TB SPINE - LABORATORY DIAGNOSIS,

MANAGEMENT OF TB SPINE INCLUDING

MDR CASES

Prsentation By: Dr Pramod N K, PGT

Moderator : Dr Banikanta Sharma
Associate Professor
Dept of Orthopaedics
BACKGROUND
Skeletal TB : approximately 10% of all extrapulmonary TB

Vertebral TB m/c of skeletal system (50%).

M≡F

m/c in first 3 decades and another peak >60y

 CASE DEFINITION : TB CASE
(1) Microbiologically confirmed TB case : refers to a presumptive TB patient with
biological specimen positive for acid-fast bacilli, or positive for mycobacterium
TB on culture, or positive for TB through Quality Assured Rapid Diagnostic
molecular test.

(2) Clinically diagnosed TB case : refers to a presumptive TB patient who is not

microbiologically confirmed, but has been diagnosed with active TB by a clinician
on the basis of X-ray abnormalities, histopathology or clinical signs with a decision
to treat the patient with a full course of anti-TB treatment.
LABORATORY DIAGNOSIS OF SKELETAL TB
CBC/ESR/CRP
Montoux test
IGRA and blood based ELISA for IFN- ᵞ
AFB culture
DST by CBNAAT/Gene Xpert/ Xpert MTB/PCR &
Line probe assay
COMPLETE HAEMOGRAM
Relative lymphocytosis
Low Haemoglobin (Anemia of chronic disease)
 ERYTHROCYTE SEDIMENTATION RATE(ESR)
Rate at which RBCs settle out when anti-coagulated blood is
allowed to stand.
Specimen : Whole blood
Measurement : Westergren method
Sensitive marker of infection : Usually >20mm/h in TB
Can be used to monitor therapeutic response : Decreases as
healing progresses. Prognostic value than diagnostic.
C-REACTIVE PROTEIN(CRP)
More specific for acute infection rather than TB.
 MONTOUX TEST
Delayed type hypersensitivity, About 2 to 4 weeks after infection: previously
sensitized CD4+ cells.
1-5U of PPD injected intradermally using 27G needle on flexor aspect of
forearm. Induration measured after 48-72hr.
0-4mm: Negative, 5-9mm: Doubtful or atypical Mtb, >10mm: Positive
TST Positive:
 less susceptible to new M.TB infection than TST negative.
 Shows active TB or reactivation.
 Infection with new strain possible.
It is of no value in endemic areas.
FALSE NEGATIVE TEST IN
1. Infections (measles, mumps, chickenpox, typhoid, leprosy)
2. AIDS
3. Hodgkin’s disease, lymphoma, leukaemia, sarcoidosis
4. Protein malnutrition
5. Miliary tuberculosis, TB meningitis, overwhelming active tuberculous
disease
6. Immunosuppressive drugs
7. Newborn and elderly
8. Faulty storage or dilution of PPD
9. Errors of administration and recording
10. Live viral vaccinations.
 FALSE-POSITIVE REACTIONS
Infection by atypical mycobacteria
Prior vaccination with BCG (Bacillus Calmette-Guerin),
an attenuated strain of M. bovis that is used as a
vaccine
ZIEHL-NEELSEN STAINING
Acid and alcohol fast bacilli: First stained with
carbol fuchsin resist decolourization with 20%
H2SO4 and alcohol for 10minutes.
Abundant mycolic acid in cell wall.
Beaded form seen in Mtb and more uniform
in M Bovis.
Atleast 10000 AFB should be present per ml
of sputum for them to be readily demonstrable
in direct smear
 AFB REPORTING AFTER Z-N STAINING
No of AFB Oil immersion field Report
0 300F AFB not seen
1-2 300F Doubtful, repeat smear
1-9 100F 1+
1-9 10F 2+
1-9 1F 3+
10 or more 1F 4+

Negative report given only after examining atleat 300 fileds, taking about 10minutes
Positive report can be given only if 2 or more typical bacilli have been seen
CULTURE: GOLD STANDARD
Obligate aerobe, Slow growing(4-8weeks). Grows luxuriantly(Eugonic)
but M bovis sparcely(Dysgonic).
Solid media : Lowenstein Jensen, Dorset
Liquid media: Dubos, Middlebrook, Proskauer, Becks, Sula and Sauton
LJ Media: M/c
Coagulated henn’s egg,
Mineral salt solution
Asparagine
Malachite green : Selective agent inhibits other bacteria.
BACTEC radiometric culture takes 2 weeks.
BIOCHEMICAL TESTS
Niacin test : Mtb form niacin on egg medium.
Aryl sulphatase test: Atypical mycobacteria
Catalase -peroxidase test: Mtb is catalase & peroxidase
positive, which indicates INH sensitivity. Its lost in INH
resistance
Amidase test: ability to split amides
Nitrate Reduction test: positive in Mtb, negative in M
bovis.
HISTOPATHOLOGIC EXAMINATION
H&E Stained: Tuberculous granuloma: immune
granuloma.
Activated macrophages in granuloma have pink granular
cytoplasm(abundant) with indistinct cell boundaries:
Epitheloid cells.
Collar of lymphocytes surrounds aggregates of epitheloid
macrophages.
Older granuloma : Rim of fibroblasts and CT.
Langhans giant cells: 40-50mcm in diameter
Central area of necrosis: Grossly granular, cheesy
appearance (Caseous). Microscopically, amorphous,
structureless, eosinophilic granular debris with loss of cellular
details.
Foreign body granuloma: No T cell activation.
TYPES OF GIANT CELLS
Langhans giant cell: Nuclei are present in periphery
and in horse shoe pattern. TB
Foreign body giant cell: Nuclei arranged randomly or
haphazardly. Forign bodies like suture, talc
Touton giant cell: Formed by fusion of epitheloid cells
and contain ring of nuclei surrounded by foamy
cytoplasm. Xanthoma, fat necrosis, xanthgranulomatous
inflammation and dermatofibroma.
Physiological giant cells: Osteoclasts,
Syncytiotrophoblasts and megakaryocytes.
IGRA AND BLOOD BASED ELISA FOR IFN- ᵞ
Measuring amount of IFN-ᵞ produced by T cells in response to
highly specific M.TB antigens (ESAT-6 and CFP-10).
INF-γ is the critical mediator that enables macrophages to contain
the M. tuberculosis infection.
IFN-γ stimulates formation of the phagolysosome in infected
macrophages, exposing the bacteria to an inhospitable acidic
environment.
T-SPOT.TB (an enzyme linked immunospot (ELISpot) assay
QuantiFERON-TB-GOLD (whole blood ELISA)
More specific than TST (less cross reactivity due to BCG
vaccination & non tuberculous mycobacteria)
 MOLECULAR METHODS
Molecular Methods are developed to target rpoB gene, which consist of 81-bp- hot-
spot regions from codons 507 to 533 called RRDR(Rifampin resistance determining
region).
High resistance to RIF : Point mutation at 526, 531
Low level resistance to RIF: Point mutation at 511, 516, 518, 522, 533.
Line Probe Assay XpertMTB/RIF assay( Sn 95.6%, Sp 96.2%)
Based on reverse hybridization of DNA strip Based on real time PCR.
Report in 2-3 days Result can be obtained as early as 90min.
Detect RIF and INH resistance due to Detects only RIF resistance.
mutations in KatG and inhA.
Open tube system : Increased risk of false Closed tube system
positivity
On the basis of the CBNAAT result, patients will be categorized as
microbiologically confirmed drug-sensitive TB or RIF-resistant TB

• A RIF indeterminate result will get an additional CBNAAT to get a

valid result and in case of indeterminate on second occasion, the
specimen will be sent to the Intermediate Reference Laboratory (IRL)
for Culture and Drug Sensitivity Test (C and DST) centre for Line Probe
Assay (LPA) for Liquid Culture and Drug Sensitivity Test (LC and DST)

• Whenever facilities are available, effort should be made to obtain

DST results of all drugs.
 IMAGING
Plain X-ray :
Have no role in early diagnosis of spinal TB
As the disease progresses: Disc space narrowing and rarefaction
of end plates .
Further destruction : Kyphosis and Instability.
Useful in assessing coronal and sagittal alignment.
CXR is essential : 60-70% of spinal TB may have active
pulmonary TB.
 Foci of diameter are not demonstrable (Schmorl & Jumghanns
1959, Boxer et al 1992)
Nearly 30-40% calcium must be removed to show a radiolucent area in x ray
First trabecular destruction may be identified after a lapse of 3-4 months after beginning of infectious
process
Cervical region:
Soft tissue shadow anterior to vertebral body :0.5cm: Above cricoid and 1.5cm : below cricoid.
Upper thoracic abscess;
 If large:V shaped shadow stripping lung apices laterally & downward
 If small : squaring of borders of superior mediastinum

C7-D4: Tracheal distance from vertebrae , normal <8mm.

Abscess below D4:
 typical fusiform shape (bird nest appearance)
 If abscess too large: generalized broadening of mediastinum.

Abscess and vertebral attachment of diaphragm:

Above : remain within thoax and Below : extend along psoas muscle.
 1. Paradiscal Type: m/c
2. Central cystic type :
Angular Kyphosis : Wedge 3. Anterior type
collapse of 3 or more 4. Appendicial : (pedicles, laminae ,
vertebrae transverse or spinous processes)
5. Synovial
Posterior vertebral articulation
Atlanto-occipital
Atlanto-Axial
SPINE AT RISK
To identify children at risk for severe deformity.
A. Seperation facet joints in lateral
view
B. Retropulsion of posterior part of
affected vertebra
C. Lateral translation of vertebrae
in AP view
D. Toppling of one vertebra over
other vertebra ( A line drawn
from anterior surface of caudal
normal vertebra crossed the
midpoint of anterior surface of
cranial normal vertebra)
 CT SPINE
 Demonstrates vertebral destruction well before Xay.
Extremely useful in identifying
 Extent of bony destruction
 Posterior column involvement
 Junctional pathologies
 Joint involvement
 Regional stability.
4 types of destruction noticed: in decreasing order of frequency
Fragmentary, Osteolytic, Subperiosteal, Localized sclerotic lesion.
Also of immense value in obtaining percutaneous CT guided biopsy.
MRI SPINE
Imaging modality of choice.
Able to detect earliest changes.
Gd enhanced MRI helps in differentiating TB from
other causes of infective spondylitis.
Extent of soft tissue involvement, Spread of
abscess, Neural compression are best visualized.
Also in assessing response to treatment.
IMAGING: CLINICO- RADIOLOGICAL CLASSIFICATION
18F-FDG PET SCAN
Helps in real time assessment of disease
activity.
18F-FDG is known to accumulate in
inflammatory cells (Neutrophils, activated
macrophages) at the site of inflammation.
HOWEVER
None of the imaging options are reliable in
distinguishing spinal infection and neoplasm.
Radiological and MRI evidence of healing lags
behind biological processes in Spinal TB
(Despite satisfactory clinical and favourable lab
findings : Xray/MRI done upto 5months of ATT may
show deterioration).
IF MRI after 6months no improvement: Alternative
pathology/therapeutically refractory disease.
 TO SUMMARIZE
Diagnosis of spinal TB is based on correlating
clinical and classical image findings on MRI and is
confirmed by either culture and sensitivity, Gene
Xpert PCR or HPE study.
 MANAGEMENT OF TB SPINE
Evolution
Pre antibiotic era:
Orthodox conservative regime or by various operative
procedure
Post antibiotic era:
Operative in all cases in conjunction with ATT
ATT in all cases with operation for failures or complications
 ORTHODOX TREATMENT

Strongly advocated recumbency, immobilization by means of body casts,

plaster beds and braces.
Atharvas (1800-1000BC) treat with Sipudru (Herbal preparation) and
Sunshine.
Hippocrates and Galen(131-201AD) tried to correct kyphotic deformity by
manual pressure , traction & mechanical appliances but failed.
In Specialized hospitals: Heliotherapy and open air.
Sir Robert jones & Dame agnes: fresh air, sunshine, adequate food and
rest.
Avrg time of hospitalization : 1 -5 years
RESULTS OF ORTHODOX TREATMENT
Alvik 1949, Dobson 1951, Fellander1955, Fox 1962: Of all treated
patients
 30-44% : full working capacity
 Rest : either died or severely crippled.
In Dobsons(1951) series: out of 394 cases
 31% : developed paraplegia
 25% of paralyzed : died
Girdlestone & Somerville(1965): 28% mortality our of 130 nonparaplegic
cases
Paus (1964): Kyphosis could develop or increased when treated with plaster
bed.
Failure in preventing onset of paraplegia
 CLASSIFICATION OF TUBERCULOUS PARAPLEGIA
Group A: Early onset paraplegia
Within first 2 years
During active stage of disease
Due to
Inflammatory edema
Tuberculous granulation tissue, abscess,
caseous tissue. Rarely ischemic lesion of
cord.,
Group B :Late onset paraplegia
More than 2 years after disease has
persisted in spine.
Due to
• Mechanical pressure:
Tb caseous tissue, debris, sequestra
from vertebral body &disc, Internal
gibbus, stenosis if vertebral canal or
severe deformity
• Recruidescence(recurrence/relapse)
of disease: similar to early onset
paraplegia.
STAGING OF POTT’S PARAPLEGIA
PROGNOSIS FOR RECOVERY OF CORD FUNCTION
CONVENTIONAL TREATMENT: TULI
Anti tubercular drugs are the most important therapeutic measure
ATT must be continued for about 18 months( must include Isoniazide)
Patients with early disease can achieve full clinical healing
Indications of surgery are mainly for complications than for the disease control
MIDDLE PATH REGIMEN : TULI
No neurological recovery after 4 weeks of ATT
Development of neurological deficit during the course of chemotherapy
Recurrence of neurological deficit after initial improvement
Worsening of neurological deficit while on chemotherapy
Advanced case of neurological involvement
MIDDLE PATH REGIMEN
Rest : Hard bed, plaster of paris bed, Traction
Drugs :
 Intensive Phase: H(300-400mg)+ R(450-600mg)+ Ofx(400-600mg) for 5-6 months
 Continuation Phase : H+Z for 3-4 months followed by H+R for 4-5 months
 Prophylactic phase : H+E for 4-8 months

Radiographs and ESR taken & called for check up at 3-6months interval
CT/MRI scan for Craniovertebral , cervicodorsal, lumbosacral regions and SI joints and at 6 months
interval for 2 years
Gradual mobilization : if no neuro deficits using brace. After 3-9wks extension exercises
Abscesses : aspirated when near surface & 1g of Streptomycin with or without INH
Sinuses : large majority heals within 6wk to 12 wks
Neural complications
Surgical procedures
 NATURAL COURSE OF DISEASE
Pre antibiotic era
Severe crippling deformities
Cold abscesses
Multiple discharging sinuses
Spread to other parts
Paraplegia and its complications
Amyloidosis
Modern era with ATT
Paradiscal (Predestructive stage): Heales with no
radiological deformity, except diminished disc space
In early stage:Ivory vertebra( disease focus surrounded
by sclerotic bone): Rx Sharpening of fuzzy paradiscal
margins
If several vertebral bodies involved: large gap, fibrous
tissue
If disc space completely destroyed: Gap obliterated by,
Collapse and telescopy heals by bony ankylosis or bone
block
MANAGEMENT ALGORITHM : POTTS PARAPLEGIA
MAIN INDICATIONS FOR SURGERY IN TB SPINE
Due to ATT surgical indications redused to 5% of uncomplicated and 60%
cases with neurodeficits
 CURRENT TRENDS IN THE SURGICAL
MANAGEMENT OF SPINAL TUBERCULOSIS
AIMS:
Correction of kyphosis
Early fusion
Prevention of progression of kyphosis
Prevention of late onset paraplegia
CURRENT TRENDS
Anterior debridement and anterior column reconstruction
with bone grafting or CAGE
 Helps in neurological recovery and produces early fusion
 However, achieves only limited correction of kyphosis and may not be
able to prevent progression

Debridement, posterior instrumentation and fusion :

 Aggressive correction of kyphosis can be achieved
 Prevents recurrence of kyphosis
 Not beneficial without anterior debridement and fusion
Combined anterior and posterior :
CORRECTION OF KYPHOSIS
ANTERIOR DEBRIDEMENT AND
ANTERIOR COLUMN RECONSTRUCTION
POSTERIOR AND COMBINED
 ANTI TUBERCULAR THERAPY
Latest RNTCP guideline.
Patient diagnosed with TB
 Start ATT 1st line: HRZE. Send specimen for DST.
If no resistence : 2HRZE+6HRE: 6months
If needed in case of skeletal TB, CP can be extended 3months.
For extension of CP beyond 3 months expert decision is required.
If resistance detected follow guidelines for MDR TB.
DISCOVERY OF ANTI TUBERCULAR DRUGS
Streptomycin - 1944 :Discovered by Schatz, Bugie and Waksman
Pyrazinamide – 1949 Weight category Adults=A
HRZE(75/150/400/275)
Isoniazid – 1951 25-39kg 2
40-54kg 3
Rifampicin – 1957
55-69kg 4
Ethambutol – 1961 >=70 5

Weight category Children: HRZE(50/75/150/100)

1st line ATT Per Kg/Day
4-7kg 1
H 5
8-11kg 2
R 10
12-15kg 3
Z 25 16-24kg 4
E 15 25-29kg 3+1A
30-39kg 2+2A
 ATT
First line drugs Second line drugs

1. Isoniazid (H) • Ethionamide (Eto)

2. Rifampin (R) • Rifabutin
3. Pyrazinamide (Z) • Prothionamide (Pto)
4. Ethambutol (E) • Cycloserine (Cs)
5. Streptomycin (S) • Terizidone (Trd)
• Para-aminosalicylic acid (PAS)
• Thiacetazone (Thz)

Fluoroquinolones:
Ofloxacin (Ofx), Levofloxacin (Lvx/Lfx), Moxifloxacin
(Mfx), Ciprofloxacin (Cfx)

Injectable drugs
• Kanamycin (Km)
• • Amikacin (Am)
• Capreomycin (Cm)
HIV & TB CO-INFECTION
Start ATT first .
Start ART as soon as TB treatment is tolerated (between2 wks and
2m).
Start ART irrespective of any clinical stage/CD4 count of any
value
Start ART Regimen TLE(300/300/600mg) for patients not on
ART.
For patients already on ART, ZLN, shift to ZLE & continue ZLE even
after ATT is stopped.
INH PREVENTIVE THERAPY FOR PLHIV
Adults/Adolescents/Children with HIV who are unlikely to
have active TB on symptom based screening.
All children with HIV who have completed Rx for TB.
Adults & adolescents: Daily INH 300mg+B6 50mg X 6
months.
Children(>1yr): Daily INH 10mg/kg+B6 25mg X 6
months.
 DRTB
1. Mono resistance (MR) – A TB patient whose biological specimen is resistant to one
first-line anti-TB drug only.
2. Poly resistance (PDR) – A TB patient whose biological specimen is resistant to
more than one first-line anti-TB drug, other than both INH and Rifampicin.
3. Multi-drug resistance (MDR) – A TB patient whose biological specimen is resistant
to both INH and Rifampicin with or without resistance other first-line ATD, based on
results from a Quality Assured Laboratory.
4. Rifampicin resistance (RR) – Resistance to Rifampicin detected by phenotypic or
genotypic methods with or without resistant to other ATD excluding INH. Patient with
RR should be managed as if they are in MDR TB case.
5. Extensive drug resistance (XDR) – MDR TB case whose biological specimen was
resistant to a Fluroquinolone (FQ) and a second-line injectable ATD from a Quality
Assured Laboratory.
MDR TB
MDR/RR TB cases (without additional resistance)
Treatment regimen for MDR TB contains
6–9 months of IP with Kanamycin, Levofoxacin,
Ethambutol, Pyrazinamide, Ethionamide and Cycloserine and
18 months of CP with Levofoxacin, Ethambutol,
Ethionamide and Cycloserine
 “ Level of INH resistance
• If RR by CBNAAT, add INH in std. dose till reports of Liquid culture DST/LPA
are known.

”
INH
Liquid Culture High Level Resistance Omit
Low level resistance High dose
LPA(Line Probe Assay) KatG mutation Omit
report InhA mutation High dose
Type Of DRTB IP CP

RR (6-9) Km Lfx Eto Cs Z E H (18) Lfx Eto Cs E H

MDR (6-9) Km Lfx Eto Cs Z E (Modify treatment (18) Lfx Eto Cs E

based on the level of
INH resistance as per the footnote)

MDR/RR+ER (6-9) Km Lfx Eto Cs Z (18) Lfx Eto Cs

MDR/RR+ZR (6-9) Km Lfx Eto Cs E (18) Lfx Eto Cs E

MDR/RR+ER+ZR (6-9) Km Lfx Eto Cs PAS (18) Lfx Eto Cs PAS

MDR/RR+LfxR (6-9) Km Mfx Eto Cs Z E PAS Cfz (18) Mfx Eto Cs E PAS Cfz

MDR/RR+MfxR (6-9) Km Lfx Eto Cs Z E PAS Cfz (18) Lfx Eto Cs E PAS Cfz

MDR/RR+All FQR (6-12) Km Eto Cs Z E PAS Cfz Lzd (18) Eto Cs E PAS Cfz Lzd
 “
Type Of DRTB IP CP

MDR/RR+KmR (6-9) Cm Lfx Eto Cs Z E (18) Lfx Eto Cs Z E

”
MDR/RR+All SLInjR (6-12) Lfx Eto Cs Z E PAS Cfz Lzd (18) Lfx Eto Cs E PAS Cfz Lzd

XDR (6-12) Cm PAS Mfx High dose H Cfz (18) PAS Mfx High dose H Cfz Lzd
Lzd Amx/clv Amx/clv

For mixed resistance pattern, consider oral drugs in following sequence of preference:
Z(If sensitive), E, Eto, Cs, PAS, Cfz, Lzd, Amx/Clv, High dose INH, Clarithromycin.
ADVERSE EFFECTS
 MONITORING DRUG TOXICITY
m/c reaction of significance is hepatitis.
For all patients before starting ATT , baseline LFT.
If signs & symptoms of drug induced hepatitis(Dark urine,
loss of appetite) : Repeat LFT
If patient using alcohol daily or h/o hepatitis(esp HepC):
Monthly LFT
If symptomatic hepatitis & ALT increased more than 3
times
To stop ATT and to reintroduse after LFT returned to normal.
If gouty arthritis due to Z : Stop Z
If autoimmune thrombocytopenia secondary to R : stop R