Review Article MRI in Transverse Myelitis Christine Goh, MBBS, FRANZCR,* Patricia M. Desmond, MSc, MD, FRANZCR, and Pramit M. Phal, MBBS, FRANZCR Transverse myelitis is an acute inflammatory disease of the spinal cord, characterized by rapid onset of bilateral neurological symptoms. Weakness, sensory disturbance, and autonomic dysfunction evolve over hours or days, most progressing to maximal clinical severity within 10 days of onset. At maximal clinical severity, half will have a paraparesis, and almost all patients have sensory dis- turbance and bladder dysfunction. Residual disability is divided equally between severe, moderate and minimal or none. The causes of transverse myelitis are diverse; etiolo- gies implicated include demyelinating conditions, collagen vascular disease, and parainfectious causes, however, despite extensive diagnostic work-up many cases are con- sidered idiopathic. Due to heterogeneity in pathogenesis, and the similarity of its clinical presentation with those of various noninflammatory myelopathies, transverse myeli- tis has frequently been viewed as a diagnostic dilemma. However, as targeted therapies to optimize patient out- come develop, timely identification of the underlying etiol- ogy is becoming increasingly important. In this review, we describe the imaging and clinical features of idiopathic and disease-associated transverse myelitis and its major differentials, with discussion of how MR imaging features assist in the identification of various sub-types of trans- verse myelitis. We will also discuss the potential for advanced MR techniques to contribute to diagnosis and prognostication. Key Words: transverse myelitis; MRI; spinal cord; mye- lopathy; parainfectious myelitis; neuromyelitis optica J. Magn. Reson. Imaging 2014;40:1267–1279. V C 2014 Wiley Periodicals, Inc. The diagnostic work-up of acute transverse myelopa- thy first requires emergent MRI cord to exclude acute cord compression. Further investigation will then entail contrast enhanced MRI of cord and brain, serum and CSF analysis (autoimmune markers, auto- antibodies, microbial serology and PCR), and special- ised investigations such as visual evoked response testing. The critical initial treatment is often based upon a presumptive diagnosis made with reference only to the clinical features, MRI findings and basic CSF analysis. Specialised investigations such as autoanti- body testing may have greater specificity, but unfortu- nately results are not usually available until well after treatment has been instituted. This underscores the importance of the careful assessment of MR imaging appearances in narrowing the differential diagnosis sufficiently to allow the early institution of the appro- priate therapy. Due to the diversity of aetiologies in transverse mye- lopathy, a thorough understanding the clinical as well as the imaging features of these conditions assists the radiologist in their assessment. GENERAL CONCEPTS Diagnostic Criteria The diagnostic criteria proposed by the Transverse Myelitis Consortium Working Group (1) is outlined in Table 1. The first requirement is an appropriate clini- cal picture of bilateral symptoms referable to the spi- nal cord, evolving to maximal clinical severity between 4 h and 21 days. The lower limit of 4 h onset is designed to prevent cases of cord infarction, typically of abrupt onset, from being erroneously diagnosed as transverse myelitis. An active inflammatory process must be confirmed by the presence of a cellular infil- trate and/or elevated protein on CSF analysis, or by contrast enhancement on MRI of the spinal cord. Further criteria divide transverse myelitis into two main groups. Idiopathic transverse myelitis is a diagnosis of exclusion, while those cases which are attributable to underlying processes including demye- lination (multiple sclerosis, MS; neuromyelitis optica, NMO), a systemic autoimmune condition such as sys- temic lupus erythematosus (SLE) and Sjogren’s syn- drome, or an infectious/parainfectious etiology, are referred to as disease-associated transverse myelitis. Longitudinally Extensive Versus Acute Partial Transverse Myelitis Although no reference is made by the diagnostic crite- ria to the length of the cord lesion, distinguishing between longitudinally extensive transverse myelitis Department of Radiology, Royal Melbourne Hospital, Parkville, Melbourne, Australia. *Address reprint requests to: C.G., Department of Radiology, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, Australia 3050. E-mail: [email protected] Received September 8, 2013; Accepted December 19, 2013. DOI 10.1002/jmri.24563 View this article online at wileyonlinelibrary.com. JOURNAL OF MAGNETIC RESONANCE IMAGING 40:1267–1279 (2014) CME V C 2014 Wiley Periodicals, Inc. 1267 15222586, 2014, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.24563 by Readcube (Labtiva Inc.), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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MRI in Transverse MyelitisChristine Goh, MBBS, FRANZCR,* Patricia M. Desmond, MSc, MD, FRANZCR,
and Pramit M. Phal, MBBS, FRANZCR
Transverse myelitis is an acute inflammatory disease of the spinal cord, characterized by rapid onset of bilateral neurological symptoms. Weakness, sensory disturbance, and autonomic dysfunction evolve over hours or days, most progressing to maximal clinical severity within 10 days of onset. At maximal clinical severity, half will have a paraparesis, and almost all patients have sensory dis- turbance and bladder dysfunction. Residual disability is divided equally between severe, moderate and minimal or none. The causes of transverse myelitis are diverse; etiolo- gies implicated include demyelinating conditions, collagen vascular disease, and parainfectious causes, however, despite extensive diagnostic work-up many cases are con- sidered idiopathic. Due to heterogeneity in pathogenesis, and the similarity of its clinical presentation with those of various noninflammatory myelopathies, transverse myeli- tis has frequently been viewed as a diagnostic dilemma. However, as targeted therapies to optimize patient out- come develop, timely identification of the underlying etiol- ogy is becoming increasingly important. In this review, we describe the imaging and clinical features of idiopathic and disease-associated transverse myelitis and its major differentials, with discussion of how MR imaging features assist in the identification of various sub-types of trans- verse myelitis. We will also discuss the potential for advanced MR techniques to contribute to diagnosis and prognostication.
Key Words: transverse myelitis; MRI; spinal cord; mye- lopathy; parainfectious myelitis; neuromyelitis optica
J. Magn. Reson. Imaging 2014;40:1267–1279. VC 2014 Wiley Periodicals, Inc.
The diagnostic work-up of acute transverse myelopa- thy first requires emergent MRI cord to exclude acute cord compression. Further investigation will then entail contrast enhanced MRI of cord and brain, serum and CSF analysis (autoimmune markers, auto- antibodies, microbial serology and PCR), and special-
ised investigations such as visual evoked response testing.
The critical initial treatment is often based upon a presumptive diagnosis made with reference only to the clinical features, MRI findings and basic CSF analysis. Specialised investigations such as autoanti- body testing may have greater specificity, but unfortu- nately results are not usually available until well after treatment has been instituted. This underscores the importance of the careful assessment of MR imaging appearances in narrowing the differential diagnosis sufficiently to allow the early institution of the appro- priate therapy.
Due to the diversity of aetiologies in transverse mye- lopathy, a thorough understanding the clinical as well as the imaging features of these conditions assists the radiologist in their assessment.
GENERAL CONCEPTS
Diagnostic Criteria
The diagnostic criteria proposed by the Transverse Myelitis Consortium Working Group (1) is outlined in Table 1. The first requirement is an appropriate clini- cal picture of bilateral symptoms referable to the spi- nal cord, evolving to maximal clinical severity between 4 h and 21 days. The lower limit of 4 h onset is designed to prevent cases of cord infarction, typically of abrupt onset, from being erroneously diagnosed as transverse myelitis. An active inflammatory process must be confirmed by the presence of a cellular infil- trate and/or elevated protein on CSF analysis, or by contrast enhancement on MRI of the spinal cord.
Further criteria divide transverse myelitis into two main groups. Idiopathic transverse myelitis is a diagnosis of exclusion, while those cases which are attributable to underlying processes including demye- lination (multiple sclerosis, MS; neuromyelitis optica, NMO), a systemic autoimmune condition such as sys- temic lupus erythematosus (SLE) and Sjogren’s syn- drome, or an infectious/parainfectious etiology, are referred to as disease-associated transverse myelitis.
Longitudinally Extensive Versus Acute Partial Transverse Myelitis
Although no reference is made by the diagnostic crite- ria to the length of the cord lesion, distinguishing between longitudinally extensive transverse myelitis
Department of Radiology, Royal Melbourne Hospital, Parkville, Melbourne, Australia.
*Address reprint requests to: C.G., Department of Radiology, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, Australia 3050. E-mail: [email protected]
Received September 8, 2013; Accepted December 19, 2013.
DOI 10.1002/jmri.24563 View this article online at wileyonlinelibrary.com.
JOURNAL OF MAGNETIC RESONANCE IMAGING 40:1267–1279 (2014)
CME
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(LETM), which extends over more than three segments and involves all or most of the cross-section of the cord, and acute partial transverse myelitis (APTM), which has less than two segments of eccentric or asymmetric cord involvement, is a helpful concept in the search for an underlying etiology and may assist in prognosis (2,3).
In combination with a normal initial MRI brain, APTM has 10% risk of progression to clinically definite multiple sclerosis (MS) over 61 months follow-up (4); in a longer term study this increases to 21% risk of progression at 20 years follow up (5). When nonspe- cific white matter lesions are present in the brain, there is a higher risk of progression to clinically defi- nite MS, with rates of up to 88% reported (5).
LETM is associated with a very low rate of conversion to MS (<2%), but up to 60% will be diagnosed with NMO. Presence of autoantibodies to aquaporin 4 fur- ther stratifies risk, with 83% of positive versus 25% of negative patients going on to a diagnosis of NMO (6).
There is some evidence that the distinction between LETM and APTM is less useful in the pediatric popula- tion. Two studies of children with transverse myelitis found that in children with LETM a higher proportion (10%) went on to a confirmed diagnosis of MS (7,8).
CLINICAL AND IMAGING FEATURES OF IDIOPATHIC AND DISEASE ASSOCIATED TRANSVERSE MYELITIS
Idiopathic Transverse Myelitis
Essentially a diagnosis of exclusion, it is not yet clear that there exists a distinct pathogenetic entity of idio- pathic transverse myelitis. Idiopathic transverse myeli- tis comprised 16.5% of acute myelopathy presentations in one large series (9). However, heterogeneity of patient demographics, treatment response, and outcome sug- gests that this diagnosis incorporates several underly- ing entities. As pointed out in a 2006 editorial in Neurology entitled “Is the idiopathic form vanishing?”
due to advancements in our understanding of the pathogenesis of disease associated transverse myelitis, and as increasingly sensitive and specific microbial assays and autoimmune markers are developed, idio- pathic transverse myelitis may in future represent a lesser proportion of myelopathy presentations (10).
The typical MRI appearance in transverse myelitis is a central T2 hyperintense spinal cord lesion extending over more than two segments, involving more than two- thirds of the cross sectional area of the cord (11–14). Although any cord level can be affected, the classic description includes a preference for the thoracic cord (14).
In half, the involved cord segment is expanded, and enhancement is present in 37–74% of cases. Enhancement patterns of lesions are variable: diffuse enhancement, heterogeneous enhancement, and peripheral enhancement have all been described. When diagnostic criteria have not been met due to lack of enhancement and normal CSF parameters, follow-up imaging can be helpful, as enhancement has been reported to be more frequent in the suba- cute stage than at initial acute presentation (9,11,12).
Multiple Sclerosis
Transverse myelitis remains an uncommon initial pre- sentation of MS, an inflammatory demyelinating dis- order affecting brain, cord, and optic nerves. The McDonald criteria for diagnosis requires clinical and MRI evidence of characteristic lesions which are disse- minated in time and space.
In contrast to transverse myelitis, classic spinal cord lesions in MS are small, involve less than two seg- ments, and often dorsolateral in location (Fig. 1) (15). Active lesions are T2 hyperintense, with contrast enhancement. Enhancement and cord swelling decreases in subacute phase, and chronic lesions may be associated with focal cord thinning. The relapsing nature of MS helps differentiate MS from transverse myelitis on imaging follow-up. In the rare cases where
Table 1
Inclusion criteria for diagnosis of transverse myelitis (idiopathic or disease associated)
Development of sensory, motor or autonomic dysfunction attributable to the spinal cord
Bilateral symptoms
Exclusion of compressive aetiology by MRI or CT myelography
Spinal cord inflammation demonstrated by CSF pleocytosis or elevated IgG or gadolinium enhancement
Progression to clinical nadir between 4 hours and 21 days from onset of symptoms
Exclusion criteria for diagnosis of transverse myelitis (idiopathic or disease associated)
History of radiation to the spine within 10 years
Clear arterial distribution clinical defect consistent with anterior spinal artery occlusion
Abnormal flow voids on the surface of the cord consistent with AVM
Exclusion criteria for idiopathic transverse myelitis
Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behcet’s disease, Sjogren’s syndrome, SLE, mixed connective
tissue disorder)
CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, Mycoplasma, other viral infection.
Brain abnormalities suggestive of MS
History of clinically apparent optic neuritis
*Transverse Myelitis Consortium Working Group, 2002.
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transverse myelitis is the first presentation of MS, later examinations may demonstrate new lesions in cord and brain. Presence of oligoclonal bands in CSF, found in more than 80% of patients, supports the diag- nosis (16).
Neuromyelitis Optica
Compared with MS, this severe relapsing demyelinat- ing condition is diagnosed at an older age (mean age, 39 years compared with 29 years at diagnosis), has a greater female predominance and a higher incidence in the non-white population (17,18). The spinal cord and optic nerves are the main sites of involvement, although classic brain lesions have now also been described. Like MS, NMO is a relapsing disorder, but attacks are often more severe and result in greater residual disability. Oligoclonal bands are present in only 15–30% of NMO cases compared with 85% of MS cases, and CSF neutrophilia is often present (17).
Although previously considered to be related to MS, more recent work on the immunopathogenesis of NMO has identified an autoantibody to the CNS water channel protein aquaporin 4, highly specific (91%) and sensitive (73%) to NMO and correlating with dis- ease severity (19,20). In 2006, the diagnostic criteria for NMO were revised to incorporate this new marker for the disease. In patients with acute myelitis and optic neuritis, the diagnostic combination of two of three criteria: NMO IgG positivity, longitudinally extensive cord lesion, or onset MRI brain nondiagnos-
tic for MS, provides 99% sensitivity and 90% specific- ity for NMO (21).
In the presence of the NMO autoantibody, patients with isolated LETM or optic neuritis can be consid- ered part of a spectrum of NMO disorders, analogous to the clinically isolated syndrome of MS. In LETM, patients positive for the NMO autoantibody have a greater relapse rate and level of disability. A total of 83.3% convert to NMO (60% in the first 2 years from onset) compared with 25% in those negative for the autoantibody (6).
On MRI the typical finding is long segment cord involvement, more commonly unifocal than multifocal (see Fig. 1). T1 hypointensity within the acute cord lesion favors NMO over MS, thought to reflect the greater tissue destruction in NMO. Enhancement and cord expansion is common in acute lesions (18).
Although myelitis can extend cranially to involve the brainstem, in the past MRI evidence of noncontiguous brain involvement at presentation was excluded by definition. However, it is now recognized that up to 60% will develop nonspecific white matter lesions, and 10% will have lesions meeting McDonald criteria for MS (22).
Characteristic T2 hyperintense brain lesions of NMO occur at sites of high expression of aquaporin 4, involving hypothalamus and periependymal regions, typically periaqueductal and about the third and fourth ventricles (Fig. 1) (23).
Ten to 40% of NMO patients have a coexistent auto- immune disorder, most commonly SLE, antiphospho- lipid disorder, and Sjogren’s syndrome, but also
Figure 1. The longitudinally extensive transverse myelitis typical of neuromyelitis optica (B) involves more than three seg- ments and more than two thirds of the cross-sectional area of the cord, compared with multiple short segment eccentrically positioned lesions usually seen in multiple sclerosis (A). In some cases, characteristic brain lesions such as hypothalamic involvement (C, arrows) may assist in the diagnosis of neuromyelitis optica.
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Systemic Autoimmune Conditions
Transverse myelitis attributed to a systemic autoim- mune conditions has been most frequently reported in SLE and antiphospholipid syndrome, but has also been described in Sjogren’s syndrome, mixed connec- tive tissue disease, sarcoidosis, Behcet’s disease, rheumatoid arthritis, and ankylosing spondylitis. Although an uncommon complication, incidence in those with connective tissue diseases far exceeds that of the general population. In one study of acute mye- lopathy presentations, 16.5% were attributed to a sys- temic autoimmune condition, and in almost half of these cases transverse myelitis was the presenting condition leading to that diagnosis (26).
Historically, pathogenesis of transverse myelitis in systemic autoimmune conditions has been attributed to vasculitis and arterial thrombi related to autoim- munologic phenomena causing ischemic necrosis within the cord. Autopsy studies in SLE patients have described perivascular inflammation, and ischemic necrosis, infarction or myelomalacia of the cord (27).
The more recent understanding of NMO as an auto- immune disorder and the recognition of that up to half of NMO patients also meet criteria for systemic autoimmune conditions have given rise to an alterna- tive theory: that in many cases transverse myelitis previously attributed to conditions such as SLE or Sjogren’s syndrome are due to unrecognized NMO spectrum disorder (24,28,29).
However, two studies investigating SLE and Sjog- ren’s patients, respectively, describe divergent clinical pictures of myelopathy which suggest that, while coexistent NMO is an important cause of myelopathy in the setting of systemic autoimmune diseases, there is also a separate entity of transverse myelitis related to the underlying vasculitic process (30).
In the largest such cohort studied, Birnbaum et al (30) found that 22 patients with SLE and myelitis could be divided on clinical and outcome measures into two groups. One had a rapid onset (<6 h in 72.7%) of flaccid paralysis, hyporeflexia, and urinary retention, leading a poor outcome with persistent par- aplegia, occurring on a background of a febrile pro- drome, clinical and ESR evidence of active SLE, and CSF profile of neutrophilia and elevated protein. The other group had a more subacute onset of spasticity, hyperreflexia, and mild to moderate weakness over 1 to 30 days, followed by a relapsing course. Rates of optic neuritis (0% group 1 and 54.5% group 2) and NMO IgG positivity (12.5% group 1 and 57.1% group 2) were significantly different between the two groups.
Williams and Butler (31), in their review of 17 previ- ously reported cases of Sjogren’s syndrome and myeli- tis, were able to distinguish between two distinct clinical patterns. The first was rapid onset of severe sensory and motor deficit with neck and interscapular pain, with high mortality. The second had a subacute onset of gait, sensory and urinary disturbance pro-
gressing to eventual paraplegia, associated with optic neuritis in four out of five cases.
Systemic Lupus Erythematosis
CNS manifestations in SLE occur in more than half of patients, most commonly aseptic meningitis and cere- brovascular disease. While myelopathy is relatively uncommon, occurring in less than 3%, it is the initial presentation in up to half of cases (27,29,32).
Variability in descriptions of the clinical prodrome, correlation with markers of lupus activity, clinical out- comes, and imaging features in published cases of mye- litis in SLE patients may potentially be accounted for by the differences between SLE-associated myelitis and NMO. The clinical presentation of SLE-associated myeli- tis has been described as acute in onset, accompanied by a short prodrome of fever, headache, and malaise. CSF protein levels are elevated, without oligoclonal bands (27,32). Co-existent optic neuritis, described in 21–48%, probably reflects the previously unrecognized subset of patients with co-existent SLE and NMO.
MRI findings also vary in the literature; as most reports were published before recent advances in understanding of NMO, it is unsurprising that most reports describe long segment central T2 hyperinten- sity and expansion, with enhancement common but variable (see Fig. 2). However, MRI of the spinal cord is normal at presentation in 16–30% of patients with clin- ical myelitis (32,33) and a few reports describe small multifocal T2 hyperintense lesions (26,27,30,32).
Sjogren’s Syndrome
The hallmark of this chronic inflammatory exocrinop- athy is the sicca complex of keratoconjunctivitis sicca, xerostomia, and salivary gland inflammation, although any organ system can be affected. Sjogren’s syndrome can be associated with rheumatoid arthritis and less commonly other autoimmune disorders such as SLE. There is marked female predominance with onset usu- ally in the 5th or 6th decade (34). CNS complications are described in 25–30% of patient, but transverse myelitis is rare, occurring in up to 1% of patients with Sjogren’s syndrome (29,34).
In published cases that describe MRI findings, long segment central T2 hyperintense cord lesion with expansion and variable enhancement is the most commonly described finding, but multifocal lesions have also been described (26,31,35,36).
Behcet’s Disease
Rare in the Western world, this systemic inflammatory disease is most prevalent in those of eastern Mediter- ranean and Middle Eastern descent, with the highest prevalence in Turkey. Onset is typically at 3rd to 5th decade, with 2:1 male predominance (37,38).
The hallmark of Behcet’s disease is the triad of uvei- tis with recurrent oral and genital ulcers. CNS manifes- tations, reportedly twice as common in male patients, occur in around 10% and may include meningoence- phalitis (in 75%) and myelitis (in 10%) and venous thrombosis (in 18%) (38).
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Neuro-Behcet’s disease (NMD) in an acute trans- verse myelitis presentation may be suspected based on known history or the presence of uveitis and ulcers, but is occasionally the presenting condition. Typically patients have a CSF pleocytosis and elevated ESR, which correlates with active disease (37).
On MRI of the spinal cord, the typical finding is T2 hyperintense lesions extending over more than two segments, with preference for the posterolateral cord (37–39). Myelitis is most often an isolated CNS mani- festation. However, some cases of spinal involvement have occurred in combination with meningoencephali- tis, which typically manifests on MRI as unilateral T2 hyperintensity, edema, and enhancement in the brainstem, thalamus, and basal ganglia (38).
Paraneoplastic Myelopathy
Paraneoplastic neurological syndromes occur in per- haps 0.1% of patients with cancer, either affecting an isolated area or with multifocal involvement which may include limbic encephalopathy, cerebellar dys- function, necrotizing myelopathy, inflammatory mye- lopathy, peripheral neuropathy, or retinopathy. Lung and breast cancer are most commonly associated, but hematological and gastrointestinal malignancies have also been reported.
Many patients with paraneoplastic myelopathy have identifiable autoantibodies in serum and CSF. Those which have been associated with myelopathy, often in association with encephalitis or cerebellar dysfunc- tion, include amphiphysin antibody, antineuronal nuclear autoantibody type 2 (ANNA-2 or anti-Ri), ANNA-3, collapsing response-mediator protein 5, ANNA-1 (anti-Hu), Purkinje-ell cytoplasmic autoanti-
body type 2 (PCA-2), PCA-1 (antiYo), anti-Ma, and anti-Ta (40–42). The malignancy is often undiagnosed at time of presentation and frequently remains occult, but the combination of the pattern of clinical involve- ment and autoantibody type can suggest the site of underlying cancer (40).
In a review of 31 cases of clinically isolated para- neoplastic myelopathy (41), neuronal autoantibody was detected in 81%, and cancer was diagnosed after the myelopathy symptom onset in 67%, with 12 months the median time to cancer detection. One third of patients had a normal MRI spinal cord. In 48%, MRI showed symmetric T2 hyperintensity in a tract/gray…
and Pramit M. Phal, MBBS, FRANZCR
Transverse myelitis is an acute inflammatory disease of the spinal cord, characterized by rapid onset of bilateral neurological symptoms. Weakness, sensory disturbance, and autonomic dysfunction evolve over hours or days, most progressing to maximal clinical severity within 10 days of onset. At maximal clinical severity, half will have a paraparesis, and almost all patients have sensory dis- turbance and bladder dysfunction. Residual disability is divided equally between severe, moderate and minimal or none. The causes of transverse myelitis are diverse; etiolo- gies implicated include demyelinating conditions, collagen vascular disease, and parainfectious causes, however, despite extensive diagnostic work-up many cases are con- sidered idiopathic. Due to heterogeneity in pathogenesis, and the similarity of its clinical presentation with those of various noninflammatory myelopathies, transverse myeli- tis has frequently been viewed as a diagnostic dilemma. However, as targeted therapies to optimize patient out- come develop, timely identification of the underlying etiol- ogy is becoming increasingly important. In this review, we describe the imaging and clinical features of idiopathic and disease-associated transverse myelitis and its major differentials, with discussion of how MR imaging features assist in the identification of various sub-types of trans- verse myelitis. We will also discuss the potential for advanced MR techniques to contribute to diagnosis and prognostication.
Key Words: transverse myelitis; MRI; spinal cord; mye- lopathy; parainfectious myelitis; neuromyelitis optica
J. Magn. Reson. Imaging 2014;40:1267–1279. VC 2014 Wiley Periodicals, Inc.
The diagnostic work-up of acute transverse myelopa- thy first requires emergent MRI cord to exclude acute cord compression. Further investigation will then entail contrast enhanced MRI of cord and brain, serum and CSF analysis (autoimmune markers, auto- antibodies, microbial serology and PCR), and special-
ised investigations such as visual evoked response testing.
The critical initial treatment is often based upon a presumptive diagnosis made with reference only to the clinical features, MRI findings and basic CSF analysis. Specialised investigations such as autoanti- body testing may have greater specificity, but unfortu- nately results are not usually available until well after treatment has been instituted. This underscores the importance of the careful assessment of MR imaging appearances in narrowing the differential diagnosis sufficiently to allow the early institution of the appro- priate therapy.
Due to the diversity of aetiologies in transverse mye- lopathy, a thorough understanding the clinical as well as the imaging features of these conditions assists the radiologist in their assessment.
GENERAL CONCEPTS
Diagnostic Criteria
The diagnostic criteria proposed by the Transverse Myelitis Consortium Working Group (1) is outlined in Table 1. The first requirement is an appropriate clini- cal picture of bilateral symptoms referable to the spi- nal cord, evolving to maximal clinical severity between 4 h and 21 days. The lower limit of 4 h onset is designed to prevent cases of cord infarction, typically of abrupt onset, from being erroneously diagnosed as transverse myelitis. An active inflammatory process must be confirmed by the presence of a cellular infil- trate and/or elevated protein on CSF analysis, or by contrast enhancement on MRI of the spinal cord.
Further criteria divide transverse myelitis into two main groups. Idiopathic transverse myelitis is a diagnosis of exclusion, while those cases which are attributable to underlying processes including demye- lination (multiple sclerosis, MS; neuromyelitis optica, NMO), a systemic autoimmune condition such as sys- temic lupus erythematosus (SLE) and Sjogren’s syn- drome, or an infectious/parainfectious etiology, are referred to as disease-associated transverse myelitis.
Longitudinally Extensive Versus Acute Partial Transverse Myelitis
Although no reference is made by the diagnostic crite- ria to the length of the cord lesion, distinguishing between longitudinally extensive transverse myelitis
Department of Radiology, Royal Melbourne Hospital, Parkville, Melbourne, Australia.
*Address reprint requests to: C.G., Department of Radiology, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, Australia 3050. E-mail: [email protected]
Received September 8, 2013; Accepted December 19, 2013.
DOI 10.1002/jmri.24563 View this article online at wileyonlinelibrary.com.
JOURNAL OF MAGNETIC RESONANCE IMAGING 40:1267–1279 (2014)
CME
15222586, 2014, 6, D ow
nloaded from https://onlinelibrary.w
nline L ibrary on [23/03/2023]. See the T
erm s and C
articles are governed by the applicable C reative C
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ons L icense
(LETM), which extends over more than three segments and involves all or most of the cross-section of the cord, and acute partial transverse myelitis (APTM), which has less than two segments of eccentric or asymmetric cord involvement, is a helpful concept in the search for an underlying etiology and may assist in prognosis (2,3).
In combination with a normal initial MRI brain, APTM has 10% risk of progression to clinically definite multiple sclerosis (MS) over 61 months follow-up (4); in a longer term study this increases to 21% risk of progression at 20 years follow up (5). When nonspe- cific white matter lesions are present in the brain, there is a higher risk of progression to clinically defi- nite MS, with rates of up to 88% reported (5).
LETM is associated with a very low rate of conversion to MS (<2%), but up to 60% will be diagnosed with NMO. Presence of autoantibodies to aquaporin 4 fur- ther stratifies risk, with 83% of positive versus 25% of negative patients going on to a diagnosis of NMO (6).
There is some evidence that the distinction between LETM and APTM is less useful in the pediatric popula- tion. Two studies of children with transverse myelitis found that in children with LETM a higher proportion (10%) went on to a confirmed diagnosis of MS (7,8).
CLINICAL AND IMAGING FEATURES OF IDIOPATHIC AND DISEASE ASSOCIATED TRANSVERSE MYELITIS
Idiopathic Transverse Myelitis
Essentially a diagnosis of exclusion, it is not yet clear that there exists a distinct pathogenetic entity of idio- pathic transverse myelitis. Idiopathic transverse myeli- tis comprised 16.5% of acute myelopathy presentations in one large series (9). However, heterogeneity of patient demographics, treatment response, and outcome sug- gests that this diagnosis incorporates several underly- ing entities. As pointed out in a 2006 editorial in Neurology entitled “Is the idiopathic form vanishing?”
due to advancements in our understanding of the pathogenesis of disease associated transverse myelitis, and as increasingly sensitive and specific microbial assays and autoimmune markers are developed, idio- pathic transverse myelitis may in future represent a lesser proportion of myelopathy presentations (10).
The typical MRI appearance in transverse myelitis is a central T2 hyperintense spinal cord lesion extending over more than two segments, involving more than two- thirds of the cross sectional area of the cord (11–14). Although any cord level can be affected, the classic description includes a preference for the thoracic cord (14).
In half, the involved cord segment is expanded, and enhancement is present in 37–74% of cases. Enhancement patterns of lesions are variable: diffuse enhancement, heterogeneous enhancement, and peripheral enhancement have all been described. When diagnostic criteria have not been met due to lack of enhancement and normal CSF parameters, follow-up imaging can be helpful, as enhancement has been reported to be more frequent in the suba- cute stage than at initial acute presentation (9,11,12).
Multiple Sclerosis
Transverse myelitis remains an uncommon initial pre- sentation of MS, an inflammatory demyelinating dis- order affecting brain, cord, and optic nerves. The McDonald criteria for diagnosis requires clinical and MRI evidence of characteristic lesions which are disse- minated in time and space.
In contrast to transverse myelitis, classic spinal cord lesions in MS are small, involve less than two seg- ments, and often dorsolateral in location (Fig. 1) (15). Active lesions are T2 hyperintense, with contrast enhancement. Enhancement and cord swelling decreases in subacute phase, and chronic lesions may be associated with focal cord thinning. The relapsing nature of MS helps differentiate MS from transverse myelitis on imaging follow-up. In the rare cases where
Table 1
Inclusion criteria for diagnosis of transverse myelitis (idiopathic or disease associated)
Development of sensory, motor or autonomic dysfunction attributable to the spinal cord
Bilateral symptoms
Exclusion of compressive aetiology by MRI or CT myelography
Spinal cord inflammation demonstrated by CSF pleocytosis or elevated IgG or gadolinium enhancement
Progression to clinical nadir between 4 hours and 21 days from onset of symptoms
Exclusion criteria for diagnosis of transverse myelitis (idiopathic or disease associated)
History of radiation to the spine within 10 years
Clear arterial distribution clinical defect consistent with anterior spinal artery occlusion
Abnormal flow voids on the surface of the cord consistent with AVM
Exclusion criteria for idiopathic transverse myelitis
Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behcet’s disease, Sjogren’s syndrome, SLE, mixed connective
tissue disorder)
CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, Mycoplasma, other viral infection.
Brain abnormalities suggestive of MS
History of clinically apparent optic neuritis
*Transverse Myelitis Consortium Working Group, 2002.
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transverse myelitis is the first presentation of MS, later examinations may demonstrate new lesions in cord and brain. Presence of oligoclonal bands in CSF, found in more than 80% of patients, supports the diag- nosis (16).
Neuromyelitis Optica
Compared with MS, this severe relapsing demyelinat- ing condition is diagnosed at an older age (mean age, 39 years compared with 29 years at diagnosis), has a greater female predominance and a higher incidence in the non-white population (17,18). The spinal cord and optic nerves are the main sites of involvement, although classic brain lesions have now also been described. Like MS, NMO is a relapsing disorder, but attacks are often more severe and result in greater residual disability. Oligoclonal bands are present in only 15–30% of NMO cases compared with 85% of MS cases, and CSF neutrophilia is often present (17).
Although previously considered to be related to MS, more recent work on the immunopathogenesis of NMO has identified an autoantibody to the CNS water channel protein aquaporin 4, highly specific (91%) and sensitive (73%) to NMO and correlating with dis- ease severity (19,20). In 2006, the diagnostic criteria for NMO were revised to incorporate this new marker for the disease. In patients with acute myelitis and optic neuritis, the diagnostic combination of two of three criteria: NMO IgG positivity, longitudinally extensive cord lesion, or onset MRI brain nondiagnos-
tic for MS, provides 99% sensitivity and 90% specific- ity for NMO (21).
In the presence of the NMO autoantibody, patients with isolated LETM or optic neuritis can be consid- ered part of a spectrum of NMO disorders, analogous to the clinically isolated syndrome of MS. In LETM, patients positive for the NMO autoantibody have a greater relapse rate and level of disability. A total of 83.3% convert to NMO (60% in the first 2 years from onset) compared with 25% in those negative for the autoantibody (6).
On MRI the typical finding is long segment cord involvement, more commonly unifocal than multifocal (see Fig. 1). T1 hypointensity within the acute cord lesion favors NMO over MS, thought to reflect the greater tissue destruction in NMO. Enhancement and cord expansion is common in acute lesions (18).
Although myelitis can extend cranially to involve the brainstem, in the past MRI evidence of noncontiguous brain involvement at presentation was excluded by definition. However, it is now recognized that up to 60% will develop nonspecific white matter lesions, and 10% will have lesions meeting McDonald criteria for MS (22).
Characteristic T2 hyperintense brain lesions of NMO occur at sites of high expression of aquaporin 4, involving hypothalamus and periependymal regions, typically periaqueductal and about the third and fourth ventricles (Fig. 1) (23).
Ten to 40% of NMO patients have a coexistent auto- immune disorder, most commonly SLE, antiphospho- lipid disorder, and Sjogren’s syndrome, but also
Figure 1. The longitudinally extensive transverse myelitis typical of neuromyelitis optica (B) involves more than three seg- ments and more than two thirds of the cross-sectional area of the cord, compared with multiple short segment eccentrically positioned lesions usually seen in multiple sclerosis (A). In some cases, characteristic brain lesions such as hypothalamic involvement (C, arrows) may assist in the diagnosis of neuromyelitis optica.
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Systemic Autoimmune Conditions
Transverse myelitis attributed to a systemic autoim- mune conditions has been most frequently reported in SLE and antiphospholipid syndrome, but has also been described in Sjogren’s syndrome, mixed connec- tive tissue disease, sarcoidosis, Behcet’s disease, rheumatoid arthritis, and ankylosing spondylitis. Although an uncommon complication, incidence in those with connective tissue diseases far exceeds that of the general population. In one study of acute mye- lopathy presentations, 16.5% were attributed to a sys- temic autoimmune condition, and in almost half of these cases transverse myelitis was the presenting condition leading to that diagnosis (26).
Historically, pathogenesis of transverse myelitis in systemic autoimmune conditions has been attributed to vasculitis and arterial thrombi related to autoim- munologic phenomena causing ischemic necrosis within the cord. Autopsy studies in SLE patients have described perivascular inflammation, and ischemic necrosis, infarction or myelomalacia of the cord (27).
The more recent understanding of NMO as an auto- immune disorder and the recognition of that up to half of NMO patients also meet criteria for systemic autoimmune conditions have given rise to an alterna- tive theory: that in many cases transverse myelitis previously attributed to conditions such as SLE or Sjogren’s syndrome are due to unrecognized NMO spectrum disorder (24,28,29).
However, two studies investigating SLE and Sjog- ren’s patients, respectively, describe divergent clinical pictures of myelopathy which suggest that, while coexistent NMO is an important cause of myelopathy in the setting of systemic autoimmune diseases, there is also a separate entity of transverse myelitis related to the underlying vasculitic process (30).
In the largest such cohort studied, Birnbaum et al (30) found that 22 patients with SLE and myelitis could be divided on clinical and outcome measures into two groups. One had a rapid onset (<6 h in 72.7%) of flaccid paralysis, hyporeflexia, and urinary retention, leading a poor outcome with persistent par- aplegia, occurring on a background of a febrile pro- drome, clinical and ESR evidence of active SLE, and CSF profile of neutrophilia and elevated protein. The other group had a more subacute onset of spasticity, hyperreflexia, and mild to moderate weakness over 1 to 30 days, followed by a relapsing course. Rates of optic neuritis (0% group 1 and 54.5% group 2) and NMO IgG positivity (12.5% group 1 and 57.1% group 2) were significantly different between the two groups.
Williams and Butler (31), in their review of 17 previ- ously reported cases of Sjogren’s syndrome and myeli- tis, were able to distinguish between two distinct clinical patterns. The first was rapid onset of severe sensory and motor deficit with neck and interscapular pain, with high mortality. The second had a subacute onset of gait, sensory and urinary disturbance pro-
gressing to eventual paraplegia, associated with optic neuritis in four out of five cases.
Systemic Lupus Erythematosis
CNS manifestations in SLE occur in more than half of patients, most commonly aseptic meningitis and cere- brovascular disease. While myelopathy is relatively uncommon, occurring in less than 3%, it is the initial presentation in up to half of cases (27,29,32).
Variability in descriptions of the clinical prodrome, correlation with markers of lupus activity, clinical out- comes, and imaging features in published cases of mye- litis in SLE patients may potentially be accounted for by the differences between SLE-associated myelitis and NMO. The clinical presentation of SLE-associated myeli- tis has been described as acute in onset, accompanied by a short prodrome of fever, headache, and malaise. CSF protein levels are elevated, without oligoclonal bands (27,32). Co-existent optic neuritis, described in 21–48%, probably reflects the previously unrecognized subset of patients with co-existent SLE and NMO.
MRI findings also vary in the literature; as most reports were published before recent advances in understanding of NMO, it is unsurprising that most reports describe long segment central T2 hyperinten- sity and expansion, with enhancement common but variable (see Fig. 2). However, MRI of the spinal cord is normal at presentation in 16–30% of patients with clin- ical myelitis (32,33) and a few reports describe small multifocal T2 hyperintense lesions (26,27,30,32).
Sjogren’s Syndrome
The hallmark of this chronic inflammatory exocrinop- athy is the sicca complex of keratoconjunctivitis sicca, xerostomia, and salivary gland inflammation, although any organ system can be affected. Sjogren’s syndrome can be associated with rheumatoid arthritis and less commonly other autoimmune disorders such as SLE. There is marked female predominance with onset usu- ally in the 5th or 6th decade (34). CNS complications are described in 25–30% of patient, but transverse myelitis is rare, occurring in up to 1% of patients with Sjogren’s syndrome (29,34).
In published cases that describe MRI findings, long segment central T2 hyperintense cord lesion with expansion and variable enhancement is the most commonly described finding, but multifocal lesions have also been described (26,31,35,36).
Behcet’s Disease
Rare in the Western world, this systemic inflammatory disease is most prevalent in those of eastern Mediter- ranean and Middle Eastern descent, with the highest prevalence in Turkey. Onset is typically at 3rd to 5th decade, with 2:1 male predominance (37,38).
The hallmark of Behcet’s disease is the triad of uvei- tis with recurrent oral and genital ulcers. CNS manifes- tations, reportedly twice as common in male patients, occur in around 10% and may include meningoence- phalitis (in 75%) and myelitis (in 10%) and venous thrombosis (in 18%) (38).
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Neuro-Behcet’s disease (NMD) in an acute trans- verse myelitis presentation may be suspected based on known history or the presence of uveitis and ulcers, but is occasionally the presenting condition. Typically patients have a CSF pleocytosis and elevated ESR, which correlates with active disease (37).
On MRI of the spinal cord, the typical finding is T2 hyperintense lesions extending over more than two segments, with preference for the posterolateral cord (37–39). Myelitis is most often an isolated CNS mani- festation. However, some cases of spinal involvement have occurred in combination with meningoencephali- tis, which typically manifests on MRI as unilateral T2 hyperintensity, edema, and enhancement in the brainstem, thalamus, and basal ganglia (38).
Paraneoplastic Myelopathy
Paraneoplastic neurological syndromes occur in per- haps 0.1% of patients with cancer, either affecting an isolated area or with multifocal involvement which may include limbic encephalopathy, cerebellar dys- function, necrotizing myelopathy, inflammatory mye- lopathy, peripheral neuropathy, or retinopathy. Lung and breast cancer are most commonly associated, but hematological and gastrointestinal malignancies have also been reported.
Many patients with paraneoplastic myelopathy have identifiable autoantibodies in serum and CSF. Those which have been associated with myelopathy, often in association with encephalitis or cerebellar dysfunc- tion, include amphiphysin antibody, antineuronal nuclear autoantibody type 2 (ANNA-2 or anti-Ri), ANNA-3, collapsing response-mediator protein 5, ANNA-1 (anti-Hu), Purkinje-ell cytoplasmic autoanti-
body type 2 (PCA-2), PCA-1 (antiYo), anti-Ma, and anti-Ta (40–42). The malignancy is often undiagnosed at time of presentation and frequently remains occult, but the combination of the pattern of clinical involve- ment and autoantibody type can suggest the site of underlying cancer (40).
In a review of 31 cases of clinically isolated para- neoplastic myelopathy (41), neuronal autoantibody was detected in 81%, and cancer was diagnosed after the myelopathy symptom onset in 67%, with 12 months the median time to cancer detection. One third of patients had a normal MRI spinal cord. In 48%, MRI showed symmetric T2 hyperintensity in a tract/gray…
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