Imaging in multiple sclerosis
NMR Research Unit,
Department of Neuro-inflammation,
Institute of Neurology,
University College London,
London, UK
Multiple Sclerosis (MS) is a common central nervous system (CNS)disease characterised pathologically by the development of multi-focal inflammatory demyelinating white matter lesions. Magnetic resonance imaging (MRI) is the gold standard imaging technique for the identification of demyelinating lesions which can be used to support a clinical diagnosis of MS, and MS can now be diagnosed in some patients after a clinically isolated syndrome (CIS)using new MRI diagnostic criteria. Clinical trials of disease modifying treatments include MRI outcome measures of disease activity. The use of MR techniques to study the evolution of MS pathology in vivo is an important tool for obtaining better insights into patho-physiological mechanisms underlying the clinical course. This article will concentrate on the practical application of MRI in the management of MS.
Fluid attenuated inversion recovery (FLAIR) sequence. The problem of identifying lesions in the periventricular region, which is a common site for MS lesions, can also be addressed by suppressing the signal from CSF yet maintaining heavy T2 weighting using a fluid attenuated inversion recovery (FLAIR)sequence (fig 1
T1 weighted imaging without contrast
Some high signal lesions on T2 weighted imaging will also be visible on T1 weighted images as areas of low signal compared to the normal white matter and are commonly known as "blackholes" (fig 2
T1 weighted imaging with gadolinium enhancement
A gadolinium chelate administered intravenously five minutes before T1 weighted imaging detects blood–brain barrierbreakdown in association with active inflammation. New lesions appear enhanced (fig 1
NON-CONVENTIONAL MRI IN MS
The conventional MR techniques already discussed are restricted to the PD, T1, and T2 signal contrast behaviour of MS lesions. While these have transformed the diagnosis of MS and provided information about the significance of lesions, not all the pathological features of lesions can be studied using PD, T2, and T1 weighting, and CNS tissue that appears normal with such images can show pathological changes using quantitative MR techniques that are now discussed.2,3
Magnetisation transfer imaging (MTI)
Tissues contain protons in the liquid phase (mobile pool) and protons which are bound to macromolecules including proteins and lipids (bound pool). The latter have a very broad magneticresonance frequency that normally decays too quickly for the scanner to detect. Bound pool protons are constantly in a state of exchange with the mobile pool. If a strong radiofrequency pulse is applied far enough away from the resonance of the mobile pool but is still able to excite the bound pool, some of the magnetisation is transferred from the bound to the mobile pool. This produces a magnetisation transfer (MT) weighted image and the magnetisation transfer ratio (MTR) can be calculated from the MT image and an image without MT weighting. Magnetisation transfer imaging (MTI) has been shown to be a sensitive marker of pathological change in many neurological disorders and, as a general rule, MTR decreases with increasing pathological change. Correlative MTI–pathological studies have suggested that the myelin content and the axonal count are the most relevant substrates of MTR changes in patients with MS, especially the former.
MTI in MS has focused on three main areas: (1) using MTI with gadolinium to improve lesion detection (discussed earlier);(2) distinguishing lesions of differing severity; (3) studying MTR in brain tissues that appear normal on conventional MRI. In vivo studies have shown that T1-hypointense lesions ("blackholes") have a lower MTR than T1 iso intense lesions, supporting the idea that these lesions occur as a result of destructive pathology. MTR values fall considerably when gadolinium enhancement occurs in lesions, with a recovery of MTR over the following months, although not usually back to normal. In some studies, brain MTR declines for several years. The severity of tissue damage has some correlation with the course of MS, as secondary progressive patients display lower lesion MTR than patients with benign MS. Whole brain MTR and segmented normal appearing white matter MTR are lower in patients than in healthy subjects, and independently predict subsequent disability.
MTI can be used to study the time course of lesion development and has shown that some lesions develop in previously normal appearing tissue in which there is declining MTR up to two years before gadolinium enhancement appears. Such lesions are less likely to recover MTR values compared to lesions developing in tissue with a previously normal MTR. Given the sensitivity of MTI to detect pathological change, guidelines for its use in future clinical trials have been developed
Diffusion weighted imaging (DWI)
Diffusion is the random motion of molecules in any fluid system including biological tissue. Diffusion weighted imaging (DWI)refers to the process of making MRI sensitive to the molecularmotion of water molecules and is potentially a useful technique for studying white matter structure and pathology. Water diffusion can occur in any direction but occurs preferentially along the orientation of axons because their cell membranes act as barriersto diffusion. Such diffusion is said to be anisotropic and is dependent on the structural integrity of white matter tracts. Any disruption to white matter tracts or axonal membrane permeability should lead to an increase in the apparent diffusion coefficient(ADC) and mean diffusivity (MD), a measure of average molecularmotion, and also to a decrease in fractional anisotropy (FA),a measure of the directional preponderance of diffusion which can be obtained with diffusion tensor imaging (DTI).
DWI has been applied qualitatively in clinical practice where it can be used to detect ischaemic changes within 30–90minutes of acute stroke. DWI and DTI have supplemented conventional MRI techniques for the quantitative study of MS pathology invivo. DTI studies in MS have shown increased ADC and MD with decreased FA in chronic T1 hypointense lesions compared to T1isointense lesions which is compatible with evidence that T1hypointense lesions represent more extensive tissue loss. FA is lower in acute, gadolinium enhancing lesions compared tonon-enhancing lesions because extra cellular oedema alters the anisotropic pattern of diffusion. ADC and MD values are raised, but the extent may depend upon the lesion age.
Abbreviations
o ADC: apparent diffusion coefficient
o ADEM: acute disseminated encephalomyelitis
o CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy
o CIS: clinically isolated syndrome
o CNS: central nervous system
o CSF: cerebrospinal fluid
o DTI: diffusion tensor imaging
o DWI: diffusion weighted imaging
o EDSS: expanded disability status scale
o FA: fractional anisotropy
o FLAIR: fluid attenuated inversion recovery
o MD: mean diffusivity
o MRI: magnetic resonance imaging
o MRS: magneticresonance spectroscopy
o MS: multiple sclerosis
o MTI: magnetisationtransfer imaging
o MTR: magnetisation transfer ratio
o SLE: systemiclupus erythematosus
o PD: proton density
o PML: progressive multifocalleucoencephalopathy
o PPMS: primary progressive multiple sclerosis
o VEP: visual evoked potential
Changes in normal appearing brain tissue in MS patients have been detected by diffusion measures. As with MTI changes, these can occur early in the clinical course of MS and can precede new lesion formation. Several studies have reported a relation between DWI changes in normal appearing brain tissue and disability in different MS subtypes. DWI has not yet been included in clinical trials but may be useful in future studies of treatments which may prevent axonal loss.
The production of maps by DTI showing the principal direction of diffusion on a voxel by voxel basis allows the path of white matter tracts to be traced through the brain, and this is known as tractography. This novel technique has emerging promise for investigation of white matter pathology in MS and other disorders.
Magnetic resonance spectroscopy (MRS)
Proton magnetic resonance spectroscopy (MRS) enables the invivo investigation of metabolic alterations associated with brain pathology, and provides a quantitative method for investigating the abnormalities in the normal appearing white matter. At longer MRI echo times, N-acetyl-aspartate (a neuroaxonal marker), creatine and phosphocreatine, and choline containing compounds may be quantified, while at shorter echo times additional metabolite peaks may be seen from myo-inositol (a potential marker of glialcells), glutamate and glutamine, and mobile lipids.
MRS studies in patients with established MS have demonstrated significant abnormalities in the concentration of metabolitesin the normal appearing white matter, with notably reduced N-acetyl-aspartate, raised myo-inositol, and raised glutamate. A decrease in N-acetyl-aspartateis thought to indicate axonal dysfunction or loss, while an increase in myo-inositol has been proposed to reflect an increasinglial cell activity or numbers, and raised glutamate may have a role acutely in axonal injury. The stage at which these abnormalities first appear is less clear but two studies of patients with a CIS have shown separately that N-acetyl-aspartateis reduced and myo-inositol is raised. It is relevant to study this early phase of disease in order to search for prognostic markers for the future clinical course and to gain insights into early pathological processes.