The clinical usefulness of routine MRI assessment.
Abstract: Although the diagnostic value of magnetic resonance imaging (MRI) in multiple sclerosis (MS) is widely accepted, the clinical usefulness of routine MRI for monitoring the evolution of patients with MS is less widely accepted. It is not uncommon for clinicians to say that they 'treat the patient, not the MRI'. In this review, we highlight some of the evidence that routine MRI surveillance of patients with MS provides important information about disease activity that is not evident clinically, and that this information can help with prognosis and management decisions. Specific recommendations for MRI surveillance of MS patients are provided.
Article Type: Clinical report
Subject: Magnetic resonance imaging (Usage)
Multiple sclerosis (Development and progression)
Multiple sclerosis (Patient outcomes)
Multiple sclerosis (Diagnosis)
Authors: Arnold, D.L.
Stone, L.
Pub Date: 07/01/2010
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: July, 2010 Source Volume: 17 Source Issue: 2
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 256365661
Full Text: What does Magnetic Resonance Imaging Show?

The first thing we must consider when we discuss magnetic resonance imaging (MRI) monitoring in multiple sclerosis (MS) is what it meant when a clinician says, "Let's see what the MRI shows".

When clinicians 'look at the MRI' they generally make a qualitative assessment and form a gestalt view of the sequences obtained in a conventional, clinical MRI examination. Clinicians assess activity based on gadolinium (Gd)-enhancing or new T2 lesions, and the burden of disease based on T2 lesion volume. Practitioners often estimate qualitatively the amount of atrophy and T1 hypointense lesions (black holes), which they assume to be chronic and a marker of the amount of tissue permanently lost.

Common clinical practice does not include either quantitative assessment of the above, or the assessment of non-lesional pathology, which requires non-conventional acquisition methods. The quantitative assessment of atrophy on a routine basis in the clinic has been elusive. Clinicians can tell if a brain is very atrophic, but cannot usually detect whether there has been atrophy over the course of year, as this amounts to change on the order of only 1 % or so. In addition, all of these qualitative assessments can be affected by variability in scan acquisition technique, such as slice thickness and acquisition with or without gaps.

[FIGURE 1 OMITTED]

For the reasons above, the discussion below is limited mainly to the qualitative assessment of Gd-enhancing lesions and T2-weighted lesions. Quantitative assessments of non-lesional pathology that are performed in the laboratory will not be considered.

Does What we Visualize on Conventional MRI Matter Clinically and Should we be Using it for Routine Monitoring?

These two questions are best considered separately.

Do the Findings on MRI Matter Clinically?

MRI shows aspects of the pathobiology of MS that reason tells us must matter. The focal white-matter lesions are known to be associated with demyelination and axonal loss, both of which are known to be associated with impairment of neurological function. Cerebral redundancy and plasticity can compensate for cerebral injury up to a point, so that the disability associated with focal demyelination and axonal injury may not be obvious clinically, unless sophisticated testing is employed or the white-matter lesions affect a particularly eloquent area of the nervous system. However, there is value in knowing about the subclinical accumulation of irreversible central nervous system (CNS) injury. The disability associated with white-matter lesions may be delayed due to cerebral re-organization and delayed neurodegeneration, and long-term follow-up studies show that white-matter lesions are strongly associated with the eventual development of clinical disability. (1)

Should we use MRI for Monitoring Patients as a Window on Subclinical Activity?

The question of whether we should use MRI for clinical monitoring relates to whether it is worth knowing that a patient is 'active', when the patient appears to be doing well clinically and the available therapies are only partially effective. Patients with extreme levels of activity on MRI tend to have evidence of this, either by clinical status or multiple relapses; the MRI is not essential to making clinical decisions in these patients, although it may ensure that the patient has not developed a secondary problem such as an infection or lymphoma.

The debate regarding the use of MRI for routine monitoring pertains primarily to patients who are stable, or nearly so clinically, but still have evidence of disease activity or progressive pathology on MRI.

MRI Monitoring of the Different Stages of MS

The value of monitoring patients using conventional MRI depends on the stage of disease and whether the patient is on therapy or not.

Clinically Isolated Syndrome

Diagnosis

Most clinicians would agree that patients with clinically isolated syndrome (CIS) should undergo an initial MRI for diagnostic purposes. If required evidence of DIS or DIT is not present on the initial scan, then it is necessary to follow the patient over time in order to obtain the evidence necessary to make a diagnosis of MS. The inclusion of MRI evidence of DIS and DIT in the criteria for diagnosing MS allows this diagnosis to be made much sooner in patients monitored by MRI than in patients followed clinically until they have a second relapse.

Specific diagnostic criteria for MS that incorporate MRI findings (the McDonald criteria) were proposed by an international panel in 2001. (2) The McDonald criteria for DIS were based on the work of Barkhof et al, who assessed different MRI criteria used to predict conversion of suspected MS to clinically definite MS (CDMS). Logistic regression analysis was used to remove redundant information, and a diagnostic model was built using receiver operating characteristic analysis. In their model, one lesion was the optimum number for Gd-enhancing and juxta-cortical lesions, but three lesions was the optimum for periventricular lesions, and nine for the total number of T2-lesions. A final model that included Gd-enhancement, juxtacortical, infratentorial and periventricular lesions had an accuracy of 80%. The model performed better than the criteria of Paty et al (3) and of Fazekas et al. (4) The McDonald criteria also provided an operational definition for DIT based on the detection of new Gd-enhancement or new T2 lesion formation. In 2005, an international panel revised the McDonald criteria to simplify the criteria for DIT (as well as primary progressive MS [PPMS], and to clarify the role of spinal cord imaging). (5) The new criteria for DIT require a second scan showing a Gd-enhancing lesion at least 3 months after onset of the initial clinical event, or a new T2 lesion at any time compared with a reference scan done at least 30 days after onset of the initial clinical event. A minimum of 3 months was chosen as the required interval because Gd-enhancing lesions associated with the initial event are not expected to last longer than 1-2 months. Therefore, any Gd-enhancing lesion present at 3 months after a clinical event is likely to represent a new event.

Tintore et al evaluated the original McDonald criteria and found that 80% of patients fulfilling them developed a second clinical event with a mean follow-up of 49 months. One year after symptom onset, more than three times as many patients with CIS were diagnosed with MS using the McDonald criteria incorporating MRI compared with clinical criteria alone. (6)

Concerned by a relative lack of sensitivity of the McDonald criteria, Swanton et al in 2006 suggested modification of the original McDonald criteria to use a less stringent definition for DIS (at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, or spinal) and to allow any new T2 lesion after 3 months as evidence for DIT. (7) These criteria were compared with the original McDonald criteria and the 2005 revision. (8) The specificity and sensitivity of MRI criteria for CDMS after 3 years was assessed in 208 patients. The specificity of all criteria for CDMS was high (2001 McDonald, 91%; 2005 McDonald, 88%; 2006 Swanton, 87%). (2,3,7) Sensitivity of the criteria proposed by Swanton et al. 2006 (72%) and the 2005 revision of the McDonald (60%) criteria were higher than the 2001 McDonald criteria (47%). Swanton et al concluded that the new criteria they proposed were simpler than the McDonald criteria without compromising specificity and accuracy.

MRI as a Predictor of Disability

In patients with CIS, early MRI events have been shown to be predictive of disability in the longer term. Patients with more than 10 T2 lesions at presentation with CIS had a median Expanded Disability Status Scale (EDSS) of 6 after 14 years, whereas patients with 1-3 lesions at presentation had a median EDSS of only 2 after 14 years. (9) Although the relation between the number of white-matter lesions and disability is not straightforward and may not be strong in short-term clinical trials, over the long term, greater T2-weighted lesion volume is associated with the accumulation of greater disability, as well as the development of secondary progression and earlier death. (1) In patients with CIS, Gd-enhancing lesion number is also associated with the development of more brain atrophy, (10) which in turn is associated with the development of greater disability. (11)

Relapsing-Remitting MS

Untreated Patients

Patients or clinicians who may be reluctant to initiate treatment at the time of diagnosis, may find evidence of new or active lesions on MRI sways their decision to initiate treatment. In untreated patients with established relapsing-remitting MS (RRMS), the presence of Gd-enhancing lesions is only weakly correlated with concurrent relapses and disability progression. (12) However, Gd-enhancing lesions leave behind new or enlarging T2-weighted lesions and the gradual accumulation of T2-weighted lesions is associated with greater disability and greater risk of progression to secondary progressive MS (SPMS) over the long term. In the study by Fisniku et al (1) the estimated rate of lesion growth over 20 years was 0.80 [cm.sup.3]/year in patients who retained an RRMS course, and 2.89 [cm.sup.3]/year in those who developed SPMS.

Treated Patients

In treated patients with established RRMS, the presence of Gd-enhancing or T2-weighted lesions is associated with a suboptimal response to therapy and progression of disability on the EDSS scale.

Rudick et al examined this relationship in the context of the Phase III trial of interferon beta (IFNB)-1a given intramuscularly in order to evaluate criteria for 'treatment response'. (13) Patients were classified as responders or non-responders using (1) the number of relapses during the 2-year trial; (2) the number of new T2 lesions after 2 years; and (3) the number of Gd-enhancing lesions at Year 1 and 2 on the study. Outcomes included 2-year change in the EDSS, Multiple Sclerosis Functional Composite, and brain parenchymal fraction. The authors found that subgroups with high on-study relapse numbers had more disease progression, but differences between responder subgroups were similar in the IFNB-1a and placebo arms. In contrast, subgroups with high numbers of new MRI lesions had significantly more disease progression only in the IFNB-1a arm. Baseline characteristics failed to account for differential outcome. The authors concluded that new MRI lesion activity during IFNB-1a treatment correlates with poor response to IFNB-1a and that MRI classification may facilitate rational therapeutic decisions. A number of other studies have confirmed that Gd-enhancing lesions and new T2 lesions predict relapses and disability progression. (12) The risk of having a suboptimal response to treatment with IFNB increases eight- (14,15) to 10-fold (16) in patients who have a single active lesion after 1 year of treatment. Evidence of MRI activity 3-6 months after starting treatment with IFN predicts clinical activity over the next 18 months with a predictive value of 60-70%. (17) Inflammatory activity on the MRI also predicts brain atrophy in treated patients, which in turn predicts disability. (11) Thus, MRI evidence of ongoing disease activity warrants a re-examination of therapeutic options.

Progressive MS

Patients with progressive MS may benefit less from MRI monitoring except in specific instances. In patients with SPMS, MRI activity as assessed by white-matter lesions can dissociate from disability progression, particularly in patients who no longer have clinical or MRI evidence of active focal white-matter inflammation. (18) This appears to be due to the fact that the majority of the progression in these patients has a different pathogenesis that does not involve the concurrent formation of white-matter lesions. The nature of this alternate pathway underlying disability progression is unknown. Speculation includes compartmentalized inflammation in the CNS, a delayed degeneration of chronically demyelinated axons, and primary degenerative mechanisms. Markers for assessment of these processes are not routinely available in the clinic as they require non-conventional MRI acquisition techniques, such as magnetic resonance spectroscopy and magnetization transfer ratio (MTR) imaging, or quantitative measurements of subtle atrophy on conventional MRI.

In patients with SPMS who are transitioning from RRMS and who still have relapses or MRI evidence of focal white matter inflammatory activity, disease-modifying therapy appears to still have a benefit. (19) Thus, the MRI still provides useful information in such patients if therapeutic decisions need to be made.

Data from the Rituximab trial in PPMS suggests that focal inflammatory activity in the white matter is also a predictor of treatment response as assessed by slowing of disability progression in patients with PPMS. (20)

Recommendations for MRI Monitoring in the Clinic

In our view, the MRI assessment of MS 'activity' based on markers of focal white-matter inflammation (Gd-enhancement and T2-weighted lesion formation) is another aspect of the assessment of the inflammatory activity of the disease, similar to the clinical assessment of relapses. How closely to monitor patients should be individualized in order to answer the specific questions that are relevant to an individual patient at their particular stage of disease and situation. Scans should be done more frequently in early MS than in later disease, and more frequently in patients who are not doing well, or in whom the presence of ongoing disease activity would influence therapeutic decisions The timing of scans may have to be adapted to financial and resource limitations.

Specific recommendations for MRI monitoring in MS, based on the Mellen Center approach, (21) are to perform MRI:

a) In patients with CIS or non-specific MRI findings who need follow-up MRI for diagnosis

b) In patients starting disease-modifying therapy, as a baseline

c) In patients on disease-modifying therapy, to determine MRI activity despite treatment with good compliance. (Many clinicians consider 6-12 months an appropriate frequency for this.)

d) In patients who decline therapy, to determine MRI disease progression for treatment recommendations

e) In patients with a very active MRI, to assess radiological stabilization with or without intervention.

Comparison of serial MRI data is facilitated if serial scans are obtained on the same magnet using the same acquisition sequences. We recommend that the acquisition follow the revised CMSC protocol as available on the MSCARE.org website to ensure optimization of imaging. The use of contrast-enhanced scans is to be encouraged, as this may allow the detection of ongoing focal white-matter inflammation that may not be otherwise evident.

Conclusion

As options become available for new, more effective therapies that may be more expensive or more dangerous than older therapies, the importance of identifying sub-optimal responses to ongoing therapy will become more important for therapeutic decision making. MRI should be an integral part of this process.

Conflicts of Interest

No conflicts of interest were declared in relation to this article.

Received: 25 March 2010

Accepted: 30 March 2010

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DL Arnold [1] and L Stone [2]

[1.] Montreal Neurological Institute 3801 University Street, Montreal, Quebec, Canada;

[2.] Mellen Center for MS Treatment and Research, Cleveland Clinic, 9500 Euclid Avenue, U10 Cleveland, Canada

Address for Correspondence

Douglas L Arnold

Montreal Neurological Institute

3801 University Street

Montreal

Quebec

Canada

E-mail: douglas.arnold@mcgill.ca
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