with spinal disease and worsening neurological deficits progressing while on
appropriate therapy
●Patients with spinal disease and kyphosis >40 degrees at the time of presentation
●Patients with chest wall cold abscess
Forms of surgical intervention may include decompression, use of hardware for stabilization of
spine, abscess drainage, and/or debridement of infected material
Monitoring of the disease
Response can be monitored by clinical indicators such as pain, constitutional
symptoms, mobility, and neurologic findings.
Typically, responses to therapy are relatively slow (several months).
The role of inflammatory markers in monitoring the response to TB therapy is
limited.
It is not useful to perform serial radiographs since radiographic findings may
appear to progress during appropriate treatment
Take home messages
1. The presentation of CNS and bone TB can be subacute and subtle. Thus
vigilance diagnosis is needed.
2. The diagnostic tools are not absolute and should be interpreted in the clinical
context
3. Follow up is mainly with clinical and aided by imaging
4. The disease course can be affected by disease and treatment related
complications and need timely management.
Thank you
Any questions ?????
