Brain Imaging in Multiple Sclerosis _Magnetic Resonance Imaging

The advent of MRI has revolutionized the diagnosis and monitoring of MS. MRI is well established as the preferred imaging modality for depicting MS lesions. In patients with clinically definite MS (CDMS), MRI demonstrates a high rate of abnormal findings compatible with the diagnosis. In a study by Lukes et al, lesions were demonstrated in 10 patients with CDMS.^[13] In a larger study by Robertson et al, MRI findings were abnormal in 124 of 133 patients with CDMS. Ormerod et al found that 112 of 114 patients with CDMS had abnormal MRI findings and that 102 of 114 had discrete white matter lesions.^[14]
Another major use of MRI has been the evaluation of patients who have had only 1 episode of neurologic impairment and who do not meet the clinical criteria for the diagnosis. The overall risk of developing MS after a single episode of neurologic impairment is estimated to be as low as 12% (2y follow-up study by Beck et al) to as high as 45% (12.9y follow-up study by Sandberg-Wollheim et al^[15] ) or 58% (14.9y follow-up study by Rizzo et al^[16] ).
MRI has been proven to be the most useful investigation for predicting the progression to MS. In a 10-year follow-up study of patients with a clinically isolated event, 45 (83%) of 54 patients with abnormal MRI findings went on to develop clinical MS, whereas only 3 of 27 with normal MRI findings developed MS.^[17]

Degree of confidence

Tintoré et al followed up 70 patients for an average of 28.3 months after an isolated neurologic event and compared various MRI criteria for the diagnosis MS, as defined by Paty et al, Fazekas et al, and Barkhof et al.^{[1, 2, 18, 19]} With the method of Paty et al, which requires 3 or 4 lesions (1 of which is periventricular), the authors reported a sensitivity of 86% but a specificity of only 54%.
The criteria of Fazekas et al resulted in the same sensitivity and specificity. These criteria require 3 lesions with 2 of the 3 following characteristics: infratentorial location, periventricular location, and lesion greater than 6mm. The criteria of Barkhof require 1 infratentorial lesion, 1 juxtacortical lesion, 3 periventricular lesions, and either 1 gadolinium-enhanced lesion or more than 9 lesions on T2-weighted MRI scans. These criteria resulted in a sensitivity of 73% and a specificity of 73%. Thus, as the MRI criteria become more stringent in the diagnosis of MS, specificity increases at the expense of decreasing sensitivity.
In a cohort of the BENEFIT study (a multicenter, randomized, clinical study of 468 patients), the modified Barkhof criteria showed moderate predictive value for conversion to CDMS over 3 years, despite the fact that all patients received interferon beta-1b therapy for at least 1 year. Follow-up MRI was found to be most informative after 9 months in patients without dissemination in space at baseline. The overall conversion rate to CDMS was 42%. Barkhof criteria with the strongest prognostic value were the presence at baseline of at least 9 T2-weighted lesions and at least 3 periventricular lesions.^[20]
According to a study of postmortem MS tissue by Pitt et al, 3-dimensional (3-D), T2*-weighted, gradient-echo (T2*GRE) and white matter–attenuated, turbo-field-echo (TFE) sequences at a 7T field strength can detect most cortical lesions. The 3-D T2*GRE and white matter–attenuated TFE sequences retrospectively detected 93% and 82% of all cortical lesions, respectively.^[21]

Typical findings and pulse sequences

Because of the inflammation and breakdown of the blood-brain barrier in MS lesions, the presence of extravascular fluid leads to hyperintensity on T2-weighted images. Thus, in a patient with MS, MRI scans typically demonstrate more than 1 hyperintense white matter lesion.^{[22, 23, 24, 25, 26]}
Lesions may be observed anywhere in the CNS white matter, including the supratentorium, infratentorium, and spinal cord; however, more typical locations for MS lesions include the periventricular white matter, brainstem, cerebellum, and spinal cord. Ovoid lesions perpendicular to the ventricles are common in MS and occasionally are called Dawson bars or fingers, which occur along the path of the deep medullary veins. Perhaps the most specific lesions in MS are noted in the corpus callosum at the interface with the septum pellucidum.^[27] The imaging characteristics of MS are depicted on the MRI scans below.
Sagittal T1-weighted MRI depicts multiple hypointense lesions in the corpus callosum; this finding is characteristic of multiple sclerosis. Axial T2-weighted MRI in a patient with multiple sclerosis demonstrates numerous white matter plaques in a callosal and pericallosal white matter distribution. Axial T1-weighted, gadolinium-enhanced MRI in a patient with multiple sclerosis demonstrates several intensely enhancing pericallosal white matter lesions compatible with active disease. Axial diffusion-weighted MRI in a patient with multiple sclerosis shows several hyperintense lesions, a feature of inflammatory disease activity. Axial proton density–weighted MRI through the posterior fossa in a patient with multiple sclerosis demonstrates multiple bright foci in the brainstem and cerebellum. Proton density–weighted sequences are highly sensitive for the detection of plaques in multiple sclerosis, especially in the posterior fossa. Axial proton density–weighted MRI demonstrates multiple lesions in a distribution characteristic of multiple sclerosis. Specifically, the periventricular lesions and the more peripheral white matter lesions near the gray matter–white matter junction are typical MRI findings in multiple sclerosis. Axial T1-weighted, gadolinium-enhanced MRI in a patient with multiple sclerosis depicts enhancement of a plaque in the right temporo-occipital lobe, signifying disease activity. Note the C-shaped, or arclike, enhancement, which is fairly characteristic of multiple sclerosis. Sagittal proton density–weighted MRI in a patient with multiple sclerosis demonstrates the characteristic corpus callosal and pericallosal white matter lesions. Axial T1-weighted, gadolinium-enhanced MRI in a patient with multiple sclerosis depicts several enhancing lesions, at least 2 of which show characteristic C-shaped, or arclike, peripheral enhancement. Axial diffusion-weighted MRI in a patient with multiple sclerosis shows several hyperintense lesions, a feature of inflammatory disease activity. Proton density (PD)–weighted MRI has an advantage over standard T2 imaging, because on PD series, MS lesions remain hyperintense, while the CSF signal is suppressed. Therefore, the lesions are easily identified. Depending on the PD technique, the CSF signal is suppressed to a variable degree, rendering it isointense to hypointense relative to the brain parenchyma. This sequence results in substantial suppression of Virchow-Robin spaces, which are perivascular CSF spaces that may penetrate to the subcortical white matter. These spaces may appear as hyperintense spots on standard T2-weighted MRI scans.
Compared with other techniques, nonenhanced T1-weighted MRI is far less sensitive in detecting MS lesions. Acute lesions usually are not depicted at all. With T1-weighted MRI, the clinician can gain a general appreciation of the global cerebral atrophy that occurs with advanced chronic MS. Global atrophy has been suggested to have the strongest imaging correlation with disability.
Chronic MS lesions usually result in localized leukomalacia, and they may appear as hypointense lesions that represent loss of tissue.
Gadolinium-enhanced T1-weighted MRI scans can depict acute, active MS lesions. These appear as enhancing white matter lesions; the presence of an enhancing lesion has been shown to increase the specificity for MS.^{[2, 18]}

FLAIR MRI

Newer MRI pulse sequences and techniques, including fluid-attenuated inversion recovery (FLAIR) MRI and MR spectroscopy, have emerged that are potentially useful in the evaluation of patients with MS.
FLAIR MRI is a heavily T2-weighted technique that dampens the ventricular (ie, free-water) CSF signal. Thus, the highest signals on the sequence are from certain brain parenchymal abnormalities, such as MS lesions, while the CSF appears black. This appearance is different from that on PD-weighted MRIs, on which periventricular MS lesions may appear nearly isointense to the adjacent CSF. (See the image below.)
Coronal fluid-attenuated inversion recovery (FLAIR) MRI in a patient with multiple sclerosis demonstrates periventricular high–signal intensity lesions, which exhibit a typical distribution for multiple sclerosis. FLAIR MRI is a highly sensitive sequence for lesion detection, particularly supratentorially. The greater relative suppression of CSF on FLAIR images compared with PD-weighted series increases the contrast between periventricular lesions and CSF, enhancing their detection. FLAIR has been shown to be superior to PD-weighted sequences in the detection of MS lesions in the cerebral hemispheres. However, PD-weighted imaging remains the investigation of choice for infratentorial lesions.^[28]

MR spectroscopy

Magnetic resonance (MR) spectroscopy uses the characteristic spectra of specific biochemical markers to quantitate organic compounds in vivo. N -acetylaspartate (NAA) is a relatively specific neuronal marker that is present in sufficient concentrations in the brain to be revealed on MR spectroscopic images. By comparing the spectral signal of NAA with that of creatinine (Cr), MR spectroscopic can be useful in assessing neuronal and axonal loss.
Arnold et al noted that the NAA-Cr ratio in the CNS was decreased in moderate to advanced MS. White matter that appeared normal on T1- and T2-weighted images also demonstrated the reduction.^[29] In addition, a normal ratio was noted in the area of a recently active lesion associated with clinical deficits that subsequently resolved. The findings led the authors to propose that MR spectroscopic findings may be able to help identify irreversible axonal damage.
In a study involving 88 patients with MS, De Stefano et al found a strong correlation between disability scores and NAA-Cr ratios.^[30] The ratio exhibited a stronger correlation in patients with MS patients who had milder disability scores. Because MR spectroscopy appears to be capable of depicting changes in white matter that are not detected with routine pulse sequences and because the findings are correlated with disability scores, the use of MR spectroscopy may prove valuable in monitoring patients after treatment and in formulating their prognosis.

Nonstandard MRI sequences

Beyond the standard MRI sequences that are used in clinical practice (T1 +/- Gad, T2, diffusion-weighted imaging, FLAIR), more advanced MRI techniques have been used for research purposes for several years. Many of these series require greater magnetic field strengths over the popular 1.5T, but with the increasing availability of 3T MRI, these sequences will likely find their way more and more into standard clinical practice.
Diffusion tensor imaging (DTI) can utilize diffusion-weighted imaging techniques in different orientations to establish pathology along white matter tracts in the CNS. DTI can identify demyelination and loss of axons along tracts that would otherwise go undetected by conventional techniques.^{[31, 32, 33]} DTI can also identify disease activity in and injury to gray matter structures, which in turn can be used as a markers of disease activity and severity.^{[34, 35, 36, 37]}
Double inversion recover (DIR) sequences can also detect cortical lesions with increased sensitivity over standard MRI sequences, with higher MRI field strengths improving sensitivity.^[38]
Magnetization transfer imaging (MTI) is capable of identifying MS lesions before they can be detected by conventional MRI techniques.^{[39, 40]}

Limitations

In virtually all patients with clinically well-established MS, MRI scans demonstrate the corresponding changes. False-negative findings occur more frequently in patients with early MS and a minimal clinical history of neurologic impairment than in other patients.
O'Riordan et al prospectively found that in 3 of 27 patients with normal MRI findings, MS subsequently developed.^[17] However, the patients with normal MRI findings all developed lesions detectable on MRI scans when the disease became established. Similarly, as patients are followed for longer periods, the rate of false-positive findings decreases, because in many patients with abnormal MRI findings after a single neurologic event, the clinical criteria for MS eventually develop.
Gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis (NSF), also called nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MR angiography scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.