Study of Clinicoradiological Profile and Prognosis of Longitudinally Extensive Transverse Myelitis from a Single Tertiary Center in Eastern India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.294544
Source of Support: None, Conflict of Interest: None
Keywords: Aquaporin 4 antibody, longitudinally extensive transverse myelitis, multiple sclerosis, neuromyelitis optica
Acute transverse myelitis (ATM) is a pathologically heterogeneous inflammatory disorder of the spinal cord. Longitudinally extensive transverse myelitis (LETM) is defined as a hyperintense spinal cord lesion extending over three or more vertebral levels on sagittal T2-weighted (T2W) spinal magnetic resonance imaging (MRI). Neuromyelitis optica (NMO) is the most common cause of LETM. LETM is accepted as one of the supportive diagnostic criteria of NMO. The other causes of LETM are infections, rheumatic disorders, sarcoidosis, dural arteriovenous fistula, and multiple sclerosis (MS). Differentiating NMO from other etiologies is clinically important to provide early accurate treatment, which may prevent future attacks and avoid subsequent severe disability.,, A variety of conditions were discovered with anti-AQP4-IgG-positive state necessitating the coining of the term NMO spectrum disorders (NMOSDs).
LETM has been described in various studies from India., But the frequency of AQP4 antibody (Ab) positivity varies greatly in various studies. Therefore, this study was performed with the purpose of identifying clinical manifestations, laboratory and neuroimaging features, and prognosis of patients with LETM.
This is a hospital-based cross-sectional prospective study. It was performed in the Department of Neurology, SCB Medical College and Hospital, Cuttack, a tertiary care center of eastern India, serving almost half of the population of the state of Odisha. This study was performed during 2016–2017. The study was approved by Institutional Ethics Committee/Institutional Review Board. We included 37 patients who presented with paraplegia/paresis or quadriplegia/paresis to our institute with MRI showing LETM of three or more segments. Written informed consent was obtained from the participants or family. They were evaluated in terms of gender, age of presentation, history of preceding infection or vaccination, various clinical presentation like paraplegia/paresis, quadriplegia/paresis, bilateral/unilateral vision loss, bladder involvement, and other associated features like painful tonic spasm (PTS). History regarding myelitis in the past was also recorded. The detailed general and neurological examination was done.
Routine tests like complete blood count, renal function test, liver function test, serum vitamin B12 level, and serum HIV (ELISA) status were recorded. Antinuclear antibody (ANA) and ANA profile including anti-SSA/Ro and anti-SSB/La were checked when appropriate. MRI of spinal cord both cervical and thoracic and brain T1W, T2W, and FLAIR sequences with gadolinium contrast using 1.5 T machine were done. MRI was performed at the earliest presentation. The cerebrospinal fluid (CSF) was analyzed for routine tests and for oligoclonal bands (OCBs) in appropriate cases. Pattern reversal visual evoked potential was done to diagnose optic neuritis in all patients.
We did serum aquaporin 4 (AQP4) antibodies in 26 of 37 patients. Eleven patients could not do AQP4 testing due to financial factors. Serum NMO Ab (NMO-IgG-Ab) also known as AQP4 Ab detection was done by immunofluorescence (IFA) method using transfected HEK-2 cells and primate optic nerve as substrate. Revised Wingerchuk criteria were used to diagnose patients with NMO, and revised McDonald criteria were used for MS. Transverse myelitis consortium working group criteria were used to diagnose acute idiopathic transverse myelitis. However, the idiopathic nature is a diagnosis of exclusion.
All the patients with acute myelitis were treated with intravenous methylprednisolone 1 g daily for 5 days. Patients fulfilling diagnosis of NMO were given oral prednisone 1 mg/kg for a month and then gradual tapering off over six month's period. All patients with NMOSD, both with and without AQP4 Ab positivity, were given prophylactic immunosuppressive therapy like azathioprine (AZA) or rituximab (RX). All the patients were followed up for at least one year. The disability was scored by means of Expanded Disability Status Scale (EDSS) by neurologist at admission, at six months, and at one year.
Data analysis was performed using SPSS software (version 17; SPSS Inc., Chicago, IL, USA). The different groups were compared with each other using Chi-square test. P value of less than 0.050 was regarded as statistically significant.
Totally, 37 patients were included in our study. The mean age in our series was 35.97 ± 13.2 years (range 10–64 years). Most of the patients (54.05%) were in the age range of 20–40 years. There was a slight female predominance of LETM in our series with a female: male ratio of 1.05:1 [Table 1].
In all, 28 patients presented with paraplegia/paresis (75.68%), while 24.32% of patients presented with quadriplegia/paresis. Bladder and bowel dysfunction was present in 33 (89.19%) patients. Twelve patients (32.43%) had relapsing course with recurrent myelitis. The remaining 25 patients had monophasic illness. Visual impairment due to optic neuritis was present in 20 (54.05%) patients. PTS was observed in only two patients with LETM.
In our series, thoracic spinal cord segments were most commonly (56.76%) affected [Figure 1] followed by combined cervicothoracic cord affection (24.33%). LETM with holocord affection was seen in only two patients. In our series, the tendency to involve three to five segments is more common in 40.54% followed by 6–10 segments involvement in 37.84% of patients with LETM. Involvement of more than 10 segments was found in only eight patients (21.62%).
Serum AQP4 Ab test was done in 26 patients with LETM. Among them, AQP4 Ab was found positive in nine patients (34.62%). Totally 22 (59.46%) patients with LETM were clinically diagnosed as NMO according to revised Wingerchuk criteria. Four patients were diagnosed as postinfectious myelitis. Tuberculous myelitis and subacute combined degeneration of spinal cord due to vitamin B12 deficiency were present in one patient each [Table 2]. No cause could be determined in nine patients and termed as idiopathic LETM.
CSF analysis revealed pleocytosis ranging from 8 to 42 cells/mm3 in 15 patients. Of 22 clinically diagnosed patients with NMO, 10 patients had lymphocytic pleocytosis. Other causes of pleocytosis were postinfectious myelitis (two patients), tuberculosis (one patient), and two patients with idiopathic myelitis. CSF proteins were elevated (more than 50 mg/dL) in 17 patients, of which 12 patients were with NMO, one patient with postinfectious and tubercular each, and in remaining three patients, cause was undetermined. CSF OCB testing was done in eight patients with LETM and all were negative. Prognosis of LETM in the form of EDSS at one year was poor in patients with NMO when compared with postinfectious myelitis and patients with idiopathic LETM (P = 0.009) [Table 3].
On comparison between AQP4-Ab-positive and AQP4-Ab-negative patients with LETM [Table 4], we found that patients with LETM with positive AQP4 Ab had female predominance (F: M ratio 3.5:1), and in AQP4-Ab-negative group, there was male predominance (F: M ratio 0.42:1). The mean age of onset for AQP4-Ab-positive patients with LETM (39.00 ± 5.27 years) was slightly more than that of AQP4-Ab-negative patients (34.24 ± 14.21 years). All AQP4-Ab-positive patients fulfilled the Wingerchuk diagnostic criteria for NMO, while only eight (29.41%, P = 0.042) AQP4-Ab-negative patients with LETM were diagnosed with NMO. Weakness and bladder dysfunction were the two most common initial presentations. History of optic neuritis was present in 77.78% of cases with AQP4 Ab positivity and in 47.06% of cases with AQP4 Ab negativity. Relapsing–remitting course was observed in 77.78% of patients with LETM with positive AQP4 Ab and in only 29.41% of cases with negative AQP4 Ab (p = 0.042). Involvement of 6–10 segments in MRI spinal cord was more common (55.55%) in LETM cases with positive AQP4 Ab. Whereas in LETM cases with negative AQP4 Ab, involvement of 3–5 segments (35.29%), 6–10 (35.29%), and more than 10 segments (35.29%) were almost equal. MRI brain was abnormal in the form of nonspecific white matter lesion in 33.33% of patients with LETM with positive AQP4 Ab and in 11.76% of patients with negative AQP4 Ab.
Nineteen of the total 22 patients with NMO received prophylactic immunosuppressive therapy. AZA at a dose of 2.5 mg/kg was given to seven of nine patients with provisional diagnosis of NMO with positive AQP4 Ab and 10 of 13 patients with diagnosis of NMO without or unknown AQP4 Ab. Two of the patients with NMO with AQP4 Ab received RX.
During the follow-up period of 1 year, two of the patients with NMO with AQP4 Ab receiving AZA developed relapse. None of the patients with RX or NMO without or unknown AQP4 Ab with AZA developed relapse during the follow-up period. EDSS score at 1 year was higher in patients with LETM with positive AQP4 Ab (5.28 ± 1.28) when compared with patients with negative AQP4 Ab (4.24 ± 2.46), but it is not statistically significant.
LETM has been described in various studies from India and worldwide., The identification and proper evaluation of patients with LETM are very much necessary due to poor prognosis of LETM in NMO group of patients. In our study, the most common age group of presentation was 20–40 years of age which was similar to other studies. In our series, there is a slight female predominance (51.35%) with an F:M ratio of 1.05:1 which was unusual for LETM series from different parts of the world. In a study by Chang et al., there was female predominance with an F: M ratio of 5:1.
In our study, common symptoms were bladder-bowel dysfunction (89.19%), paraparesis/plegia (75.68%), quadriparesis/plegia (24.32%), and visual impairment, which is almost similar to the series by Jain et al. and Chang et al.
Demyelinating disorders were the most common cause of LETM, among which NMO was the most common etiology in 59.46% cases in our series. We could not find any patient with LETM with MS in our series. In the study by Kitley et al., only 3.95% of patients with LETM fulfilled diagnostic criteria of MS. The absence of MS as a cause of LETM in our series may be due to small sample size in our study.
AQP4 IgG Ab is very specific for NMO. Various laboratory methods such as ELISA, flow cytometric assay, and transfected cell-based assay (CBA) are available to detect AQP4 IgG antibodies. The CBA and ELISA assays have 100% specificity, but sensitivity was 68% and 60%, respectively. The fluorescence immunoprecipitation assay and tissue-based IFA assay have sensitivity of 48%–53%.
In our series, serum AQP4 Ab was positive in 34.62% of patients with LETM. In the study by Jain et al., AQP4 Ab was positive in only 20.31% of patients with LETM. In the study by Chang et al., AQP4 Ab was positive in 60% of cases of LETM. In the study by Kitley et al., 57.89% of cases with LETM were positive for AQP4-Ab. Weinshenker et al. found AQP4 Ab seropositivity in 37.9% of patients with LETM. According to another Indian study by Unni et al., among the 11 patients with LETM, 6 (54.5%) were positive for AQP4 Ab. Pandit et al. found AQP4 Ab positivity in 55.55% of patients with NMO and in 40% patients with recurrent transverse myelitis in the form of LETM.
In our series, there was a group of patients, who were clinically diagnosed as NMO but found to be serum AQP4-Ab-negative. There is much difference in different studies regarding the positivity of AQP4 Ab. Wingerchuk et al. tried to explain this discrepancy by three possible causes: (a) inadequate diagnostic criteria, (b) suboptimal assay sensitivity, and (c) closely related autoimmune disorder with a different target autoantigen. Thus, the difference in diagnostic criteria and anti-AQP4 assay methods may account for heterogeneity in epidemiologic data and may explain some of the observed discrepancies in interpretation.
Among the 22 patients with LETM with NMO, 12 patients (54.55%) had relapsing and remitting course. Weinshenker et al. found that the presence of AQP4 Ab predicts the recurrence of LETM or conversion to NMO. Our study also had similar observation; patients with NMO with positive AQP4 Ab had more relapsing and remitting course when compared with AQP4-Ab-negative patients. In our series, we noted relapse during follow-up in two of seven (28.6%) patients of NMO with AQP4 Ab who were receiving AZA. No relapse was seen in patients receiving RX and those patients with NMO without or unknown AQP4 Ab status receiving AZA. Hence, early and appropriate immunosuppressive therapy should be prescribed to these patients. In our study, prognosis in terms of EDSS at 1 year was poor among patients with NMO with LETM when compared with postinfectious, tubercular, and idiopathic myelitis (P = 0.009).
On comparing AQP4-Ab-positive and AQP4-Ab-negative patients with LETM in our series, relapsing–remitting course was very common (77.78%) in AQP4-Ab-positive patients when compared with 29.41% cases in AQP4-Ab-negative patients, which was statistically significant (P = 0.042). A similar observation was also made in various other studies. In the study by Iorio et al., relapsing cases were found in 75% of LETM cases with AQP4-Ab-positive and in 24% cases with negative AQP4 Ab. In our series, poor prognosis in the form of higher EDSS was found in AQP4-Ab-positive patients with LETM when compared with AQP4-Ab-negative patients with LETM.
Our study has several limitations. First, our study has a small sample size. Not all suspected cases of NMOSD had AQP4 Ab testing done and OCB data were available in only a few cases. MOG IgG antibody testing is not available in our center, which is a drawback of our study. Some of the NMO-Ab-negative patients may be positive for MOG Ab. The follow-up period in our study was one year, for which it is very difficult to assess the long-term prognosis in our patients.
It was very difficult to assess the clinical pattern of LETM in our study due to the small sample size. The patients should be followed up for a longer period to know the clinical course of LETM. Because of poor recovery of patients with LETM due to NMO, these patients should be diagnosed early, so that appropriate and early treatment can be given to prevent future relapses.
We thank all the participants in the study and faculties of MRI center of SCB Medical College for their support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]