Tuberculosis of The Spinal Cord.5
Tuberculosis of The Spinal Cord.5
Tuberculosis of The Spinal Cord.5
Abstract
Tuberculosis involving the spinal cord is associated with high mortality and disabling long‑term sequelae. Although tuberculous radiculomyelitis
is the most frequent complication, pleomorphic clinical manifestations exist. Diagnosis can be challenging among patients with isolated spinal
cord tuberculosis due to diverse clinical and radiological presentations. The principles of management of tuberculosis of the spinal cord are
primarily derived from, and dependent upon, trials on tuberculous meningitis (TBM). Although facilitating mycobacterial killing and controlling
host inflammatory response within the nervous system remain the primary objectives, several unique features require attention. The paradoxical
worsening is more frequent, often with devastating outcomes. The role of anti‑inflammatory agents such as steroids in adhesive tuberculous
radiculomyelitis remains unclear. Surgical interventions may benefit a small proportion of patients with spinal cord tuberculosis. Currently,
the evidence base in the management of spinal cord tuberculosis is limited to uncontrolled small‑scale data. Despite the gargantuan burden of
tuberculosis, particularly in lower and middle‑income countries, large‑scale cohesive data are surprisingly sparse. In this review, we highlight
the varied clinical and radiological presentations, performance of various diagnostic modalities, summarize data on the efficacy of treatment
options, and propose a way forward to improve outcomes in these patients.
meningitis. The impact of such interventions on SCTB is For reprints contact: [email protected]
unclear. Moreover, fibrinolysis has been employed with DOI: 10.4103/aian.aian_578_22
112 © 2022 Annals of Indian Academy of Neurology | Published by Wolters Kluwer - Medknow
Garg, et al.: Spinal cord tuberculosis
the past 10 years but also referenced important older reports SCTB originates in one of three ways: 1) rupture or evolution
and seminal descriptions. Articles in English were included. of hematogenously disseminated tubercular foci on the
We also cross‑searched reference lists of articles identified spinal meninges or spinal cord, 2) downward extension of
by this search strategy. We included systematic reviews and intracranial exudates to subarachnoid space producing spinal
meta‑analyses, randomized trials, case series and case reports, arachnoiditis, and 3) extension of adjacent vertebral disease
and animal research, wherever relevant. to spinal meninges.[1,12,13] The commonest mechanism is via
the hematogenous route.
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atypical forms of spinal tuberculosis such as tubercular inflammation, 2) the arachnoiditis phase defined by ongoing
myelitis, intradural tuberculosis, and spinal cord fibroblast proliferation and collagen deposition causing
complications of tubercular meningitis.[8] Mycobacterium nerve root adhesions, and 3) the final adhesive arachnoiditis
tuberculosis (MTB) gains entry to the host through droplet phase identified by atrophied nerve roots encapsulated in
inhalation. Bacterial phagocytosis by macrophages triggers dense collagen.[14] The subarachnoid space in patients with
a cascade of inflammation resulting in the primary complex. spinal TBM contains thick gelatinous exudates, encasing the
During the short period of bacteremia, MTB can spread spinal cord and radicles partially or completely. There may
hematogenously to the central nervous system (CNS) and be hyperemia and edema of the cord and radicles because of
form granulomas on meninges, sub‑pial, and sub‑ependymal inflammation.[8,13,15] The exudates may cover several spinal
surfaces known as “Rich foci,” which may later rupture or segments and are predominantly located posteriorly, possibly
grow. due to the prolonged supine position of patients.
The first description of spinal arachnoiditis leading to The pathogenesis of TBRM shares similarities with models
subarachnoid obstruction and myelopathy was given by of experimental allergic encephalomyelitis (EAE).[16] The
Sir Victor Horsley. [9] In 1947, Ransome and Montiero characteristic features of TB myelitis include inflammatory cell
published four cases of tuberculous myelopathy in the infiltration, perivascular demyelination, axonal damage, and
absence of Potts’s disease, contrary to the belief that TBRM activation of glial tissue [Figure 1].[12,13] Inflammatory exudates
was always a complication of vertebral tuberculosis. [10] can damage the parenchyma by direct infiltration or cause
Dastur reviewed 74 cases of tuberculous paraplegia without subarachnoid block due to elevated cerebrospinal fluid (CSF)
evidence of Pott’s spine. [11] He observed extradural protein. Occasionally, extensive exudates compress the cord
granulomas and arachnoid lesions without dural involvement without direct invasion. Demyelination of the entrapped nerve
in 64% and 20% of patients, respectively. Intramedullary roots and white matter damage leads to axonal loss. Occlusion
lesions and subdural extramedullary lesions were present of the spinal vessels by necrotizing granuloma or vasculitis
in 8% each. can cause spinal cord infarction.[13,16]
Figure 1: Pathological changes associated with early and late tuberculous radiculomyelitis
final stages.
Syrinx develops as a late complication of TBM, though
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the spinal cord, with thoracic regions receiving nearly 45% myelitis (LETM) have been reported in the literature and
of total cord blood flow. Diagnosis may be challenging as, should enter the differential diagnosis for TM in countries in
unlike the brain, ring enhancement on MRI may be minimal which tuberculosis is endemic. In a review of 10 patients with
to absent in the spinal cord.[29] Epidural and spinal subdural tuberculous LETM, extensive myelitis extending up to the
tubercular abscesses may also occur, rarely without osseous conus was described.[40] Most of these patients presented with
involvement.[30,31] acute or subacute onset paraplegia with bladder involvement,
in association with fever, headache, or altered sensorium. The
Syrinx formation
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the fact that only 15% of the patients in the Vietnamese cohort of the involved structures and associated complications.
were HIV positive, who are expected to have higher bacillary Imaging abnormalities may present as enhancement along
loads in the CSF. the surface of the cord and thickening and enhancement
of the nerve roots, the presence of nodular enhancement
Pyrosequencing along the surface of the cord, edema within the cord, and
Pyrosequencing (PSQ) is real‑time PCR providing information ring‑enhancing lesions within the substance of the cord.[2,60,61]
on extremely drug‑resistant (XDR)‑defining mutations within MRI is also a useful tool to assess epidural collection secondary
6 h in the MTB genome. A small pilot study comprising
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diagnosis in 84.6% of the patients compared to Xpert MTB/ more than 50% of cases in patients with TBRM.[2,61] The most
Rif (15%) and TBMGIT (30.7%).[58] It detected six patients important imaging differential for nodular enhancement along
with drug‑resistant TB, who were not detected by TBMGIT the surface of the cord/nerve roots would be drop metastases
culture. A further larger study conducted on 100 patients from an intracranial primary, whereas for intramedullary
with suspected TBM found that the diagnostic accuracy of tuberculoma, it would be focal metastasis. Table 3 enlists the
pyrosequencing was significantly higher compared to Xpert imaging differences between tuberculous and non‑tuberculous
MTB/Rif and TBMGIT (98% vs. 43% vs. 45%) in the diagnosis myelitis, supported by Figures 5a and b.
of TBM.[58] Despite the limitations of the small sample size,
the retrospective nature of the study, lack of information about Predictors of asymptomatic spinal cord involvement in
HIV status, and the inherent limitations of the test (expensive, patients with TBM
requirement of molecular expertise), the ability of this test to Patients with TBM, especially with concomitant HIV
provide information on XDR‑defining mutations within 6 h infection, are at a higher risk of developing cord involvement.
when performed directly on the CSF sample with excellent A gadolinium‑enhanced MR imaging of the spine in these
diagnostic performance may have significant implications cases may help in detecting occult nodules/granulomas,
on clinical outcomes, especially in regions endemic for if present.[23] A pilot study performed by Srivastava et al.
drug‑resistant TB. found that 3/16 patients with TBM with no symptoms
suggestive of spinal cord involvement had evidence of spinal
Next‑generation sequencing arachnoiditis on MRI when performed within 1 month of
Newer molecular techniques such as targeted next‑generation diagnosis of TBM. These patients had higher CSF protein
sequencing and whole‑genome sequencing are presently (520 ± 48.5 mg/dL vs. 300 ± 43.7 mg/dL) compared to those
being evaluated in the diagnosis of tuberculosis. Although without radiculomyelitis.[62] Wadia et al. noted patients with
pyrosequencing provides information on resistance to isoniazid, TBM with no symptoms suggestive of spinal cord involvement
rifampicin, fluoroquinolones, and aminoglycosides, whereas and showed the presence of exudates around the spinal cord and
targeted next‑generation sequencing provides additional nerve roots.[8] Gupta et al., in a prospective study comprising
information on resistance to pyrazinamide, ethambutol, 71 consecutive patients of newly diagnosed TBM, found
linezolid, bedaquiline, capreomycin, and clofazimine. A recent that 11% had evidence of spinal meningitis on MRI despite
study on 40 uncultured sputum samples found that tNGS being asymptomatic.[2] Univariate analysis showed that high
provided results for 39/40 samples with a significantly faster CSF protein and a baseline‑modified Barthel index < 12 were
time than phenotypic MGIT (3 vs. 21 days, P: 0.0068).[59] significant predictors of spinal cord involvement in patients
The utility of these molecular techniques in TBM and spinal with TBM, though multivariate analysis did not find these
cord involvement remains uncertain and may offer an exciting factors to be statistically significant.
avenue for research.
Patients with osseous forms of spinal tuberculosis comprise yet
Imaging another important population, which may be at a higher risk
Magnetic resonance imaging (MRI) is the most sensitive of cord involvement. Sae‑Jung et al., in a retrospective study
tool for the anatomical assessment of the spinal cord and comprising 125 patients with spinal tuberculosis, found that
surrounding nerve roots [Table 2]. In the setting of tuberculous cord signal changes and notable Cobbs angle were significant
infection, MRI provides an accurate estimate of the extent predictors of neurological deterioration.[63] A similar study
a c d e
f g h j
Figure 3: Imaging findings in spinal tuberculosis. Sagittal and axial imaging of the spine (T2‑weighted images a, b, e, f, g, i, j and post‑contrast
T1‑weighted c, d, h) showing thickening and nodularity along the cauda equina nerve roots (a and b) associated with post‑contrast enhancement
(c and d) suggestive of radiculitis. A well‑defined oval, partially cystic lesion (e) is seen involving the thoracic cord with edema out of proportion to the
lesion suggestive of an evolving abscess. Image (f) demonstrates a long‑segment cord hyperintensity and expansion suggestive of myelitis associated
with the syrinx. Multiple T2W hypointense lesions involving the cord with mild surrounding edema (g) suggest the presence of multiple intramedullary
tuberculomas, whereas nodular and ring‑like enhancement along the surface of the cord suggest meningeal inflammation and tuberculomas (h).
Image (i) demonstrates long‑segment myelitis, whereas cord compression secondary to tuberculous spondylodiscitis‑associated extradural abscess
is seen in image (j)
a b c d
Figure 4: Sagittal imaging of the cervicothoracic spine (b) (T2‑weighted images a and c and post‑contrast T1‑weighted images b and d) demonstrate
inflammatory exudates along the dorsal aspect of the thoracic cord (a) causing anterior displacement of the cord with cord hyperintensity (a) and
post‑contrast enhancement (b). Image (c) demonstrates scalloping of the thoracic cord with resultant cord edema secondary to chronic arachnoiditis.
No obvious post‑contrast surface enhancement is seen (d); however, there is an enhancing parenchymal granuloma involving the cervical cord
from India found that kyphosis >30 degrees, cord edema, and The WHO guidelines for the treatment of drug‑susceptible CNS
canal encroachment (>50%) were significant predictors of TB recommend the administration of ATT in two phases.[66]
neurological deficit.[64] Wang et al. found that elderly patients The initial 2 months of the intensive phase are followed by
with cervical and lumbar vertebral involvement were more at a continuation phase of 7 or 10 months. In the intensive
risk of developing neurological disturbances.[65] phase, the patient receives a combination of four first‑line
drugs (isoniazid, rifampicin, pyrazinamide, and streptomycin).
To summarize, in patients with TBM, high CSF protein is
In the continuation phase, 2‑drug (isoniazid and rifampicin)
an important predictive marker of asymptomatic spinal cord
ATT is given. The British Infection Society (BIS) and National
disease. Concurrent spine screening by gadolinium‑enhanced
Institute for Health and Care Excellence (NICE) guidelines
MRI may be helpful in these cases. In those with osseous spinal
also recommend at least 12 months of ATT for all forms of
cord involvement, old age, kyphosis of more than 30 degrees,
CNS TB; isoniazid, rifampicin, pyrazinamide, and ethambutol
and cord edema were important predictors of neurological
for initial 2 months followed by isoniazid and rifampicin
deterioration.
for 10 months.[68] The NICE guidelines advocate managing
tuberculous involvement of the spinal cord as CNS TB. The
Treatment of Spinal Cord TB American Thoracic Society (ATS) recommends 9–12 months
What do guidelines say? of ATT for meningeal involvement; isoniazid, rifampicin,
The established guidelines for the management of CNS pyrazinamide, and ethambutol for the initial 2 months followed
TB largely focus on TBM.[5,6,66‑68] There are no specific by isoniazid and rifampicin for 7–10 months.[6] Similarly,
recommendations to treat SCTB. Management principles the Index‑TB guidelines in India recommend 2 months of
for TBRM are derived from the treatment guidelines for isoniazid, rifampicin, pyrazinamide, and ethambutol followed
CNS TB. by isoniazid, rifampicin, and ethambutol for 7 months for the
Myelitis Long‑segment cord hyperintensity Long segment cord iso/hypointensity Patchy areas of cord enhancement ‑
with expansion in the acute phase with expansion in the acute phase in the acute phase
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treatment of CNS TB.[5] Whether patients with extensive spinal review of 10 reported cases of tubercular LETM, treatment
arachnoiditis will benefit from prolonged ATT is unclear. with ATT and steroids resulted in clinical and radiological
improvement.[40] Patients with damaged anterior horn cells
Role of ATT in spinal cord TB
have poor recovery with ATT.[73] The patient should receive a
TB myelitis combination ATT for at least 9–12 months. Further extension
Neurological insufficiency in TB myelitis is secondary to
of therapy in some cases is dictated by an amalgamation of
inflammatory activity.[1] Previous reports suggest an excellent
clinical, radiological, and other supportive evaluations that
response of TB myelitis to a combination of ATT (isoniazid,
suggest active disease, although guidelines remain unclear
rifampicin, pyrazinamide, ethambutol/streptomycin) and
on this issue.
adjuvant steroids.[24,69,70] Early initiation of ATT is important.
In two different series, involving four cases of longitudinally Corticosteroids and hyaluronidase may be an adjuvant therapy
extensive transverse myelitis (LETM) because of TB, medical to ATT. Steroids are often used as a pulse therapy in patients
therapy alone resulted in a favorable outcome.[71,72] In a recent with severe concerns, such as LETM or severe arachnoiditis,
a
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Figure 5: (a) Imaging findings in non‑tuberculous myelitis. Long‑segment T2W hyperintensity on sagittal imaging of the cord. Image a demonstrates
heterogeneous cord hyperintensity associated with swelling seen with melioidosis of the cord. Image b1 shows long‑segment cord hyperintensity
extending up to the conus. Digital subtraction angiography (image b2) demonstrates an abnormal tortuous vessel along the surface of the cord
confirming the diagnosis of a dural arteriovenous fistula. Image c1 shows a long‑segment cord hyperintensity in a patient with hyperacute paraplegia
raising suspicion for cord infarct. Diffusion restriction is seen on diffusion imaging (c2) confirming the diagnosis. (b) Image a1 shows localized T2W
cord hyperintensity with the scalloping of the cord suggestive of arachnoiditis. During surgery, the thecal sac was found to contain multiple cysticercal
cysts. Image a2 shows central cord signal changes in the same patient secondary to cysticercal arachnoiditis. Image b demonstrated short‑segment
cord T2W cord hyperintensity in a patient with disseminated CMV infection. Images c1 and c2 show a solidary cysticercus granuloma with a ring‑like
post‑contrast enhancement. The lesion showed significant regression with steroids. Image d demonstrates smooth enhancement of the cauda equina
nerve roots in a patient with acute inflammatory demyelinating polyneuropathy; whereas nodular enhancement is seen (image e) in a patient with
leptomeningeal carcinomatosis
intramedullary tuberculoma and abscess.[2,21,24,28] Adjunctive evaluating the benefits of steroid therapy and other alternative
corticosteroid therapy results in a favorable outcome. With agents are needed.
early diagnosis and treatment, one can avoid complications
and unnecessary surgical intervention. Surgery is indicated Evidence for other interventions
in the management of spinal intramedullary tuberculoma for Fibrinolysis
1) a large lesion with rapid progression of neurological deficits, The use of hyaluronidase as an adjuvant in the treatment of
2) deterioration of neurological status despite medical therapy, tuberculous arachnoiditis has been described in non‑randomized
studies in the 1980s and 90s [Table 4].[80‑82] In a recent
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Therapy for spinal cord paradoxical worsening optico‑chiasmatic arachnoiditis, weekly hyaluronidase for
Corticosteroids are the main immunomodulatory therapy in 10 weeks was administered, besides ATT and steroids. Of
CNS TB. The evidence is largely derived from patients with 19 patients with spinal arachnoiditis, 10 were independent
TBM without HIV infection. Importantly, corticosteroid at the completion of therapy.[83] The benefits of fibrinolysis
therapy decreases mortality without impact on disability in reported from observational literature need augmentation by
TBM. Corticosteroids probably beneficially impact SCTB as further evaluation in a randomized trial setting.
well, as close to a third of TBM patients have concomitant
spinal cord involvement. However, no randomized trials Surgical management
have evaluated the role of steroids in spinal TB so far. Intramedullary tuberculomas, intra‑conal abscess
The percentage of paradoxical worsening in SCTB is Patients with intramedullary TB can present with a mass‑like
higher than in TBM. Often paradoxical worsening happens presentation mimicking intramedullary tumor, sometimes
despite receiving adequate steroids. The role of adjunctive like an intramedullary abscess. The aim of surgery is to
immunomodulatory therapy in these individuals is unclear. perform safe surgical excision of the lesion without causing
Adjunctive thalidomide therapy at low doses (3–5 mg/kg/day) new neurological deficits. The surgical procedure involves
produced a favorable response in two children with tuberculous laminectomy done at the level of the lesion. The dura is opened,
mass lesions involving the spinal cord.[78] The duration of and CSF is let out to allow the pulsations of the cord. A midline
thalidomide therapy used in these patients was 8 weeks myelotomy is performed after identifying the lesion. After
although some advocate shortened regimens of less than a identifying the lesion, a plane is developed to safely excise the
month. However, longer durations have been used in children lesion. Intraoperative neuromonitoring helps in safe surgical
with optic neuritis (median 2, interquartile range [IQR] excision. The pia mater is closed by welding technique and
1.3–7.3 months).[78] Painful paresthesia may develop with the dura is closed primarily.
longer regimens due to the development of sensory axonal
neuropathy. Infliximab, a tumor necrosis factor‑alpha inhibitor Syringomyelia
has been successfully used in three patients with paradoxical The best management for post‑TB syringomyelia is
worsening involving the brain and spinal cord.[79] Larger studies unclear. Often patients are treated by placing a
syringe‑subarachnoid shunt with mixed results.[24] A focal meningitis, 29 (14.6%) had spinal tubercular meningitis, and
laminectomy is performed. The dura and the arachnoid are among those who completed therapy, 84% were dependent for
opened. A small myelotomy is done in the center of the syrinx their activities of daily living.[71]
to open it. One of the shunt tubes is gently guided cranially or
Unique anatomical location within a restricted space, complex
caudally into the syrinx. The other end of the tube is placed
vascularity, and close proximity of neural tracts predispose to
in the subarachnoid cavity beneath the dentate ligament. This
poor outcomes. There may be several further reasons for poor
helps to keep the shunt in place. The dura is then closed. Spinal
outcomes, mainly engendered by the underlying pathology.
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Table 5: Outcomes of spinal cord tuberculosis (reporting studies with at least 20 patients; studies chiefly reporting on
tuberculous spondylodiscitis were excluded
Study Number of Types of HIV infection Paradoxical Adjunctive Follow‑up
patients involvement worsening therapy
Gupta, 2015, 71 patients Spinal cord and Unknown Eleven (26.82%) All received Good outcome at 6 months
Single‑center spinal nerve root 8 weeks of defined as modified
prospective study, involvement steroids Barthel’s Index of ≥12 in
India[2] 27 (66%) patients
Marais, 2018, 274 patients, The majority had 209/274 69 patients had Details not Among the 89 patients
Retrospective 89 followed up spinal disease patients (76%) paradoxical available who followed up at 9
single‑center, South at the end of 9 without bony worsening (62 in months, 38 (44%) were
Africa[22] months involvement HIV infected and 7 able to walk
among uninfected)
Liu, 2018, 52 patients All patients have All HIV 26 patients All patients The overall outcome
retrospective prominent spinal uninfected (52%); median received steroids was unclear; none of the
single‑center, cord involvement duration 30 days patients died; outcomes
China[51] (isolated after initiation of were similar regardless
spondylitis was therapy of whether patients
excluded) developed paradoxical
worsening or not
Goyal et al., 2019, A total of 244 All patients had None Not known 93.4% of the Poor outcome defined by
Ambispective patients with arachnoiditis total cohort modified Rankin scale ≥3
single‑center cohort CNS TB; 25 had received steroids in 21 patients (84%).
study, India[84] arachnoiditis
Acknowledgments
We would like to thank our institutes for their support.
Financial support and sponsorship
Nil.
Figure 6: Future direction in spinal cord tuberculosis
Conflicts of interest
unclear. Although the thick characteristic gelatinous exudative There are no conflicts of interest.
inflammation is responsible for adhesive complications such
as arachnoiditis, the molecular mechanisms responsible are References
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