Inflammatory Demyelinating Diseases

1.2.1

Introduction

The spinal cord is a common site of involvement in inflammatory demyelinating diseases of the central nervous system (CNS). The most common such disease, multiple sclerosis, is the leading cause of nontraumatic disability in young adults, with an enormous socioeconomic impact. Neuromyelitis optica (NMO), an increasingly recognized and recently redefined condition, also has prominent and very characteristic spinal cord involvement, which is typically much more severe than MS-related transverse myelitis. The critical importance of spinal cord imaging in these conditions is also highlighted by the inclusion of spinal cord magnetic resonance imaging (MRI)-derived metrics in the internationally utilized diagnostic criteria of MS and NMO. However, with the constant evolution of the MS diagnostic criteria, new discoveries pertaining to the pathogenesis and biomarkers of NMO, and the evolving definitions of transverse myelitis, acute disseminated encephalomyelitis (ADEM), pediatric MS, and systemic autoimmune disease-associated and paraneoplastic myelopathies, one might feel overwhelmed when attempting to classify, characterize, diagnose, and manage these conditions. Neuroimaging, specifically MRI, plays a key role in the correct diagnosis of these conditions, and it provides a critically important aid for treatment monitoring. With the advent of advanced MRI techniques enabling quantitative analysis methods, MRI provides a reliable tool in monitoring and characterizing disease progression, and it also enables a unique insight into the generally poorly understood pathogenesis of these disorders.

In this chapter, we will discuss the currently available and constantly evolving MRI-based quantitative tools. These will be discussed in the context of the most common forms of acute and subacute inflammatory myelopathies, including MS-related transverse myelitis, longitudinally extensive transverse myelitis (LETM) related to NMO and NMO spectrum disorder, and idiopathic inflammatory transverse myelitis in the context of MS and as a stand-alone condition. The vast majority of the published quantitative MRI literature clearly has focused on MS, with a smaller but growing proportion of studies related to NMO; for that reason, these two diseases are the main focus when we discuss quantitative methods. Finally, we will outline future perspectives and challenges in the evolving field of quantitative MRI in inflammatory myelopathies.

1.2.2

Classification of Inflammatory Myelopathies

While there is currently no single universally accepted and utilized classification of inflammatory myelopathies, one can consider several features of these conditions to establish clinically useful classifications. One such feature is the lesion location or “lesion type” ( Table 1.2.1 ). In addition, an important classification strategy also followed in the recently published American Academy of Neurology guidelines is whether the TM episode is complete or partial, which is an especially helpful distinguishing feature at first presentation with transverse myelitis.

1.2.3

Transverse Myelitis: A Practical Definition Based on MRI

Transverse myelitis is a collective term for segmental inflammatory disorders of the spinal cord. While TM can be seen in the context of infections, which are typically easily recognized given the associated systemic features and/or CSF findings, most cases represent idiopathic inflammatory diseases, including MS, NMO, and less commonly ADEM, paraneoplastic disorders, or sarcoidosis. Metabolic diseases such as vitamin B ₁₂ or copper deficiency also may look like TM on conventional MRI, but even with conventional imaging usually there are clear clues regarding their noninflammatory nature.

The most important classifying feature of idiopathic TM is based on its MRI appearance on axial and sagittal scans: lesions that encompass one-fourth to one-third of the cord crosscut surface area, typically abut the CSF, have a wedge-like appearance, and on sagittal images rarely extend beyond one or two segments are typical MS lesions. By contrast, lesions that are mostly gray matter centered, encompass one-half or more of the crosscut surface area, are longitudinally extensive usually beyond three segments, and during their acute stage are associated with mass effect are typical NMO lesions. TM lesions with NMO-like characteristics are often labeled as LETM.

1.2.4

The Significance of TM and Its Relationship to MS and NMO

It is important to note that a single idiopathic TM event should be considered a CIS that may evolve into MS or NMO later, or may be a stand-alone disease without conversion to a more disseminated demyelinating disease. From the standpoint of a classic MS-like TM evolving into clinically definite MS (CDMS, defined as MS with more than one clinical event clearly related to demyelinating disease), the most important clue is whether upon presentation more than just the symptomatic cord lesion is visualized. If additional MS-like lesions are seen in either the brain or spinal cord, and especially if these lesions meet the Barkhof–Tintore “dissemination in space” criteria ( Table 1.2.2 ), then the patient would fall into the “high conversion risk group,” which has a >80% risk of developing CDMS over the next 20 years, with a hazard ratio of over 6.4 and most of them converting early on. If, in addition to nonsymptomatic MS-like lesions, the CSF is also positive for common markers of MS (immunoglobulin G (IgG) index elevation and oligoclonal bands positivity), the conversion risk is even higher, and conversion occurs earlier, typically within the first couple of years.

In 2010, a new set of criteria was proposed for MS, which represents the second modification of the original McDonald MS criteria from 2001. Of note, the 2001 McDonald criteria were the first to incorporate MRI characteristics in the diagnosis of MS. The new 2010 criteria further refine the MRI-based dissemination in space and dissemination in time (DIT) criteria, with special emphasis placed on spinal cord lesions in the dissemination in space criteria ( Table 1.2.2 ) and in the criteria of primary progressive MS (PPMS). The presence of spinal cord lesions in general increases the diagnostic certainty in MS, as many of the “MS mimics” do not lead to cord lesion formation. In PPMS, and in progressive forms of MS in general, the main symptom is that of a slowly progressive myelopathy, which is reflected by the extensive use of cord-derived MRI parameters in the new diagnostic criteria. Advanced MRI methods are becoming especially important in progressive forms of MS, especially in PPMS: in this MS subtype, the most typical clinical presentation is that of a slowly progressive myelopathy, with only minimal if any accompanying MRI activity on conventional MRI despite the ongoing progression. This MS subtype also represents the most universally disabling form of MS (apart from the very rarely seen cases of fulminant MS such as the Marburg variant), and typically PPMS is also the least likely to respond to currently available treatments. Advanced quantitative MRI will likely play a very important role in monitoring PPMS, especially in upcoming tissue restorative treatment trials, and will likely also shed light on the pathogenesis of this very poorly understood entity.

The new DIT criteria ( Table 1.2.3 ) do not have a cord-specific component but enable one single scan at one time point to fulfill DIT: if a scan has both enhancing (“new”) and nonenhancing (“old”) lesions in the typical configuration for MS, DIT criteria are met. While the new DIT criteria certainly will lead to earlier diagnosis and as such may have important treatment ramifications, one must be very cautious with this new development: if more than one pathology is present, such as a one-time demyelinating event intermixed with another pathology that may lead to the presence of enhancing lesions, such as dural AV fistulas in the spinal cord or venous angiomas in the brain, one may encounter cases that do meet DIT criteria but for reasons unrelated to MS. In effect, it can be stated that, as a result of the newly introduced changes, the specificity of the new criteria is lower, while the sensitivity to classify as MS is higher ( Figure 1.2.1 ).