EDITOR'S NOTE

MRI has revolutionized the evaluation of demyelinating disease. The finding of subcallosal striations on sagittal thin slice FLAIR images is the earliest imaging manifestation of multiple sclerosis. Gadolinium-enhanced T ₁ -weighted images are currently the most sensitive imaging technique for following multiple sclerosis, particularly for patients on the new immunotherapies. This issue of Applied Imaging discusses not only these generally accepted uses for MRI, but also new MR techniques that may be available in the near future.--William G. Bradley, Jr., MD, PhD, FACR

Demyelinating Disease

Detection of demyelinating disease was one of the earliest applications in which MRI demonstrated superiority over CT. ¹ Multiple sclerosis (MS) and its monophasic counterpart acute disseminated encephalomyelitis (ADEM) are quite common in northern latitudes, with an incidence of 80 per 100,000. ² Since the disease has a variety of clinical presentations, it is often included in the differential diagnosis when there are positive neurologic findings, particularly in young adults. Despite its being considered a disease of young women, the female:male ratio is only 2:1, and 10% of the patients present after age 50. ³

In order to make a "definite" diagnosis of MS, there must be multiple neurologic lesions in space and time, i.e., involvement of at least two different parts of the central nervous system separated in time by at least 24 hours. "Probable" MS is defined as multiple lesions in the CNS occurring at a single time or a single lesion coming and going over a period of time. "Possible" MS is a single lesion at one time. ²

ADEM is an autoimmune, postviral leukoencephalopathy. ⁴ Classically, it occurs several weeks following an exanthemous viral infection during which time the patient's immune system is directed against his/her own white matter. Clinically, the patient may be comatose or present with seizures--features that may be indistinguishable from an acute encephalitis. Fortunately, ADEM has a totally different appearance from viral encephalitis on MRI. ADEM involves the white matter first with centrifugal spread to the cortex, whereas a viral meningoencephalitis starts peripherally and spreads centripetally from the gray matter into the white matter. Distinguishing these two entities is important clinically as they have different treatments. Viral encephalitis may be treated with antiviral agents, such as acyclovir; whereas ADEM is treated with steroids or plasmapheresis, if it is treated at all.

It may be impossible to distinguish possible or probable MS from ADEM. They have the same CSF abnormalities (myelin basic protein and oligoclonal bands) and they have a similar (if not identical) MR appearance. While the plaques of ADEM are supposed to be larger than those of MS, this is probably not true for the acute tumefactive form of MS. The classic MR imaging findings in MS include focal areas of hyperintensity on proton density or T ₂ -weighted or FLAIR images. Classically, these lesions have an ovoid appearance with the long axis pointing toward the ventricular surface ⁵ (Figure 1). This reflects the fact that MS is a perivenular disease and that the subependymal veins course perpendicular to the ependymal surface. Under the microscope, collections of inflammatory cells are noted, called "Dawson's fingers" after the Scottish pathologist who first described this appearance at the end of the nineteenth century.

For patients in the 40- to 60-year age range, MS has the potential of being confused with small vessel ischemic change both in the deep white matter and in the brain stem. There are several imaging features that help to distinguish these two entities. MS plaques tend to be rounded, i.e., outwardly convex, while small vessel ischemia tends to be outwardly concave. In the brain stem, MS tends to be peripheral, abutting the CSF spaces, while small vessel ischemia tends to be central (Figure 2). While involvement of the basal ganglia can occur as frequently with MS as with small vessel arteriosclerosis (i.e., lacunar infarction), the latter tends to cavitate while the former does not. Involvement of the cord is much more frequently seen in demyelinating disease than in ischemia.

While the usual 5-mm thick T ₂ -weighted axial images may detect the majority of cases of advanced MS, we have found thin-slice (2 mm), sagittal FLAIR images (Figure 3) to be even better. ⁶ In one study, 42% of the patients being evaluated for possible MS had positive findings on the 2-mm sagittal FLAIR images in the face of normal conventional images. ⁶ The earliest MR findings in MS are 1-mm thick "subcallosal striations" oriented perpendicular to the ependyma, like a stack of coins. ⁷ These findings are undoubtedly an earlier manifestation of the same perivenular disease that produces the ovoid lesion on conventional imaging.

The rationale behind the thin-slice, sagittal FLAIR technique is simple: thinner slices minimize partial volume averaging of small lesions, fast FLAIR improves contrast, and the sagittal plane optimizes viewing the undersurface of the corpus callosum. It is important to use the thinnest possible slices to minimize partial volume averaging. While MRI is perfectly capable of detecting 2-mm MS plaques on 2-mm thick slices, such lesions would not be detectable using 5-mm slices with otherwise comparable techniques. ⁸ The sagittal plane is also used because there is less white matter to cover from medial to lateral than from front to back or top to bottom. While others have suggested a role for gadolinium for the initial detection of early demyelinating disease, this author has never seen a case where enhanced images were positive and thin-slice, sagittal FLAIR was not. In fact, in one study, the association of subcallosal striations with MS was quite significant (P <0.001). ⁷

While gadolinium may be less sensitive than thin-slice sagittal FLAIR techniques for the detection of early demyelinating disease, it may add to the specificity of the diagnosis. If there has been only a single clinical episode at the time of the initial diagnosis, the highest possible clinical rating is "probable." If at this time some lesions enhance and some do not, gadolinium-enhanced MRI can be used as a "paraclinical" test to suggest multiphasic disease and therefore a "definite" diagnosis.

Gadolinium is also useful to follow patients--particularly those on the newer immunotherapies for MS. ⁹ Since these drugs produce flu-like symptoms, patients and physicians need a more objective measure of efficacy than can be provided by the clinical examination alone of a disease that tends to wax and wane. Since active and healing disease both appear bright on T ₂ -weighted images, gadolinium is needed to demonstrate active disease. We typically use interleaved 3-mm contiguous sections for this semi-quantitative evaluation.

Gadolinium also has a role in the evaluation of tumefactive MS, which might be confused with an abscess or tumor. In MS, there is incomplete rim enhancement (Figure 4A) in contradistinction to abscesses or metastases, which tend to have solid or complete rim enhancement, or gliomas, which tend to enhance throughout (if they enhance at all). On T ₂ -weighted images, tumefactive MS produces a "fried egg" appearance, ⁴ the plaque being the yolk and the surrounding vasogenic edema the white (Figure 4B). Tumefactive MS and ADEM also tend to be bright on diffusion imaging ⁹ (Figure 5).

ADEM tends to involve the periventricular white matter, the white matter of the thalami, and the middle cerebellar peduncle (Figure 6). Like acute tumefactive MS, it enhances peripherally in the zone of active demyelination. When involving the brachium pontis, ADEM can be confused with another demyelinating disease, progressive multifocal leukoencephalopathy (PML). The latter, generally seen in AIDS patients, tends not to enhance, which helps distinguish it from ADEM (which does enhance).

Acute demyelination should be included in the differential diagnosis of any young person presenting with one or more masses in the CNS.

Cord Disease

Both acute tumefactive MS and ADEM can involve the spinal cord. The resulting cord swelling may be impossible to differentiate from viral myelitis or low-grade tumor. These three inflammatory conditions generally present clinically with a "transverse myelitis," i.e., a sensory level appearing over a matter of days. This rapid onset distinguishes inflammation from neoplasms, which are more indolent. Chronic MS produces plaques that are longitudinally oriented and flame-shaped without mass effect ⁴ (Figure 7). These tend to be dorsolateral in position and are more frequently found in the cervical than in the thoracic cord. Longstanding MS can produce atrophy of the cord. These lesions are evaluated best on T ₂ -weighted fast spin echo images that minimize CSF pulsation artifact.

The Future

In addition to its current image-based evaluation of multiple sclerosis, MR can also be used to interrogate other features of MS on a microscopic level. Magnetization transfer (MT) is a technique that can quantify the ratio of protein-bound water compared to free water. Normally, most of the water in white matter is tightly bound to myelin protein. With demyelination, some of this water is freed, changing its magnetization transfer ratio (MTR). A number of investigators have shown abnormal MTRs in normally appearing white matter by conventional MRI. Future MS protocols are quite likely to include quantitative assessment of the white mater by MTR.

In the newer class of echo planar imaging (EPI) MR systems, EPI diffusion imaging has become routine, as the images can be acquired in less than a minute. In 5 to 10 minutes, a diffusion tensor can be acquired. This provides a position-independent quantitative assessment of the apparent diffusion coefficient. Using such techniques, the motion of water within a white matter voxel can be assessed quantitatively. Since water tends to flow parallel to axons rather than perpendicular to them, this measurement is generally quite anisotropic. With demyelination, the "anisotropy index" decreases, providing another microscopic measure of disease activity using MRI.

Clinical Quiz

1. Which of the following techniques is most sensitive for early detection of MS: axial proton density, axial FLAIR, sagittal FLAIR, sagittal T ₂ , axial T ₂ ?

2. All patients with suspected MS should be given gadolinium. True or false.

3. Patients being followed for MS by MRI should have T ₁ -weighted images with gadolinium. True or false.

4. The thinnest possible slices should be used when evaluating MS. True or false.

5. All patients with suspected MS should have an MRI study. True or false.

1. Sagittal FLAIR, since it optimally visualizes the undersurface of the corpus callosum and maximizes contrast against CSF.

2. False. Sagittal thin slice FLAIR is more sensitive than gadolinium for detection of early MS; thus, gadolinium is not required.

3. True. Only with gadolinium can you distinguish acute [enhancing] plaques from nonenhancing gliotic scars.

4. True. Thin slices minimize partial volume averaging and enhance detection of disease.

5. False. Patients with cardiac pacemakers and ferromagnetic intracranial aneurysm clips are precluded from having MRI studies.