The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis

Brain.

Malignancies.

Brain tumors such as a glioma can cause an area of signal hyperintensity that may be indistinguishable from demyelination presenting as a solitary or mass lesion. Lymphoma or even metastatic disease may have to be considered with multiple lesions. Short-term lesion evolution usually suffices to make a clear diagnosis if morphologic features are not sufficiently specific at first, but sometimes biopsy is required for a definitive diagnosis.

The differences in lesion distribution, shape, and size between the above disorders and MS have stimulated the development of criteria for MRI differential diagnosis.7,58 More recently, the pattern of features typical for MS lesions was expanded in a search for predictors of conversion to clinically definite MS following a first symptom22 (table 1). All three sets of criteria appear valid but the different purposes for which they were developed should be recognized. The criteria of Paty et al.58 were defined to determine MRI’s capability of predicting the development of clinically definite MS in patients with suspected MS, whereas the criteria of Fazekas et al.7 were developed in an attempt to separate MRI signal abnormalities of MS patients from incidental signal hyperintensities of the normal population. Both rely on features readily apparent on PD/T2-weighted scans. Retrospective comparison in a series of 1,500 consecutive MRI scans showed a somewhat higher specificity of the Fazekas criteria (96% versus 92%) at the cost of a lower sensitivity (81% versus 87%).15 The criteria of Barkhof et al. include findings on contrast enhanced T1-weighted MRI and are clearly of value in predicting those patients who will go on to develop clinically definite MS following an isolated first clinical symptom.22 How these criteria would perform in the distinction from other white matter diseases has not been tested.

Caution is advised not to use any of these criteria too rigidly. They all attempt to expand rather than to replace experienced image interpretation and must be viewed in the context of clinical and other investigative findings; e.g., on the one hand, just one single lesion of typical shape and location can serve to support the clinical suspicion of MS, whereas, on the other hand, it would be possible to have a patient with vascular lesions or even cerebral metastases fulfill all MRI criteria for MS but clearly not have the disease.

Spinal cord.

In contrast to the brain, there is no evidence for the occurrence of incidental intramedullary hyperintensities related to aging or cerebrovascular risk factors.59 Otherwise, the differential diagnosis of single or multiple spinal cord signal abnormalities has to consider similar etiologies as in the brain; i.e., vasculitis and immune-mediated vasculopathies, infectious and inflammatory diseases such as viral myelitis, neurosarcoidosis60 or ADEM, and glioma. Dural arteriovenous fistulas may also present with waxing and waning of focal intramedullary hyperintensity and can usually be detected on good quality MR images; in the case of suboptimal MRI studies or remaining clinical uncertainty they may have to be excluded by spinal angiography.

Brain imaging.

Maximal slice thickness should be 5 mm with an interslice gap of ≤10%. Axial scans should be obtained perpendicular to the interhemispheric fissure and parallel to either the bicommisural line or a line connecting the lower borders of the genu and splenium of the corpus callosum. To follow these landmarks, axial scanning must be planned from both coronal (position of interhemispheric fissure) and sagittal (delineation of corpus callosum) scout views using appropriate angulations. Implementation of this procedure in clinical practice ensures comparable scanning planes and thus facilitates the interpretation of follow-up studies. However, the use of MRI in follow-up of patients to make treatment decisions cannot be recommended at this time.

T2-weighted sequences (long echo time [TE] and long repetition time [TR]) are most sensitive for the parenchymal changes of MS because of the longer T2 of lesions versus normal white matter. However, it may be difficult to separate bright lesions in a periventricular or cortico-subcortical location from the high signal intensity of CSF on purely T2-weighted scans. If the signal of CSF is darker, a much better lesion–CSF contrast is obtained. This is achieved by so-called PD-weighted images (short TE and long TR). Both PD and T2 weighting can be achieved with a conventional dual spin-echo sequence or a rapid acquisition relaxation enhanced (RARE) dual spin-echo sequence. RARE sequences have been also designated as turbo or fast spin-echo techniques.

Another approach to facilitate lesion discrimination in the proximity of CSF spaces can be taken with a T2-weighted sequence that includes suppression of signal from water, such as FLAIR. Some FLAIR sequences appear less sensitive for infratentorial lesions, which is a drawback in view of the diagnostic importance of infratentorial lesions. On the other hand, FLAIR provides an apparent better delineation of signal hyperintensities in cortico-subcortical locations.23,24 Therefore, combination of a RARE T2-weighted sequence with a FLAIR sequence is another option.

To obtain scans in a second plane takes advantage of MRI’s multiplanar imaging capability and conveys further diagnostic information. T1-weighted scans are frequently used in this context as they show the anatomy of important midline structures such as the corpus callosum, optic chiasm, pituitary gland, brainstem including the aqueduct, and the craniovertebral junction. PD/T2-weighted sagittal scans add to the detection of lesions in the corpus callosum that are rather characteristic for MS16,17 but at the cost of anatomic detail. Sagittal FLAIR has the advantage of better visualization of lesions at the inferior borders of the corpus callosum but at this time may be prone to pulsation artifacts.18,61

Contrast enhancement is a means to increase diagnostic certainty. First, it may provide additional proof for the dissemination of lesions in time; i.e., the combined presence of acute contrast-enhancing and old nonenhancing lesions.22,62 In this context, it is important to note that “incidental” or microangiopathy-related white matter hyperintensities typically do not enhance. Secondly, contrast enhancement may help to clarify atypical T2 abnormalities and to visualize structural abnormalities that are not seen or may go undetected on noncontrast scans, such as leptomeningeal/cortical disease including sarcoidosis and neoplastic infiltration; vascular malformations, particularly capillary telangiectasia; dural arteriovenous malformations or venous angiomas; and meningiomas. In addition, contrast enhancement may indicate a level of disease activity that has prognostic implications.63-65 Contrast-enhanced scans may be of less additional diagnostic value if 1) clinical uncertainty is low and 2) PD/T2 scans are characteristic.

Gadolinium chelates in a dosage of 0.1 mmol/kg body weight suffice for diagnostic MRI. A minimum time interval of 5 minutes between the injection of contrast material and the postcontrast T1-weighted series should be employed. To use this interval, a T2-weighted sequence such as in the sagittal plane can be performed during this “waiting” period. Injection via a long IV line may also help to save time and to avoid patient movement. For the sake of comparison it is advisable to obtain contrast-enhanced T1-weighted scans in the axial plane and with an identical image geometry to the PD/T2 series. Magnetization transfer (MT) weighting should not be used to increase conspicuity of contrast-enhancing lesions unless a precontrast T1-weighted scan with the same technique has been obtained beforehand; otherwise, there is a high risk of falsely labeling lesions as contrast enhancing, especially when using MT saturation pulses.66 Table 2 summarizes suggestions for a routine examination protocol of the brain.

Spinal cord imaging.

Spinal cord imaging is even more quality-dependent than that of the brain. Slice thickness should not exceed 3 mm with a maximum interslice gap of 10%. The entire spinal cord should be imaged in patients with spinal cord syndromes and especially when intending to rule out compression of the spinal cord. MS lesions can be found at all levels in the cord, but more often in the cervical region.6,29 Surface coils help to increase signal to noise ratio and phased array coils are particularly useful in providing images of the whole spinal cord without moving the patient.59

Sagittal images should be performed with a T2-weighted sequence (RARE, cardiac or peripheral gated conventional spin-echo). The sensitivity of fast FLAIR has been disappointing.67,68 Complementary T1-weighted sagittal images are recommended. Axial T2-weighted images help to define lesions suspected from sagittal scans and to outline anatomic lesion location clearly. Gadolinium-enhanced scans are less likely to show contrast material uptake in MS lesions of the spinal cord69 but may be useful in the differential diagnosis, e.g., by demonstrating leptomeningeal enhancement in sarcoidosis or extramedullary disorders, such as arteriovenous malformations or neoplasms. Addition of fat suppression techniques has no direct diagnostic impact in MS but can serve to reduce artifacts from fat with more complex imaging sequences.

Imaging the uncooperative patient.

With the introduction of very fast imaging techniques such as turbo gradient spin-echo, echoplanar imaging–FLAIR, or half-fourier acquisition single-shot turbo spin-echo–FLAIR, scanning time can be reduced to a few seconds.70 These sequences minimize motion artifacts in uncooperative patients. Although limitations in signal to noise, contrast, and spatial resolution are drawbacks of these techniques, large lesions will be seen. Differences in lesion contrast compared to conventional sequences and between scanners due to different technologic implementation must also be considered. More detailed evaluation of the advantages and disadvantages of these ultrafast methods is underway.71

Follow-up studies.

Difficulties in diagnosis will sometimes necessitate repeat MRI examinations. Wherever possible, field strength and the imaging protocol should be kept identical to the preceding study if the same region of the CNS is examined. This concerns not only the pulse sequence but also image geometry such as slice position, thickness and interslice gap, field of view, and matrix.

Clinically isolated symptom suggestive of MS.

MRI of the brain is suggested in any patient presenting with a clinically isolated symptom possibly attributable to MS to collect supportive evidence and to rule out other structural disorders. Whereas the use of gadolinium may be superfluous in typical cases, its overall use is strongly recommended. A complementary MRI examination of the spine is not necessary in the absence of spinal cord symptoms although cord lesions have been seen even in patients with isolated optic neuritis72 or in those with normal brain imaging.6 Unlike the “incidental” occurrence of cerebral hyperintensities with aging, they are a pathologic finding at all ages,59 and thus increase the specificity of MRI especially in older patients.

MRI along the entire length of the spinal cord is suggested in patients presenting with cord symptoms. This is both to exclude compression or other treatable conditions and to search for support of MS. Whereas demonstration of the symptomatic lesion alone is not evidence for lesion dissemination in space, it may nevertheless intuitively contribute to diagnostic confidence. In this situation and in the absence of any cord lesion, imaging of the brain to detect additional lesions is worthwhile.30,48 Demonstration of more widespread affection of the CNS, i.e., supportive evidence for MS, may become even more important if the results of early treatment trials are in favor of initiating immunomodulatory treatment as soon as possible after the first clinical event. These results will also affect the clinical need for application of contrast material in patients with isolated symptoms. Number and extent of cerebral lesions have been repeatedly shown to parallel the risk of conversion to clinically definite MS in patients with clinically isolated symptoms whether they occur in the brain, spinal cord, or optic nerves.38-41 Presence of a contrast-enhancing lesion adds further predictive power22 and helps to satisfy the MS criterion of lesion dissemination in time.

Clinically definite MS.

Brain MRI is suggested at least once in every patient with MS. A scan will help to avoid admittedly rare but possible and potentially treatable misdiagnosis. In addition, considering the costs of modern MS therapies, it is also socioeconomically justified to avoid treatment of non-MS patients by ensuring maximal diagnostic certainty. If and how extent or pattern of lesions could influence treatment decisions or serve to extract prognostic information is a matter of debate.3,42 Complementary MRI of the spine may be considered for patients with equivocal brain findings and if spinal cord symptomatology is predominant, such as is often the case in primary progressive MS.

MRI follow-up examinations during the course of MS will be needed rarely but can be important if diagnostic issues arise. Again, they may be used to clarify equivocal findings both in the brain and spine. Spinal MRI is also recommended in patients with clinically definite MS who develop first or progressive spinal cord symptoms possibly attributable to a different etiology.

Class A: Supportive findings.

This class comprises MRI lesions typical for MS based on their location, shape, size, and contrast enhancement including previously suggested sets of criteria (see table 1).7,22,58 The respective criteria that have served to label an MRI examination as consistent with Class A findings should always be indicated.

Class B: Equivocal findings.

This class comprises MRI changes that cannot be clearly attributed to any one CNS disorder.

Class C: Normal findings.

This class comprises scans without any structural abnormality including the absence of focal and diffuse signal changes.

Class D: Clinically significant “non-MS” findings. This class comprises MRI abnormalities typical for another CNS disorder that can also explain the patient’s symptoms, e.g. infarct, tumor, etc.

These classes can be used for relating MRI abnormalities of the brain or the spine to a referral diagnosis of suspected or definite MS with following diagnostic implications:

• Class A is in support of MS (in the setting of clinical suspicion).

• Class B and C neither refute nor support a diagnosis of MS. A normal MRI of the brain, however, is clearly uncommon for MS.6

• Class D rules against a diagnosis of MS.

This categorization does not obviate the need for relating image interpretation to the clinical situation. A review of the MRI by the neurologist is always recommended for this purpose. Patients also tend to appreciate and understand their situation better if they have been shown the films. Judging the probability of an MRI class in a given situation and hence the plausibility of certain findings is impossible without knowledge of duration, stage, and course of the disease. As an example, normal findings will be expected more often in a patient with a first clinical symptom suggestive of MS than in a patient with an established course of relapsing-remitting disease of several years’ duration. Categorization of findings especially between Classes A and B will also tend to vary somewhat with patient characteristics such as age. In addition, equivocal findings of the brain and spine can supplement each other to become supportive.

By intention, proposed categories provide rather loose rules on how to handle MRI findings. This is in order not to endanger the needed interaction between clinician and interpreter by first steps to formally integrate MRI into the entire process of MS diagnosis. For research purposes, more strictly defined and detailed MRI criteria can be formulated, which will be the subject of a future review.