Incomplete transverse myelitis (ITM) of unknown origin is associated with high rates of morbidity and mortality. This prospective, open-label study was undertaken to determine whether antituberculous treatment (ATT) might help patients with ITM whose condition continues to deteriorate despite receiving IV methylprednisolone treatment. The study consisted of 67 patients with steroid-refractory ITM in whom
Transverse myelitis is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction. It is a poorly defined condition and displays heterogeneous etiopathogenesis [
ITM is a well-recognized but rare symptom of
This prospective, open-label study was conducted at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China), from Jan 2003 to Jun 2010. The Neurology Department in this hospital is a referral center focused on CNS diseases and accepts patients from other hospitals in southern china. Sixty-seven patients qualified for inclusion in the study, according to the inclusion and exclusion criteria (see below). There were 24 males and 43 females. The male to female ratio was 6 : 11. The median patient age was 39.07 ± 18.33 years. A detailed neurological examination was carried out, including evaluation of the motor, sensory, visual, and sphincter systems. A Mantoux test, chest X-ray, serum biochemistry, serum and cerebral spinal fluid (CSF) Borrelia, and human immunodeficiency virus (HIV) testing were performed to exclude other diseases. The CSF cell count, glucose, and protein levels were obtained from lumbar punctures performed prior to the onset of ATT. A direct smear for acid-fast bacillus and a
Upon admission, a spinal MRI was performed on all patients. The number of levels affected in the sagittal plane in the T2 sequence was measured. A brain MRI was also performed and if the MRI scan was not normal, the patient was excluded.
This study was conducted with patients in whom MTB was suspected clinically but not proven based on conventional measures. The inclusion criteria were (i) development of sensory, motor, or autonomic dysfunction attributable to the spinal cord, (ii) varying degrees of motor, sensory, and sphincter dysfunction (although not necessarily symmetric), but without complete paraplegia, (iii) exclusion of extra-axial compressive etiology by MRI, (iv) worsening symptoms despite at least one 5-day course of IV methylprednisolone (0.5–1 g/day), and (v) negative CSF MTB cultures with a cell count <50/mm3 and a total protein <1.5 g/L. The exclusion criteria were (i) sudden onset, (ii) history of previous radiation to the spine within the last 10 years, (iii) CNS manifestations of syphilis, Lyme disease, or HIV infection, (iv) clear arterial distribution and clinical deficit consistent with thrombosis of the anterior spinal artery, (v) history of clinically apparent optic neuritis, (vi) brain MRI abnormalities suggestive of MS or clinically definitive MS, and (vii) serologic or clinical evidence of connective tissue disease, such as, sarcoidosis, Behcet’s disease, Sjögren’s syndrome, systemic lupus erythematosus (SLE), or mixed connective tissue disorder.
The university ethics committee approved the study. All patients were informed of the potential short- and long-term drug complications of ATT. Written informed consent was obtained from patients who agreed to participate in the study. Patients were instructed to contact the study neurologist in the event of neurological symptoms. Before the start of ATT treatment, all patients received a baseline evaluation.
Prior to ATT initiation, all treatments with corticosteroids and other systemic immunosuppression therapies were discontinued. Treatment protocols consisted of three antituberculous drugs (isoniazid, rifampicin, and pyrazinamide for 9 months), followed by a combination of isoniazid and rifampicin for 24 months. The doses were isoniazid at 10 mg/kg/day, rifampicin at 10 mg/kg/day, and pyrazinamide at 25 mg/kg/day. Treatment was under extensive observation. All patients had weekly liver function tests for the first one month of therapy and subsequently every 3 monthly (serum bilirubin, serum transaminases (SGOT/SGPT), and alkaline phosphatase).
Eligible patients underwent complete physical and neurological examinations at entry, at 12 and 24 months, and as needed for assessment of acute relapses or safety. The American Spinal Injury Association (ASIA) standards [
Multiple sclerosis was diagnosed according to McDonald et al.’s criteria [
Statistical analysis was performed using Student’s
The median interval from onset to treatment with ATT was 7.5 months (range, 1–57 months). The most common modality of presentation was in the form of sensory-motor involvement (59 patients, 88%). Motor impairment presented as asymmetric weakness, paraparesis or even quadriparesis. Sensory symptoms included numbness or paresthesias. Eight patients presented with just motor involvement (12%), whereas 26 patients (38.8%) had some form of urinary symptoms in the form of absent bladder sensations, incontinence, or increased urination frequency. Three patients had definitive TB evidence upon chest radiography (Mantoux test ≥ 10 mm in 48 hours). Baseline demographic and clinical information is reported in Table
Baseline demographic and clinical information at inclusion.
Characteristic | Treatment group |
---|---|
Number | 67 |
Female/male | 43/24 |
Age of study entry (years) mean ± SD | 39.07 ± 18.33 |
Disease duration (months) | 7.55 (range, 1–57) |
Drop-out | 16 |
Mantoux test | 48 |
Patients with CSF normal finding | 12 |
Patients with abnormal MR change | 43 |
The CSF findings were as follows. Elevated opening pressure (>200 mm H2O) was present in eight patients, and pleocytosis was found in 29 patients (43.3%) with lymphocyte predominance. Protein level was increased (>0.45 g/L) in 42 patients, 5 patients (7.5%) had decreased glucose concentration, and eight patients (11.9%) revealed a low CSF chloride level. Overall, CSF was abnormal in 55 of 67 patients, with 12 (17.9%) completely normal.
Spinal MRI lesions were visible in 43 patients (64.2%). Lesions were usually hypointense or isointense on T1-weighted and hyperintense in T2-weighted sequences. In 14 cases, we observed obvious spinal cord swelling. DTPA-enhanced MRI scans were performed for 19 patients, of which 13 showed Gd-enhancement. Ring enhancement and/or heterogeneous enhancement were common findings. Two patients had associated syrinx. Brain MRI was performed for all patients but did not reveal any infectious or demyelinating lesions.
Sixteen (23.9%) of 67 patients discontinued ATT within the first year. Another three patients dropped out during the second year medication but were still followed (Figure
Trial profile.
Treatment was halted for patients experiencing deteriorating clinical symptoms since 43/51 (84%) patients experienced good response in the early course of ATT treatment. During the first week, 18/51 (35%) patients had considerable improvement in limb weakness. Sphincter symptoms gradually ameliorated in 21/26 (81%) patients. The clinical benefit was sustained and continued to improve in most cases. After one year, 49/51 (96%) of treated patients had achieved marked improvement of neurological signs, and five had experienced a full recovery without any motor or sensory sequelae. Spinal cord evaluation showed improved ASIA scores, significantly increased BI ratings, and an improved Hauser AI. The benefit was sustained and continued to improve over the second year (Table
The changes of spinal function scores on baseline and after 1 year and 2 years of ATT (51 patients).
Years | ASIA sensory scores | ASIA motor scores | Barthel index | Ambulation index |
---|---|---|---|---|
Baseline | 184.02 ± 23.57 | 78.86 ± 14.51 | 74.42 ± 22.40 | 3.92 ± 2.06 |
Year 1 | 209.33 ± 21.42* | 93.75 ± 8.03* | 93.43 ± 10.61* | 1.63 ± 1.72* |
Year 2 | 211.10 ± 19.96* | 95.10 ± 8.34* | 95.47 ± 6.25* | 1.09 ± 1.36* |
Each value represents mean ± SEM. *Improvement in values is statistically significant (
Neurological relapses were experienced by 9/51 (18%) patients, although they improved upon active treatment. During the first year followup, 13 relapses occurred, primarily in the initial three months (six relapses), with six more occurring in the second year of ATT treatment. Four patients who continued ATT treatment in relapses periods, and did not receive other immunosuppressive treatment, recovered, whereas five patients that received IVIG treatment responded well. Two patients experienced relapse of visual decline (at 6 months and 15 months, resp.) as limb weakness greatly improved, although both patients repeatedly showed a normal brain MRI. NMO diagnosis was established according to Wingerchuk’s criteria. Similar to our previous study [
Two-year observations based on MRI imaging were completed for 33/51 (65%) patients who had cord lesions. Abnormal symptoms and swollen spinal cords progressively decreased in 32 patients after therapy initiation, and T2 signal abnormalities decreased markedly in size. This happened in poorly defined, extensively swollen cord lesions (Figure
A 25-year-old woman was admitted due to the progressive weakness and parasthesia in both legs with voiding problem for 3 months. After 2-year ATT, her situation improved with good recovery of spinal function. The MRI changes are as follows: (a) first MRI performed in August 2005, T1 weighted image showing cord edema from T1 to bottom in the sagittal plane, with focal atrophy and syrinx cavity, (b) T2-weighted image showing a contiguous area of increased signal intensity, (c) cavity and band-like structure on axial T1-weighted images, (d, e) after one year of treatment, the swelling of cervical spinal cord greatly dissolved on sagittal T1-weighted image; the syrinx cavity is obviously diminished, (f) contiguous abnormal signal still left but diminished on the sagittal T2-weighted image, (g) the lesion is still obvious on axial T2-weighted images, (h, i) three years after treatment, the syrinx cavity is not obvious, and (j) some parts of thoracic cord restore normal signal on T2-weighted axial cord images. A small cavity is visible on T8, and increased signal intensity still exists below T9.
A 58-year-old female developed paraplegia and paresthesias in August 2007; weakness slowly worsened. Pulse methylprednisolone and IVIG were initiated with no resolution; she continued to deteriorate. After 2-year ATT, her situation fully recovered. The MRI changes are as follows: (a) sagittal T2-weighted image showing a contiguous area of increased signal intensity spanning T2 to T3 level, (b) axial T2-weighted images reveal the strong signals, (c) axial MRI images showing focal cord enhancement, (d) after 5 months of ATT, the lesion decreased, (e) following 1-year ATT, sagittal T2-weighted MRI of the thoracic cord reveals no abnormal signals, and (f) no lesion is visible on cross-sectional T2-weighted images.
A 51-year-old female suffered from tetraparesis and frequently paroxysmal tics of extremities for 3 months. ATT treatment quickly improved her symptoms. After 2-year ATT, she fully recovered without visible symptoms. The MRI changes are as follows: (a) sagittal T1-weighted MRI showing focal thickening of the cord at C2-C3 level, (b) sagittal T2-weighted MRI showing a focal demyelinating lesion, (c) axial T2-weighted MRI showing the lesion to involve the whole cord, (d) sagittal T2-weighted MRI after 6 months of treatment, showing the swelling of the cervical spinal cord and patchy abnormal signal have resolved, (e) axial T2-weighted MRI showing an abnormal signal remains, (f) sagittal T1-weighted MRI after 2 years of treatment is normal, (g) sagittal T2-weighted MRI after 2 years of treatment revealing no abnormal signals, and (h) axial T2-weighted cord MRI after 2 years of treatment.
A 40-year-old woman had tetraparesis, C3 sensory level, and urinary incontinence for five months. Pulse methylprednisolone and IVIG were initiated with no resolution. However, ATT greatly improved her condition. The MRI changes are as follows: (a) sagittal T1-weighted MRI showing thickening of the cervical cord, (b) sagittal T2-weighted MRI showing a contiguous area of increased signal intensity spanning C2 to C7, (c) axial T2-weighted MRI showing the strong signal derived from the whole cord, (d) sagittal T1-weighted MRI after 2 years of treatment is normal, (e) sagittal T2-weighted MRI after 1 year of treatment, showing a normal spinal cord, and (f) axial T2-weighted MRI, showing no lesions.
A 70-year-old female was admitted due to progressive paraparesis, paresthesias, and urinary retention for 2 months. After 2-year of ATT, her situation improved. The MRI changes are as follows: (a) sagittal T2-weighted image reveals a long, high intensity signal from C1 to T1 in the spinal cord before treatment regimen, (b) T1W contrast image showing patchy enhancement and thickening of the cord, (c) the diffuse lesions on axial T2-weighted images, (d) a year later the swelling of the cervical spinal cord disappeared on sagittal T1-weighted images, (e) the hyperintensity resolved following 1 year of ATT, and (f) no lesion is visible on axial T2-weighted images.
A 30-year-old male suffered from left paraparesis and paresthesias for 1 month. MRI of the cervical spinal cord revealed a demyelinating lesion in T2-weighted images extending from C4 to C7. Pulse methylprednisolone and IVIG were initiated with no resolution. The MRI changes are as follows: (a) sagittal T2-weighted image reveals a high intensity signal from C4 to C7 before ATT regimen, (b) sagittal T1-weighted MRI showing light thickening of the cord with subtle intraparenchymal hyperintensity, (c) the left local lesions on axial FLAIR sequences, (d) the hyperintensity resolved following 6 months of ATT, (e) no lesion is visible on axial T2-weighted images, and (f)–(h) no lesion is visible on follow-up MRI after 2 years of treatment.
A 67-year-old female suffered from progressive paraparesis and paresthesias for 1 month. There is a small demyelinating lesion at the level between T9 and T10. Steroid pulsed treatment worsened her condition. After ATT, her weakness quickly improved. She tried to stop ATT two times during the early stage of treatment due to drug side-effects, but failed because her condition grew worse. Although she got better, the lesion seems to have not changed after 18 month treatment. (a) Sagittal T2-weighted image reveals a small high intensity signal between T9 and T10 before our regimen; (b) sagittal T2-weighted image after 6 months of ATT; (c) the lesion still exists on sagittal T2-weighted images after 18 months of treatment.
Adverse events occurred in 16/67 patients (23.9%). Two patients had somnolence and weakness due to hyponatremia during the first months of ATT treatment and quickly recovered on active therapy. No other serious adverse effects were seen but six patients withdrawn early because of lethargy, nausea, and vague ill health. Eight patients had mild gastrointestinal syndrome on active therapy but were able to continue the trial and resolved quickly. One death that occurred during the study was considered unrelated to the trial.
We report our experience with a select group of myelopathy patients treated with ATT. This is the first clinical study to evaluate the therapeutic effects of ATT on steroid-refractory ITM. Sustained increases in ASIA scores and BI, with decreased AI scores, show that treatment is effective in most cases. This study used only pure antituberculosis chemotherapy, without adopting steroid and other immune suppressing drugs. The encouraging results are not only associated with significantly improving the neurological status of these patients, but also with beneficial changes to spinal lesions as determined by MRI. This study suggests ATT has beneficial effects in some ITM patients, and that
Tuberculosis is still a major health problem in many parts of the world, especially Asia and Africa. However, tuberculous intramedullary involvement is considered to be very rare compared with tuberculous spondylitis or arachnoiditis [
The etiology of the MRI signal abnormalities remains speculative. In the current series, the MRI signal changes in ITM vary from a small single lesion to extended longitudinal lesions over several spinal segments. In the literature, the majority of ITM cases with a single lesion is diagnosed as a clinically isolated syndrome (CIS), which later may be converted to multiple sclerosis (MS) [
In this study, 24 patients (38.2%) develop ITM without signs of demyelination or other abnormalities of the spinal cord as determined by MRI. Previous reports [
We found that subsequent neurological relapses during ATT treatment usually occur in at least some patients, potentially through a mechanism similar to paradoxical deterioration in tuberculosis. Paradoxical deterioration during ATT is usually defined as the clinical or radiological deterioration of pre-existing tuberculous lesions or the development of new lesions in a patient who initially improved [
There are still few reports describing the features of tuberculous myelopathy detected by MRI. The first documented description of using MRI to determine intramedullary spinal tuberculosis was published by Rhoton et al. in 1988 [
There are methodological limitations to the current study. This is an uncontrolled study, the number of patients in the trial was small, and relapses were less well defined. Overall, the trial provides some inspiring data and indicates ATT may be an efficient, cost-effective approach to some patients. Based on this study, a double-blind controlled study of ATT efficacy will need to be performed, preferably over a longer duration and with a larger sample size.
We have presented a prospective pilot study on steroid-refractory ITM. This study has identified, for the first time, the long-term clinical efficacy of ATT in some steroid-refractory ITM patients. Our results suggest that ATT treatment can not only stop disease activity and progression but may also result in a significant recovery of fixed neurological deficits. On the other hand, the study also suggests that tuberculosis infection might be an important and still neglected cause of myelitis. Additional efforts must be made to conduct well-designed trials since no other effective treatments currently exist.
The authors did not have funding from any of the manufacturers.
The authors are grateful to Prof. Zhiyun Yang for technical assistance, and the staff at the Department of Neuroradiology are thanked for performing the MRI. Special thanks are due to the patients for taking part in this study. This study was supported by grants from the Guangdong Natural Science Foundation (Grant nos. 31694 and 2004B33801006).