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Preceptorship on MRI in multiple sclerosis (2014)

Preceptorship on MRI in multiple sclerosis (2014)
  • Neurology

Resource type

Publication

Young clinicians and scientists from around the world currently involved in the management of multiple sclerosis (MS), and radiologists interested in MS, gathered in Milan on 31- 31 October 2014 for a live educational course on magnetic resonance imaging (MRI) at the San Raffaele Scientific Institute, with a scientific programme organised by Massimo Filippi. The meeting aimed to provide training on analysis and interpretation of MRI findings, vital in the age of innovative imaging techniques which are now available, and provide new insights into the pathogenesis of MS and its functional consequences. Through a mix of expert lectures and hands-on training, participants learned how to apply MR diagnostic criteria, distinguish clinical conditions that can mimic MS at the MR scan, summarise the novel functional and structural markers of disease severity obtained by advanced MRI techniques, and interpret MRI scans.

 

Clinical presentation and diagnosis of MS

The MRI criteria for diagnosing MS were reviewed by Jaume Sastre-Garriga (Spain). He explained why diagnostic criteria should never be applied without full clinical examination, particularly in the Middle East and Latin America, where there is a wide spectrum of differential diagnoses. Describing how the criteria have evolved since 2005, mainly due to the incorporation of new MRI criteria, J. Sastre-Garriga presented the revised McDonald criteria (Figure 1).[1]

Primary progressive MS is still very difficult to diagnose. The first criteria were developed from a consensus meeting and published in 2000,[2] and the most recent revision of the criteria uses the same radiological parameters as for relapsing-remitting MS. ‘In the future, high resolution MRI may be used in the diagnosis of MS, but new criteria are unlikely to be needed,’ said J. Sastre-Garriga.

MRI Milan

Figure 1: Diagnostic algorithm for patients with clinically-isolated syndrome

‘Differential diagnosis should not be forgotten when considering a patient who may have MS,’ said Per Soelberg Sørensen (Denmark). Diagnosis of MS remains both partly subjective and partly objective, and should exclude other explanations for the presenting signs and symptoms, and he told participants that some flexibility in applying the McDonald diagnostic criteria[3[ is needed. As well as the common presentations of MS, rare cases can present with dysphasia, cognitive dysfunction, hemianopia, or hemiparesis. Examination of the cerebrospinal fluid (CSF) is vital and can raise red flags – for example, a lymphocyte count > 50 is rare in MS, but may indicate infection. Differential diagnoses can be grouped depending on whether the patient presents with monofocal or multifocal clinical symptoms. Among differential diagnoses with multifocal presentation, inflammatory syndromes such as acute disseminated encephalomyelitis (ADEM) and infectious disorders such as Progressive Multifocal Encephalomyelitis (PML) should be excluded.

In his presentation on the use of MRI in the differential diagnosis of MS, Andrea Falini (Italy) emphasised that, although MR imaging is the most sensitive investigational technique for MS, it is important to remember that the appearance of multiple lesions on MR imaging is not specific for MS. However, MRI plays an important role in differentiating MS from other conditions, and while there are overlapping profiles, the location and pattern of distribution of the lesions indicates a specific pathology.

A. Falini explored the MR imaging protocol for clinically isolated syndrome (CIS), illustrating his presentation with many MRI scans of the brain and spinal cord. He noted that the spinal cord is a frequent site of damage in CIS at presentation, and 90% of patients with clinically definite MS (CDMS) have spinal cord lesions with characteristic small, cigar-shaped lesions which cause swelling of the cord in the acute phase and local atrophy in the chronic phase.

He went on to look at rarer variants of MS, including Balo’s concentring sclerosis, whose lesions are characterised by ring enhancement or tumefactive lesions, which can resemble brain tumours and thus be difficult to diagnose. Other demyelinating conditions, such as neuromyelitis optica, acute disseminated encephalomyelitis, and acute transverse myelitis should also be considered in the differential diagnosis of MS, along with hypoxic-ischemic vasculopathies, vasculitides, and infectious diseases.

The conclusion from both presenters was that a combination of clinical criteria, MRI cranial and spinal imaging, CSF analysis, evoked potential tests and laboratory work-up leads to a positive and correct diagnosis in more than 95% of cases of MS. The work-up for the diagnosis of early MS is shown in Figure 2.

MRI milan highlights 2

Figure 2: Flow chart of the work-up and the stages in the diagnosis of early MS

 

Imaging biomarkers in MS

A good imaging biomarker should be specific, sensitive to change, and clinically useful. Nicola De Stefano (Italy)explored this topic starting with images developed using volumetry to show structural damage, Magnetisation Transfer ratio (MTr) and Diffusion Tensor Imaging (DTI) to examine microstructural damage, and fMRI which measures functional damage and reorganisation (Figure 3).

MRI milan highlights 3

Figure 3: Imaging markers in MS

Among the new biomarkers for disease severity, cortical lesions correlate with cognitive impairment,[4[ while MRI-based brain volumetry is a valid biomarker to measure clinical state and progression in different clinical scenarios.[5] N. De Stefano concluded that only a multimodal approach, incorporating both structural and functional imaging, can provide accurate measures of whole brain damage in MS. Advanced neuroimaging in MS will help support the diagnosis, understand mechanisms of disease, track disease progression and monitor treatment.

 

The evolution of MS pathology

Structural imaging techniques

 Menno M. Schoonheim (The Netherlands) showed participants how structural MR techniques can be used to understand MS evolution. The early phase of the disease is characterised by inflammatory demyelination around the ventricles. In later stages, demyelination and inflammation spread throughout the white matter (WM) and structural damage is characterised by focal lesions, diffuse white matter damage, and atrophy of both grey matter and white matter. Focal lesions are usually detected by MR as T2 hyperintensities (Figure 4), but they have not been shown to correlate with clinical disability measures.

MRI milan highlights 4

Figure 4: T2 focal inflammatory demyelination in the white matter

T2 lesions can evolve into T1 hypointensities (black holes), and these evolve with different patterns over time, showing both demyelination and remyelination progressively, as evidenced by MTr studies.

Diffusely abnormal white matter (DAWM) develops very early in the course of MS, resulting from the cumulative effects of ongoing inflammation and axonal pathology.[6] DAWM is likely to substantially contribute to disease progression and may be an important disease marker, but it is difficult to measure. Demyelination of the grey matter (GM) is very extensive in chronic MS and different lesions types are revealed using double-inversion recovery imaging (DIR), a technique with high pathological specificity (‘the tip of the iceberg’) in comparison with post-mortem specimens. GM atrophy begins early in the disease course and becomes more prominent with disease progression, accelerating after conversion to secondary progressive disease.GM atrophy correlates with physical and neuropsychological impairment[7] and can be reliably measured with MRI techniques for use in the therapeutic setting. The evolution of lesions in MS is summarised in Table 1.

mri table 1

Table 1: Evolution of lesions in MS as seen with structural MRI techniques

‘In the future, network analysis and functional and structural connectivity using advanced quantitative MRI will provide information about interactions among brain regions and how they relate to MS pathology,’ predicted Professor Schoonheim.

Optic nerve lesions are usually seen following optic neuritis, but observing optic nerve involvement using MRI remains challenging, Declan Chard (UK) told participants. In order to study structural and microstructural lesions in optic neuritis, fat suppression sequences are mandatory and gadolinium contrast is needed. However, gadolinium enhancement of lesions only modestly predicts visual outcomes, and DTI is not sensitive enough to get high resolution images. Data show that optic nerve atrophy is related to visual outcome,[8] while axonal loss is thought to be a significant factor in the recovery of visual function following optic neuritis.[9] Optic nerve atrophy better correlates with outcome measures obtained by MTr than DTI. MTr is abnormal in affected optic nerves, initially declining and then recovering over a period of months, and reduced MTR is associated with impaired visual function. As yet, the relationship between brain atrophy and optic nerve atrophy has not been defined. Imaging techniques used at different clinical stages of disease are summarised in Table 2.

mri table 2

Table 2: Imaging techniques used at different clinical stages of optic neuritis

Spinal cord atrophy is a common finding in both Primary and Secondary Progressive MS, with disease-specific lesions.[10] Paola Valsasina (Italy) reviewed data showing that cord atrophy may result from degeneration of long fibres, and explained how several techniques have been used to demonstrate that these changes correlate with clinical progression.[11] Quantitative MRI techniques allow the calculation of structural damage to the remaining tissue. MTr is decreased in Primary and Secondary Progressive MS, whilst in benign MS DTI studies show that the cervical cord is spared. P. Valsasina concluded that high-quality MRI of the cervical cord is feasible, and has the potential to improve our understanding of the structural and functional changes which occur in the CNS in MS.

 

Functional imaging techniques

In contrast to structural techniques, Maria Assunta Rocca (Italy) explored the role of functional MRI (fMRI) techniques in MS imaging. In all the MS phenotypes, fMRI shows a bilateral activation even for simple motor tasks. Increasing recruited areas may be a sign of either adaptive or maladaptive response. ‘Variable patterns of cortical rewiring occur in MS patients, with the potential to limit the functional consequences of tissue damage,’ she said, suggesting that their disability is likely to result from a balance between structural damage and cortical reorganisation, rather than simply reflecting tissue disruption. She presented data showing that interventions that drive neuroplasticity can promote functional restoration by inducing adaptive changes or by predisposing functional systems to adaptive plasticity. As disease progression is associated with abnormal functional recruitment, fMRI could be useful for determining prognosis, Functional MRI could also be used to monitor changes in motor network recruitment induced by drugs such as rivastigmine and 4AP. Professor Rocca concluded that a better understanding of recovery systems may guide the development of new recovery-oriented strategies in MS.

 

In brief

Giancarlo Comi (Italy) looked at the importance of individualised treatment in MS. ‘Insights into genetic and pathophysiological mechanisms will provide information that can individualise treatments for patients, and pharmacogenomic markers can predict drug response,’ he said. Reviewing recent studies in MS, G. Comi weighed up the importance of disease burden with treatment burden, and noted that the pipeline of MS drugs coming on line will make it possible for patients to achieve No Evidence of Disease Activity (NEDA). Individualised treatment allows suboptimal responders to be identified early and moved to a different treatment strategy.

The impact of MS on cognition was reviewed by Federica Agosta and Massimo Filippi (Italy), who told participants that several features of MS pathology are likely to contribute to cognitive deficits in MS, especially the location of WM lesions in critical brain areas. Additionally, the application of fMRI has revealed different patterns of cortical activation associated with cognitive tasks or at rest, and these may have an adaptive role The role of compensatory mechanisms following tissue injury must be considered in future studies of this area. In particular, longitudinal studies are needed to understand the dynamics of structural and functional changes on the evolution of MS-related cognitive impairment.

‘MRI is an integral part of MS clinical trials, providing the primary efficacy outcome of preliminary proof of concept studies and important collaborating data as secondary and exploratory outcomes in pivotal trials,’ explained Gilles Edan (France).MRI provides important information on kinetics and magnitude of treatment effect and insight into potential mechanisms of action at all stages of drug development, and although it is unlikely that one single outcome measure will capture all aspects of the MS disease process, there is potential for MRI outcomes to evaluate both inflammatory and degenerative components within clinical trials. The features and benefits of using MRI in clinical trials are summarised in Table 3.

mri table 3

Table 3: Advantages of using MRI endpoints in clinical trials of MS

Finally, M. Filippi looked into the future, reviewing how the model of MRI in MS has been applied to other areas of neurology; for example, in Parkinson’s Disease 7T scanning has revealed angulation of the substantia nigra, in areas associated with motor impairment. Similarly, atrophic corpus callosum has been found in amyotrophic lateral sclerosis patients using MRI. ‘MRI is increasing used in the diagnostic work up of many neurological diseases,’ he said, adding that the insights provided by advanced imaging techniques will be invaluable in monitoring targeted therapies in the future.

 

References

1. Montalban, X. et al. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 74, 427–434 (2010).

2. Thompson, A. J. et al. Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann. Neurol. 47, 831–835 (2000).

3. Polman, C. H. et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292–302 (2011).

4. Calabrese, M., Rinaldi, F., Grossi, P. & Gallo, P. Cortical pathology and cognitive impairment in multiple sclerosis. Expert Rev. Neurother. 11, 425–432 (2011).

5. Giorgio, A. & De Stefano, N. Clinical use of brain volumetry. J. Magn. Reson. Imaging JMRI 37, 1–14 (2013).

6. Seewann, A. et al. Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis. Arch. Neurol. 66, 601–609 (2009).

7. Fisniku, L. K. et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann. Neurol. 64, 247–254 (2008).

8. Inglese, M. et al. Irreversible disability and tissue loss in multiple sclerosis: a conventional and magnetization transfer magnetic resonance imaging study of the optic nerves. Arch. Neurol. 59, 250–255 (2002).

9. Hickman, S. J. et al. A serial MRI study following optic nerve mean area in acute optic neuritis. Brain J. Neurol. 127, 2498–2505 (2004).

10. Lycklama, G. et al. Spinal-cord MRI in multiple sclerosis. Lancet Neurol. 2, 555–562 (2003).

11. Kearney, H. et al. Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration. Mult. Scler. Houndmills Basingstoke Engl. 20, 72–80 (2014).

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