by: Frederik Barkhof
by: John R. Hesselink, MD, FACR
by: Joseph P. Hornak, Ph.D.
MRI is superior to other imaging modalities in the imaging of DeMyelinating Diseases such as MS and other White Matter disorders of the Brain and Spinal Cord.
It is possible to visualize 2 - 5 mm White Matter lesions and watch their progress over time.
Contrast enhancement may make it possible to determine the acute PeriVascular involvement of new active lesions in MS.
Focal HyperIntensities similar to those of MS are seen frequently in elderly patients and are usually due to Ischemic DeMyelination or to multiple small Infarcts.
Similar lesions also can follow radiation therapy, Lyme Disease and occasionally severe recurrent Migraine headaches.
Small disseminated metastases may have a similar appearance. Contrast enhanced MRI differentiates acute plaques from old lesions.
Lesions are identified by MRI in about 95% of the patients with Clinically Definite MS, whereas CT demonstrates lesions in only about 25% of such patients.
Lesions of the Spinal Cord including areas of DeMyelination are best shown by MRI and detected in 75% of MS patients.
Prior to 1983 the diagnostic criteria for MS were based entirely on clinical evaluations.
Technological developments in Brain imaging in MS became a significant contributing factor to changing the MRI Criteria used for the diagnosis of MS.
In 1986 the National Multiple Sclerosis Society issued a statement recommending the optional use of MRI in the diagnosis of MS.
MRI is increasingly being used as a measure of pathological disease activity in monitoring the efficiency of potential new treatments for MS.
A major advantage of MRI over clinical monitoring is that it detects a large amount of SubClinical disease activity.
The two main approaches to MRI are detecting active lesions, and measuring total Lesion Load.
In Relapsing/Remitting and Secondary/Progressive MS, Gadolinium enhancement increases the number of detectable active lesions and also probably correlates with pathological activity.
An important limitation of MRI monitoring is that conventional Brain MRI abnormalities often show little or no relationship with clinical disability.
One explanation for this may be pathological Heterogeneity of lesions that all look the same on a conventional image.
Brain lesion load can be measured in a crude fashion by grading the size of the lesion by their largest diameter.
Lesion area can be measured more precisely by outlining them manually on a computerized image.
More fully automated lesion area measurement techniques, such as Thresholding and Edge Detection have been developed.
The accuracy of Lesion Load Measurement will also be increased by thinner slices, which reduce partial volume errors.
Active Brain lesions are defined by a series of criteria, but basically: ANY New, Enlarging or Enhancing Lesion is defined as Active. MRI monitoring helps make this distinction.
The Pulse Sequences used in MS assessment vary, but Fast Spin Echo (FSE) Sequences are the current method of choice. Minimizing scan time is important for both reducing cost and improving patient comfort.
Generally, 4 to 8 Echoes are used, thus reducing scan time to one quarter or one eighth of standard Spin Echo (SE) Sequences.
The appearances of SE and FSE sequences are very similar, and they are equally sensitive in detecting MS Lesions.
The FSE sequence takes 1 - 3 minutes, and thus can be obtained during the 5 minutes required between injecting Gadolinium and obtaining optimal contrast - Enhanced Images.
Other MR techniques are needed that specifically identify the pathological features, most likely to result in disability, namely DeMyelination and Axonal Loss.
Magnetization Transfer Imaging and Proton MR Spectroscopy are two techniques that show promise in this regard.
Magnetization Transfer (MT) is a technique that has the potential for detecting changes in Myelin.
The macromolecular structure of Myelin is the physical basis of MT, by using off-resonance irradiation, macromolecular protons can be saturated.
These protons then exchange with free-water protons and produce a decrease in signal intensity of the free water protons.
This is quantified by using a Magnetization Transfer Ratio (MTR) of signal intensities.
This method had been sensitive to changes in a spectrum of White Matter lesions, including regions of apparent Myelin loss in patients with MS.
Furthermore, MTR's may be abnormal in patients with Normal-Appearing White Matter, demonstrated by standard MRI imaging.
As stated, conventional MRI is a very sensitive technique for detecting abnormalities in the White Matter.
However, its major problem is that it lacks specificity. A lesion that is just edematous without Myelin loss, could appear identical on standard T2 weighted images.
Also, only macroscopic DeMyelination can be seen. We have little insight into the Normal-Appearing White Matter in MS patients.
MTR may enable subcatagorization of MS lesions into lesions with low MTR (presumed to be DeMyelinating lesions) and lesions with higher values (primarily edematous lesions).
Another important use of MT is, in conjunction with Gadolinium, to increase the number and extent of enhancing lesions.
This can improve the detection of Blood-Brain Barrier abnormalities in patients with MS.
As with any type of imaging technique, motion, producing artifacts and invalidating the transfer measurement, is a limiting factor for MT imaging.
Another important source of inaccuracy is partial volume averaging, leading to an over or underestimation of the Transfer Ratio.
MT technique is basically achieved by obtaining two sets of image, and through digital subtraction, results in transfer contrast images. The ultimate role of MT in MS is unknown.
It can be a powerful probe to subcategorize lesions and Normal-Appearing White Matter in MS patients. It could be extremely useful in following MS patients, particularly those involved in drug treatment protocols.
It may, in the future, because of its increased sensitivity to White Matter changes, enable earlier, more accurate diagnosis and perhaps have prognostic value as well.
As MRI has no medicinal value and is only used for diagnosis/prognosis of disease, there has been some debate on the use of Gadolinium Enhancement.
Arguments against it stem from the risk of side effects, albeit small, additional cost and extra scanning time required.
Arguments in favor are that it may provide additional information on current therapeutic mechanisms, and it may increase the sensitivity of MRI as a measure of disease activity.
After much research, it has been shown that Gadolinium Enhancement increases reliability and sensitivity in detecting Active Lesions.
Which strengthens the case for using it in frequent scanning during treatment trials in early Relapsing/Remitting or Secondary/Progressive MS.
Currently, it is generally accepted that enhanced T1 weighted SE images detect many more active lesions than other sequences.
However, it is also accepted that unenhanced T2 weighted SE sequences are able to detect small lesions that the enhanced T1 weighted images do not always pick up.
There is some debate whether to do the T2 weighted sequences or not as only a modest loss of information would occur.
Currently with the advent of such things as FSE, scan times are not the problem they used to be and the most common exam done contains both the unenhanced axial T2 weighted and enhanced axial T1 weighted images.
The T2 images are obtained immediately after the contrast injection as there is a 5 - 10 minute wait period before optimal enhancement.
Both sequences are performed as it would seem inappropriate to ignore even a modest gain in sensitivity in an exam if there is no increase in scanning time.
More importantly the evolution of active lesions on both the T1 and T2 weighted images will give more insight into the mechanisms of therapeutic effect.
Or in other words, if the treatment being given to the patient is having any positive effect.
In regards to scanning frequency when looking for new active lesions, a 2 - 4 week period is the general guideline.
Other scans for reasons other than looking for new, active lesion is based on the physician's discretion and the individual patient's condition.
Although MRI is one of the most effective tools used in treating MS, its future directions are not yet defined. Many questions need to be asked and many things need to be defined before the use of MRI is made optimal.
What is the predictive value of Brain MRI when a patient first presents to a physician with Neurological symptoms?
Some studies suggest disseminated Brain lesions on MRI may predict future clinical dissemination in patients with early stages of MS. This needs to be confirmed so MRI can be used more accurately in diagnostic criteria.
Does the rate of new lesions correlate to the rate of clinical deterioration?
Only more research can determine whether clinical disease correlates with the rate of lesions found by ongoing MRI scans.
As well only more research can determine the optimal rate for doing serial MRI's on MS patients.
To date, it is unclear whether the information gained in an MR scan can be directly correlated to the therapies given in MS.
In other words are the scans consistent enough to demonstrate whether a treatment is effective or not. The optimal scan has yet to be determined.
Although unenhanced axial T2 weighted and enhanced axial T1 weighted sequences are used now, it has been shown that different plaques at different stages will show differently or not at all depending on the sequence used.
For example, IRSE will show certain lesions that T2 weighted images will not. Can we discern the HistoPathology from MRI?
We need to develop methods that will improve our ability to distinguish those MRI lesions that have a definable pathological consequence and those that do not.
MRS, at extra time and cost, will help in this area but cannot currently totally resolve this problem.
These questions and many more will have to be answered by ongoing research before MRI can be considered "the ultimate " tool in treating MS, not just the best one.
In the relatively few years MRI has been available in a hospital setting, it has become and indispensable tool in the early diagnosis and follow up of MS patients.
The clinical suspicion still remains mandatory in the interpretation of MRI data in order to make an accurate diagnosis.
Once a diagnosis is established, MRI proves to be far more sensitive to the "natural history" of MS than clinical data and is therefore of utmost importance in the evaluation of treatment.
It has already been shown that MRI is more sensitive to the *treatment effect* than clinical monitoring.
It is therefore conceivable that, using MRI monitoring, therapeutic trials can be shorter because one would not have to wait for a clinical response in order to accept or discard treatment as effective.
If a treatment has no effect on the number of new, enhancing or non enhancing lesions appearing over a given period of time, a clinical response would not be expected and the treatment could be terminated.
On the other hand if there are clear signs of diminished MRI activity, but as yet no clear clinical benefit, a longer trial period is warranted.
To be able to detect the clinical benefit of the treatment which naturally remains the ultimate goal of any treatment. It is hoped that the new MRI techniques presently under development.
Such as newer Pulse Sequences, Spectroscopy, Magnetization Transfer Imaging, will further increase our understanding of the pathophysiology and the evolution of MS.
Thereby, possibly will lead to more effective treatment policies for these patients.
Even more optimistically, other research is underway looking for a cure, but that's another paper.
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