Imaging MS: A Window Into the Disease
Robert J. Fox, MD, Medical Director, Mellen Center for Multiple Sclerosis, Assistant Professor, Cleveland Clinic Lerner School of Medicine at CWRU Cleveland Clinic Foundation, Cleveland, Ohio
Introduction
Magnetic resonance imaging (MRI) has provided a new window into the injury caused by multiple sclerosis (MS) and the effects of MS therapies. MRI can be performed in a variety of ways, thereby highlighting different aspects of disease activity and tissue injury. Future advances in image acquisition and analysis will further improve this picture and allow more accurate characterization of the disease and the potential neuroprotective effects of new therapies.
Background
When MS was first studied in the 1800s, there was a distinct separation between clinical descriptions of the disease in live patients and the later pathologic studies of brain and spinal cord tissues after death decades later. The development of computed tomography (CT) imaging in the 1970s transformed the field of neurology by allowing clinicians and researchers to see diseased tissue within the skull. But the study of MS was not helped significantly by CT since only a small proportion of MS lesions can be seen on CT scans. It was not until the 1980s that MRI was developed and applied to human disease, and finally the destructive effects of MS could be clearly visualized in live patients. Over the next 2 decades, MRI has made a dramatic contribution to our understanding of MS pathogenesis and the effects of therapy. This review will outline those contributions.
MRI Basics
MRI takes advantage of a physical property of hydrogen atoms in water, whereby the magnetic spin of hydrogen atoms align themselves in a strong magnetic field. This strong, constant magnetic field is created by the large, donut-shaped machine that patients lie within during an MRI. The strength of this large magnet is many tens of thousands of times the strength of the earth’s magnetic field and is strong enough to move even very large magnetic objects. For this reason, it is very important to remove all ferromagnetic metal before coming into proximity of an MRI. Even small metal fragments in some parts of the body (i.e., metal shavings in an eye from industrial work) can be moved by the MRI magnet and cause injury. When a short, temporary second magnetic pulse is applied (which produces a loud banging or vibration noise during an MRI scan), the hydrogen atoms change their alignment briefly, and then relax to their previous alignment after the magnetic pulse is complete. This altered magnetic alignment of hydrogen atoms is not harmful to the tissues or cells, but can be detected by sensors contained in the cage-like apparatus placed around the head during a brain MRI or on the chest or under the back during a spine MRI. The water content of tissue and the cellular structures within tissue affects how the hydrogen atoms change their magnetic spin alignment and later relax, and these alterations create the contrast in an MR image.
Image Types
The short, second magnetic pulse can be applied in a variety of ways, and consequently different characteristics of tissue and the effects of disease can be appreciated. One of the most useful image types in MS is called T2-weighted imaging. Inflammation and tissue damage are seen on T2 images as bright areas and are often referred to as T2 lesions (Figures 1, 2). Although some T2 lesions can resolve and disappear over time, most T2 lesions typically remain as footprints of inflammatory damage for years to come. Accordingly, summary measures of overall T2 lesion burden are sometimes used to characterize the extent of tissue injury in MS. T1-weighted images are another useful imaging type in MS. T1 images primarily characterize tissue integrity, and dark areas on T1 images (called T1 holes) indicate areas of significant tissue injury (van Walderveen et al., 1998) (Figure 1). Active inflammation can also be appreciated on T1-weighted images after intravenous administration of gadolinium (Figure 3). Gadolinium is a compound which leaks out of blood vessels in areas of inflammation and seeps into brain tissue. This leakage of gadolinium is harmless to the brain tissue, but will look bright on T1 images and indicates ongoing, active inflammation and tissue injury. It is important to note that T2 lesions and T1 holes arise from changes in the water content and structure of the imaged tissue. Accordingly, these “lesions†are non-specific and can represent any of a number of changes within the tissues, including pathologic (disease) changes and non-specific, non-disease changes. Therefore, any MRI needs to be evaluated within a clinical context for an accurate and appropriate interpretation.
Altogether, T2 lesions, T1 holes, and gadolinium-enhancing lesions are used to characterize the extent of MS tissue injury and ongoing inflammation. Comparison to previous MRIs can identify newly-developed lesions and indicate ongoing inflammation. A standardized MS imaging approach was developed by the Consortium of MS Centers and includes T2, T1, and gadolinium-enhancing pulse sequences to accurately describe the MRI characteristics of MS (www.mscare.org/pdf/MRIProtocol2003.pdf).
Diagnosis
The diagnosis of relapsing forms of MS requires 1) multiple episodes of inflammation of the brain, spinal cord, and or optic nerve, and 2) that these episodes are separated in time and location. Diagnostic criteria for MS were developed in 1965 (Schumacher et al., 1965) and updated in 1983 (Poser et al.,1983), but both criteria focused on the clinical aspects of MS episodes. After sufficient clinical experience and research with MRI was obtained, MS diagnostic criteria were updated in 2001 (McDonald et al., 2001) to include MRI as part of the diagnostic criteria for relapsing forms of MS. These criteria still require at least one clinical episode of inflammation, but allow for the second episode to be observed solely on brain MRI. Occasionally there are patients in whom typical MS lesions are observed on brain or spine MRI despite an absence of any clinical episodes consistent with inflammation. Currently, diagnostic criteria do not allow for the formal diagnosis of MS, although clinical judgment, usually including evidence from spinal fluid studies and electrophysiological studies (i.e., visual evoked potential tests), can be used to make a probable diagnosis of MS.
MRI is not required for the diagnosis of MS, but most clinicians will obtain at least a brain MRI when the diagnosis of MS is suspected. An expert panel of the American Academy of Neurology has established guidelines for the use of MRI when MS is suspected, particularly after a single episode of inflammation (Frohman et al., 2003). Typical lesions on MRI are observed in most, but not all, patients with MS. MS can sometimes only affect the spinal cord, therefore imaging should include the spinal cord when brain MRI is normal. The diagnosis of MS should be made with extreme caution when brain and spine MRIs are normal, and the diagnostic evaluation should include other evidence to support MS, such as cerebrospinal fluid evaluation and visual evoked potential studies.
Lesion Location and Characteristics
MS lesions have a predilection for certain areas of the brain, including the corpus callosum, brainstem, spinal cord, and areas adjacent to the lateral ventricles and cortex. MS lesions can often affect the deep cerebral white matter, but these lesions have a low specificity for MS. T2 lesions in the deep cerebral white matter can be seen in a variety of other conditions, including migraine, hypertension, smoking, or even just age. Other inflammatory disorders can also demonstrate lesions on MRI that can look similar to MS. Accordingly, interpretation of any MRI needs to be incorporated along with the clinical history, examination, and other tests to accurately diagnose MS.
As in real estate, location is everything when it comes to MS lesions. The majority of MS lesions seen in the upper part of the brain (the cerebrum) are not symptomatic, owing to the remarkable redundancy and compensatory abilities of brain tissue. There usually is not a one-to-one correlation between brain lesions and symptoms, and in fact new brain lesions are observed up to 10-times more often as clinical relapse (McFarland et al., 1996). Lesions in the brainstem and spinal cord are more likely to cause symptoms of a clinical relapse, and lesions in the optic nerve (connecting the retina of the eye to the brain) are difficult to see without specialized MRI pulse sequences. Lesions in these areas are more likely the cause of later progressive disability affecting walking and arm function.
T2 lesions are usually round or ovoid, and periventricular lesions are typically perpendicular to the lateral ventricle (socalled Dawson’s Fingers). At the time of lesion development, T2 lesions usually show gadolinium enhancement. Gadolinium enhancement usually only lasts a few days or weeks, so gadolinium enhancement is not observed with most new T2 lesions unless imaging is performed very frequently. Gadolinium enhancement can involve the entire T2 lesion or just the external rim and so looks like a ring. Ring enhancement often indicates reactivation of a previous lesion. Pathologic studies have observed a very large amount of transected axons, or cut nerve fibers, in areas of active inflammation and these cut fibers probably never re-attach again (Trapp et al., 1998). The reserve capacity of the human brain helps to accommodate for these transected fibers, but the accumulation of axonal transections probably accounts in part for the progressive and permanent clinical disability observed in the later stages of MS. Although the postmortem pathologic studies cannot identify gadolinium-enhancing lesions, it is thought that gadolinium enhancing lesions probably represent the very active inflammation that is associated with permanent tissue injury.
Gray Matter
MS has traditionally been considered a disease of the “white matter,†which refers to the fibers that connect one brain area to another. MRI reinforced this characterization through demonstration of changes predominantly in the white matter. Recent pathological studies, however, have observed significant demyelination and nerve transection in the cortical gray matter, with an astounding average of 25% of cortical gray matter showing demyelination in one study (Peterson, Bèo, Mèork, Chang, & Trapp, 2001). Because of the different inflammatory characteristics in gray matter, MRI rarely shows abnormalities in the cortical gray matter and this type of brain tissue continues to be a challenge for imaging to characterize MS tissue injury.
Atrophy
MS inflammation leads to tissue injury through demyelination and axonal transection. This injury leads to loss of neurons and the supporting cells, which can be appreciated on MRI as brain atrophy. Using sensitive, quantitative software programs, brain atrophy can be measured on MRI (Rudick, Fisher, Lee, Simon & Jacobs, 1999). Brain atrophy can be appreciated at the earliest stages of disease, and its progression followed over time. Two-year changes in brain atrophy is predictive not only of future MRI activity, but also future
cognitive difficulties and clinical disability up to 8 years later (Zivadinov et al., 2001; Fisher et al., 2002).
Clinical Implications
MRI has an established place in the diagnosis of MS. After a single episode of inflammation, brain lesions on MRI are a strong predictor of the later development of clinically definite MS (Brex et al., 2002). In established MS, an increase in overall T2 lesion burden over the first 5 years of disease is a strong predictor of disability development 14 years later (O’Riordan et al., 1998). The development of T1 holes is also a strong predictor of future clinical disability (Truyen et al., 1996).
MRI findings often do not correlate with clinical disability, which emphasizes both the importance of location of MS lesions as well as the non-specificity of MRI in characterizing the degree of tissue injury. T2 lesions indicate the presence of inflammatory tissue injury, but not the degree of that injury. Patients with MS may differ in the degree of tissue injury and its location, despite a similar overall amount (i.e., number and volume) of T2 lesions. This incomplete correlation between MRI activity and MS disease progression is partly why the U.S. Food and Drug Administration (FDA) includes the following disclaimer in all drug advertising that references MRI studies: “The exact relationship between MRI findings and clinical status of patients is unknown.â€
While the role of MRI in MS diagnosis is clear, its role in management of patients with MS remains more controversial. There are no established guidelines using MRI to manage MS, but several studies have suggested that MRI is useful in monitoring disease activity and disease response to MS therapy. The studies referenced above correlating MRI changes with future clinical disability suggests that active monitoring with MRI should be useful in assessing the effect of MS therapies. Studies have found that new MRI lesions while on therapy correlate better than other clinical factors in predicting on-treatment relapses and disability progression (Rudick, Lee, Simon, Ransohoff, & Fisher, 2004). Other reports, however, have found that gadolinium enhancing lesions are only mildly predictive of future relapse rate and disability progression (Kappos et al., 1999). Enhancing lesions and new T2 lesions are common supporting evidence of therapeutic efficacy. In fact, new gadolinium-enhancing lesions are used more commonly than clinical relapses in early, Phase I and Phase II clinical trials of anti-inflammatory therapies in MS.
Precise recommendations on MRI utilization need to be tailored to the clinical situation, but many clinicians will obtain a brain MRI with and without gadolinium after about 1 year of MS therapy to augment the clinical assessment of therapeutic efficacy. When there is very active inflammation at the start of therapy, follow-up brain MRI may be done earlier. In secondary progressive MS, new gadolinium-enhancing lesions and T2 lesions are relatively uncommon, and so monitoring brain MRI is less useful in this later stage of disease (Koziol, Wagner, & Adams, 1998). Serial MRI studies have found that new brain lesions out-number new spine lesions by about 10:1.
Spine lesions are more likely to have associated clinical manifestations than brain lesions. Therefore, surveillance brain MRI in relapsing MS is probably sufficient, reserving surveillance spine MRI for specific situations. The presence of gadolinium-enhancing or new T2 lesions compared to a previous brain MRI suggests that current therapy is sub-optimally controlling disease. Decisions about changing therapy are a clinical judgment and should not be based solely on MRI findings, but rather on an integration of clinical relapse rate, disability progression, MRI findings, medication tolerance and adherence, and laboratory studies such as neutralizing antibodies.
Future Application of MRI to MS
Despite the many advantages of T2- and T1-weighted MRI, these conventional MRI modalities only indicate the presence of MS and not the degree of tissue injury. Pathologic studies have shown inflammatory injury in cortical gray matter and even in white matter that appears normal on standard T2- and T1-weighted images. More advanced MRI techniques are needed to identify these more subtle aspects of MS. Advanced MRI techniques with potential application to MS include diffusion tensor imaging, magnetization transfer imaging, and spectroscopy. These advanced MRI modalities are currently research tools for understanding MS pathophysiology and are in the early stages of application to MS therapies. It is hoped that these advanced imaging techniques will more accurately characterize the degree of tissue injury and later neurodegeneration, as well as measure the effect of potential neuroprotective therapies.
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