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The role of magnetic resonance imaging in differential diagnosis

The role of magnetic resonance imaging in differential diagnosis
  • Neurology

Lucia Moiola

Scientific Institute San Raffaele, Milan, Italy

Magnetic resonance imaging (MRI) has a high sensitivity in revealing macroscopic tissue abnormalities in patients with multiple sclerosis (MS). This, combined with its availability, repeatability, and capability of providing objective measures of overall disease activity and burden, has led to the extensive use of MRI for diagnosing MS and monitoring its evolution. In patients who are suspected of having MS, MRI has been formally included in their diagnostic work up through the definition of ad hoc sets of criteria to show disease dissemination in space (DIS) and time (DIT). Work has also been performed to identify “red flags” which should alert the clinicians and prompt them to perform non-routine tests to exclude possible alternative conditions.


Typical MRI findings in MS

Brain lesions in MS have suggestive characteristics: they are frequently located, asymmetrically, in the periventricular and juxtacortical white matter (WM), the corpus callosum (CC) and infratentorial areas (with the pons and cerebellum more frequently affected than the medulla and midbrain), and are sometimes characterized by oval or elliptical shapes.[1] Consensus has also been reached on criteria useful to identify T2-hyperintense [2] and T1-enhancing lesions.[3]

Considering the frequent involvement of the spinal cord by MS, MRI features of MS cord lesions have also been identified[4]: they are more frequently observed in the cervical than in other sections, are usually peripheral, limited to two vertebral segments in length or less, occupy less than half the cross-sectional area of the cord, and are not seen as T1-hypointensities. Acute plaques can cause a swelling of the cord and enhancement after gadolinium (Gd) administration.

The optic nerve is also frequently involved by the disease. The sensitivity of MRI for detecting optic nerve lesions in patients with optic neurites (ON) is high[5] and the use of new sequences[6-8] has led to an higher sensitivity. In MS patients, increased T2 signal can be seen for a long time after an episode of ON, despite the occurrence of an improvement of vision and normalization of visual evoked potentials, and even in the absence of acute attacks of ON.[9] T1-hypointense lesions are usually not seen in the optic nerve, whereas Gd-enhancement is a consistent feature of acute ON.[10]


MRI diagnostic criteria for MS

In 2001, MRI has been formally included in the diagnostic work up of patients suspected of having MS by an International Panel (IP) of MS experts.[11] The definition of MRI criteria for a diagnosis of MS was based, from the one hand, on the demonstration of lesion DIS and DIT, and, on the other, on the exclusion of alternative neurological conditions.[12, 13] In 2005, the original IP criteria for MS diagnosis have been revised[14] in an attempt to simplify the approach, while maintaining adequate sensitivity and specificity. Since 2005, several other proposals have been made to simplify further the revised-IP criteria and to make them easier to be implemented in clinical and research settings. According to the Swanton criteria,[15] at least one subclinical T2 lesion in at least two of the four locations defined as characteristic for MS in the revised-IP criteria (i.e., juxtacortical, periventricular, infratentorial, and spinal cord) is required for DIS. When the sensitivity and specificity of these criteria were compared with those of the original 2001 IP criteria,[11] and with the 2005 revised criteria,[14] the Swanton criteria were slightly more sensitive than the older ones, while maintaining a similarly high specificity.[16] The main advantage of the Swanton criteria is that they do not require contrast agent administration, thus saving time and costs. However, this goes at the price of a loss of differential diagnostic information. Subsequently, Rovira et al.[17] suggested that a single brain MRI study performed early (i.e. < 3 months) after the onset of a clinically isolated syndrome (CIS) is highly specific for predicting the development of definite MS in the presence of both Gd-enhancing and nonenhancing lesions, which when present are considered a marker of DIT. Both the previous criteria have been included in the recently published criteria proposed by the European Multicenter Collaborative Research Network for MRI in MS (MAGNIMS),[18] as well as in the most recent revision of the 2011 IP criteria (Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria).[19]


MRI and differential diagnosis

Another key requirement in the diagnostic work-up of patients suspected of having MS is the exclusion of alternative neurological conditions that can mimic MS.[12, 13] Avoiding misdiagnoses is particularly compelling now that there are several effective treatments for MS as well as different therapies for other disorders that can mimic MS.

A series of MRI “red flags”, derived from evidence-based findings and educated guesses, have been identified in the setting of clinically suspected MS, which should alert the clinicians to prompt the performance of “non-routine” tests and to reconsider differential diagnosis more extensively.[12, 13]

Among the differential diagnosis, it is fundamental to exclude

  • Other inflammatory-demyelinating disorders (e.g. neuromyelitis optica, acute disseminated encephalomyelitis [ADEM], variants of MS [Balo’s concentric sclerosis and Marburg acute MS], acute transverse myelitis etc),
  • Hypoxic-ischaemic vasculopathies (e.g. amyloid angiopathy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL], Susac’s syndrome, mitochondrial disorders, trombophilic conditions etc),
  • Vasculitides (e.g. primary vasculitis of the CNS, systemic immune-mediated diseases with involvement of the CNS [Behcet’s disease, sarcoidosis, neurolupus, ANCA-mediated vasculitides, small vessel vasculitis]),
  • Infectious diseases (e.g. meningo-encephalitis, intracerebral abscess, progressive multifocal leucoencephalotpathy [PML], Whipple’s disease etc),
  • Neoplastic diseases (gliomas, lymphomas, metastases etc),
  • Acquired metabolic disorders (e.g. celiac disease, folate and vitamin B12 deficiency)
  • Other forms of leucoencephalopaties (e.g. adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease etc)


Neuromyelitis optica (NMO) should be distinguished from MS by its different course, prognosis and response to immunomodulatory therapy. MRI and NMO-IgG, a serum biomarker, have been formally included in the diagnostic criteria of NMO.[20] Cerebral MRI abnormalities are found in 60% of patients: most of them (80%) are non-specific T2-hyperintensities, in 10% of the cases are indistinguishable from MS lesions and in the other 10% the brain lesions are the so called “NMO typical”. These latter lesions have a predilection for regions with a high expression of aquaporin-4, including the hypothalamus, medulla, and other brainstem areas. Myelitis in NMO, unlike that which occurs in MS, is usually accompanied in the acute phase by a T2-weighted spinal cord lesion extending over three or more spinal segments, which may be hypointense on T1-weighted MRI and associated to varying degrees of Gd-enhancement.[21]

On MRI, ADEM is characterized by multifocal, diffuse, and commonly but not exclusively symmetrically distributed lesions located in the supratentorial and infratentorial white matter. Unlike in MS, the lesions typically have poorly defined margins and are typically located in the basal ganglia, and, less frequently, in the corpus callosum, and in the periventricular white matter. Gd enhancing lesions have been described in 30 to 100% of patients depending on the stage of inflammation. Deep grey-matter lesions, if present, are in this case usually bilateral and located at the grey–white matter junction. The spinal cord can be involved in ADEM, with lesions that are usually large and swollen. Finally, follow-up MRI scans can show a partial or even a complete resolution of such lesions with no new lesions being formed.[22]

An important and very common, differential diagnosis is with hypoxic-ischaemic vasculopathies. In addition to the a priori chance of a white-matter lesion being hypoxic-ischaemic in nature (such as older age, presence of risk factors for cerebrovascular diseases, etc.), several MRI features can reinforce this notion, such as the presence of cortical infarcts, borderzone or watershed lesions, lacunes, and multifocal basal ganglia lesions.[12, 13]

MR imaging in patients with CADASIL plays a central role in the diagnosis. MRI typically shows multiple bilateral, lacunar infarcts (basal ganglia, internal capsule, thalamus, and pons), and diffuse T2-weighted hyperintensity in the deep and periventricular white matter. The two most distinctive MRI features suggestive of CADASIL are the presence of T2 hyperintensity of the anterior temporal pole, the U-fibres at the vertex, and external capsule or insular region, and multiple microhaemorrhagic foci, which can be seen on gradient-echo scans. By contrast, the cortex, corpus callosum and infratentorial regions (except the pons) are rarely affected in CADASIL.[12, 13, 23]

Concerning vasculitis of the CNS, the MRI findings of patients with primary vasculitis of the CNS are very variable, ranging from normal to diffuse white-matter changes, the presence of infarcts (in grey and white matter), large lesions with mass effect, haemorrhages, calcification, and leptomeningeal or pial and punctiform parenchymal enhancement (also involving enlarged perivascular spaces). All this neuroradiological aspects should all constitute potential red flags for the diagnosis of MS.[12-13]

In patients with CNS involvement secondary to systemic immune-mediated diseases, MRI findings are commonly 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 haemorrhages, should always raise the suspicion of neurolupus, small-vessel vasculitides, or antiphospholipid antibody syndrome. In these latter disorders, enhancing lesions and T1 black holes are much less common than in MS. In contrast to MS, spinal cord lesions are rare in systemic immune-mediated diseases and can completely disappear after steroid or immunosuppressive treatment.[12-13]

In patients with neuro-Behcet disease, the presence of white matter lesions is very typical especially in infratentorial areas: abnormalities in the upper brainstem that extend into thalamus and basal ganglia, that can be associated with swelling and enhancement in the acute phase and that can shrink or disappear at follow-up. The lesions are usually on one side but bilateral lesions can occur. These lesions are usually associated with regional atrophy of the brainstem, which is rare in MS. In some patients, cerebral white matter is diffusely involved and cerebral venous sinus thrombosis may occur, which can be detected on MRI or MR angiography.[12, 13, 24]

PML, which usually occurs in patients who are immunocompromised, is another important diagnostic challenge. In the past, the disorder was commonly reported in patients with AIDS but is less common now that highly active antiretroviral therapies are used. At present, the introduction of monoclonal antibodies for the treatment of immune-mediated disease (such as natalizumab for MS), has raised the attention for the possible development of PML in those treated patients.  PML is caused by infection of oligodendrocytes by the JC virus. Typical MRI findings include multifocal and asymmetric lesions in the cerebral white matter that commonly start in a juxtacortical location and progressively enlarge over weeks and that usually tend to involve U fibers. Typically even the large lesions do not show mass effect. These lesions never develop in the optic nerves and very rarely in the spinal cord. On T1-weighted sequences, the lesions show hypointensity and no gadolinium enhancement. Lesions may sometimes display enhancement that indicates an inflammatory immune response secondary to the immune reconstitution.[12, 13, 25]

Finally, the presence of bilateral and symmetric, diffuse T2-weighted hyperintensities in the deep and periventricular WM should be evaluated in the differential diagnosis of MS, because this is a typical MRI finding in leucoencephalopaties (i.e., adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease).[12-13]

In conclusion, with the improvement of paraclinical tools such as MRI several efforts have been made to improve the diagnostic work-up for MS. Findings from clinical history, physical examination, MRI, and other laboratory tests are usually combined to establish or to exclude a firm and clear diagnosis of MS, with a prominent role of MRI.  Several MRI sequences are used for the evaluation of the different pathophysiological mechanisms of the neurological disorders and more advanced MRI techniques are now available, which will improve pathological sensitivity and specificity in differential diagnosis of MS and of other white-matter disorders in the future.



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Milan, Italy
Oct 30 - 31, 2014
Target audience
Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
by Excemed

MS Alumni

The MS Alumni programme is an educational initiative of EXCEMED that is intended to provide ongoing support for young physicians and specialists in neurology.