The Role of MRI in the Diagnosis of Multiple Sclerosis: Page 3 of 3
The Role of MRI in the Diagnosis of Multiple Sclerosis: Page 3 of 3
Although MS predominantly affects white matter, lesions occur in gray matter and are better detected on FLAIR imaging than conventional MRI. Their small size, less severe inflammation, and partial volume artifacts in CSF and adjacent white matter make gray matter lesions difficult to detect on conventional MRI.
Up to 90% of clinically definite MS cases show T2-weighted lesions on brain MRI scans. Preexisting T2-weighted lesions can reactivate with re-enhancement, enlargement, or both. Eventually, after many reactivations, single lesions will fuse with those that are adjacent, forming confluent lesions. A net accumulation of new and enlarging lesions increase the total T2 volume by 5% to 10% per year, with a large variability among patients. Despite their exquisite sensitivity, however, T2-weighted visible lesions lack pathological specificity.
T1-weighted images. Approximately a third of T2-weighted visible lesions will appear hypointense (ie, black holes) on corresponding T1-weighted images. Although acute MS lesions also may appear hypointense on T1 images, this is a result of transient edema. They do not have the same pathology or significance as true chronic T1 black holes. A T1 hypointensity may last months after an acute event and may evolve into an isointense lesion, in which the edema is resolved and repair is suggested, or else may persist as a chronic, permanent hypointensity or true black hole.
Chronic black holes are focal areas of relatively severe tissue injury, including axonal injury, matrix destruction, and myelin loss. These lesions cannot be determined with complete certainty on a single MRI scan because, by definition, they should be persistent for at least 6 months. In routine clinical practice, however, T1 black holes are assumed to be any lesions that are hypointense but non-enhancing on post-gadolinium-enhanced T1-weighted scans. Such hypointensities are unlikely to be acute on a contrast-enhanced scan, the exception being if the patient has received high-dose corticosteroids (which suppress gadolinium enhancement by resolving the leaky blood-brain barrier) within hours to weeks of MRI.
Because of greater pathological specificity for severe axonal loss, black holes have a stronger correlation with clinical disability. In addition, T1-weighted images allow for the assessment of atrophy. Brain and spinal cord atrophy in MS are more severe in patients with secondary progressive disease. Although atrophy is measured using automated computer software, volume loss also is evaluated qualitatively and may be described by using an ordinal scale (mild-moderate-severe) based on global assessment of ventricle size and sulcal width.23
Gadolinium-enhanced T1-weighted images. Gadolinium-enhanced T1-weighted imaging is extremely useful for identifying new lesion activity (Figure 1B). Enhancing lesions are a surrogate marker for focal disruption of the blood-brain barrier associated with macroscopic inflammation, an early stage in focal MS lesions. New enhancing lesions usually last 4 weeks (range 1 to 16 weeks).24 In addition, confounding diagnoses such as leptomeningeal disease, meningioma, other mass lesions, and vascular malformation may be less well visualized or even missed without contrast-enhanced MRI scans.
Finally, the identification of enhancing lesions is an important component of the revised McDonald criteria, providing evidence for disease dissemination in space and time. Conventional doses of gadolinium-chelate (0.1 mmol/kg) are recommended with a minimum delay of 5 minutes following injection. The enhancement pattern can change with the evolution of inflammation. It is more often solid and homogeneous with acute lesions and may appear ring-like in larger and older lesions. Although enhanced MRI is considered optional for the follow-up of MS,23 it should be strongly encouraged.
MRI protocol for spinal cord. The CMSC MRI Working Group recommends using the following sequences for MRI of the cervical and thoracic spinal cord:
- Pre- and post-contrast sagittal T1-weighted scan.
- Sagittal fast spin echo PD/T2W scan.
- Axial PD/T2W scan as well as post-contrast T1W scan of suspicious lesions.
Slice thickness should be 3 mm or less without a gap between slices. If spinal MRI immediately follows contrast brain MRI (the gadolinium-chelate dose of which should be 0.1 mmol/kg), no additional gadolinium is required and the pre-contrast sagittal T1-weighted images are not included (Table 4).
For patients with symptoms involving the spinal cord, both brain and spinal cord MRI scans are recommended to exclude MS mimics such as vascular malformations and neoplasms, especially if the symptoms have not resolved.
Spinal MRI may be very useful when findings on the brain MRI scan are normal. It is recommended for patients with suspected MS when the brain MRI results are equivocal. The importance of spinal MRI has been emphasized in the revised McDonald criteria where spinal cord lesions can be included with brain lesions to fulfill the criteria of dissemination in space and time. In contrast to brain lesions, spinal cord T2-weighted visible lesions do not develop with normal aging or chronic hypertension and diabetes. Spinal cord lesions can be found in 50% to 90% of patients with clinically definite MS.
The most common site of presentation is the cervical cord. Typical MS lesions do not extend beyond 2 vertebral segments, tend to involve the posterior and lateral regions, and occupy less than half the area of the cord on axial images.
Although the diagnosis of MS relies on the demonstration of disease dissemination in space and time, the exclusion of other neurological disorders is also essential. The International Panel emphasized that even if the clinical evidence and paraclinical studies are strongly indicative of MS, there must be "no better explanation" than MS for a secure diagnosis to be made.7 However, the limited specificity of T2-weighted visible lesions may increase the likelihood of an MS diagnosis in patients affected by other disorders (Table 5).
Because the current diagnostic criteria have not explored the ability of MRI to detect features not suggestive of MS, a workshop of the European Magnetic Resonance Network in MS (MAGNIMS) was held "to define a series of MRI red flags in the setting of clinically suspected MS."25 Such red flags, derived from evidence-based findings and educated guesses, are summarized in Table 5 in a way that more closely conforms to everyday clinical practice. Recognition of such features in the workup of patients in whom MS is suspected may reduce the likelihood of a false-positive diagnosis.
The MS experts participating in the MAGNIMS workshop agreed that if a patient meets International Panel criteria and there are no MRI red flags, a diagnosis of MS is certain. No additional tests are needed beyond routine examinations.25
If the patient meets the International Panel criteria and there is at least 1 MRI red flag, diagnosis of MS can only be made after appropriate additional test results are negative. In the case of equivocal findings, repeated imaging and laboratory tests might be needed and a wait-and-see approach should be taken before starting treatment with immunomodulatory agents.
Hypoxic-ischemic lesions. The most common MS mimics radiologically are hypoxic-ischemic cerebral small-vessel disorders. They usually are asymptomatic but can present with migraine, transient ischemic attacks, stroke, or subcortical arteriosclerotic encephalopathy. In contrast to the periventricular distribution of MS lesions, hypoxic-ischemic lesions can be dominated by arterial anatomy. Lesions can be cortical infarcts, border zone, or watershed lesions; lacunes; or multifocal basal ganglia lesions.
In addition, infratentorial lesions are specific for MS, but also occur in small-vessel disorders. Although these lesions are typically located at the surface of the pons, at the base of the fourth ventricle, and in the intra-axial tri-geminal tract in MS, they are usually centrally located in the pons in subcortical arteriosclerotic encephalopathy.
Acute disseminated encephalomyelitis (ADEM). ADEM, another common MS mimic, is a monophasic immune-mediated demyelinating disease that usually occurs in response to an infection or vaccination. In the acute phase, multifocal and commonly symmetrically distributed white matter lesions tend to uniformly enhance on MRI. Dawson fingers, corpus callosum, and periventricular white matter lesions are relatively absent compared with such signs in MS. Rather, lesions are typically located in the basal ganglia and thalamus.
Follow-up MRI can be very useful in the differential diagnosis because lesions in ADEM tend to resolve or remain unchanged with no new lesions being formed, whereas the appearance of new lesions is common in MS, although cases of recurrent ADEM have been reported.26
Immune-mediated diseases. In systemic immune-mediated diseases, such as systemic lupus erythematosus and Behçet disease, MRI abnormalities may be indistinguishable from those of MS. However, the predominance of lesions located at the cortical or subcortical junction, as well as the concomitant finding of brain infarcts, calcification, or hemorrhages, should always raise the suspicion of neuropsychiatric, systemic immune-mediated diseases; small-vessel vasculitides; or antiphospholipid antibody syndrome. In these disorders, enhancing lesions and T1 black holes are much less common than in MS. Also, spinal cord lesions are rare and can completely disappear after corticosteroid or immunosuppressive treatment.27,28
In patients with Behçet disease and CNS involvement, brain stem and basal ganglia lesions can be extensive and may be associated with swelling and enhancement in the acute phase and shrink at follow-up, leading to regional atrophy, which is less common in MS.28
Progressive multifocal leukoencephalopathy (PML). PML needs particular mention because of recent reports regarding its development in patients taking the humanized monoclonal antibody natalizumab (Tysabri) and interferon beta 1a (Avonex).29,30 PML, which is caused by infection of oligodendrocytes by the JC virus, usually occurs in immunocompromised patients.
MRI scans show multifocal and asymmetric lesions in the cerebral white matter that typically start in a juxtacortical location and progressively enlarge within weeks. These lesions never develop in the optic nerves, very rarely develop in the spinal cord, and rarely display mass effect.31 Most cases show no gadolinium enhancement.30 Although no imaging feature is pathognomonic of MS or PML, in the future, MRI findings could be used to help distinguish these 2 pathologies.
HIGH-MAGNETIC FIELD MRI
With the introduction of 3 tesla (3T) MRI systems into clinical practice, several questions arise, including the comparability of 3T versus lower-than-3T imaging data. Studies comparing 1.5T with high-field MRI up to 4T revealed an increased sensitivity (up to 45%) in the detection of white matter abnormalities in patients with MS at higher magnetic fields.32 A more recent study33 has shown that high-field MRI (ie, 3T) has a substantial influence on the classification of patients with CIS according to imaging criteria. In this prospective intra-individual comparative study, 40 patients with CIS were studied consecutively with a 1.5T and 3T MRI system. Eleven patients (~ 28%) fulfilled more MRI criteria at 3T. This will have consequences for prognosis and clinical trials.
The past few years have seen increasing improvements in imaging for the diagnosis and management of MS. MRI criteria have been incorporated into formal clinical diagnostic criteria for MS, and the incidence of misdiagnosis is becoming less frequent. However, because the presence of multiple lesions on MRI is not specific for MS, particular caution should be exerted, especially in the presence of MRI red flags or features "not suggestive" of MS.
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