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Cortical lesions in Multiple Sclerosis

Cortical lesions in Multiple Sclerosis
  • Neurology

Lucia Moiola

Scientific Institute San Raffaele, Milan, Italy

Multiple sclerosis (MS) is generally defined as an inflammatory demyelinating disorder of the central nervous system with a neurodegenerative component mainly characterized by the progressive accumulation of focal white matter (WM) lesions. Despite this, the involvement of gray matter (GM) and, in particular, the presence of cortical lesion (CL) has been recently described by  the earliest pathological studies (1).

 In the last years several efforts have been made to better define the role of CL in the diagnostic work-up of MS, their pathophysiology and their  role in disease progression, generally characterized by the accumulation of irreversible clinical disability and cognitive impairment.

 Pathologic and magnetic resonance imaging (MRI) studies  have provided evidence that a significant portion of MS lesions affects the brain cortex (2-4).Recent histopathological studies 5defined three patterns of CL confined to the cortical ribbon without involving the underlying subcortical WM (“pure CL”) and cortical demyelination: Type I lesions are  contiguous with subcortical white matter lesions; Type II lesions are  small, confined to the cortex, and often perivascular; Type III lesions are extended from the pial surface to cortical layer 3 or 4. Moreover, also so called “mixed WM/GM CL” have been described, with a characteristic involvement of  both WM and i cortical GM.

MRI is the most sensitive paraclinical tool to diagnose MS and to monitor the disease evolution either natural or modified by treatment.

 Despite its good sensitivity in detecting WM lesions (6), conventional MRI (proton density, T2-weighted, FLAIR and pre- and post- gadolinium [Gd] T1-weighted sequences) is not adequate for the detection of CL, because such lesions are typically small, have poor contrast with the surrounding normal GM, and because of partial volume effects from the cerebrospinal fluid.

 Double inversion recovery (DIR) sequences markedly improved the sensitivity of MRI to detect CL lesions in vivo . Applying two inversion times to suppress the signal from both WM and cerebrospinal fluid, this technique is able to detect a greater number of CL lesions if compared to T2-weighted spin-echo and FLAIR sequences with a gain of 538% and of 152%, respectively. (7)

 The introduction of DIR sequences (7)has contributed to detect  GM lesions, which have been described in all the main clinical phenotypes of the disease, including  the clinically isolated syndrome (CIS). (8, 9)Remarkably, CL are more frequently observed in patients with secondary progressive MS (10)than in those with CIS or relapsing-remitting MS (RRMS) (8, 10), whereas in patients with benign MS (11)(Expanded Disability Status Scale [EDSS] (12)≤ 3.0 after ≥ 15 years of disease duration) they are fewer if compared to  those with early RRMS (13).

 Recently, Filippi and co-workers,(14), using DIR sequences for the detection of CL, proposed a model for the definition of the dissemination in space (DIS)9 including the presence of at least one CL, in addition to the presence of at least one infratentorial and one spinal cord or Gd-enhancing lesion.

 This new DIS MRI criterion showed a higher specificity (93%) and accuracy (86%) than the available sets of criteria while maintaining a relatively high sensitivity (77%).

These findings suggest that the detection of CL in the context of MS diagnostic work up might improve our ability to properly diagnose MS.

 Moreover, recent longitudinal studies have shown that new CL continue to form in patients with early RRMS (13)and in those with the progressive disease phenotypes over one to two year period of follow up (15-18). An association has been found between CL burden and progression of disability over the subsequent two (16)and three (15)years in patients with different disease phenotypes, as well as between CL burden and the severity of cognitive impairment in patients with relapse-onset MS (18, 19).

 Despite this, the majority of CL still go undetected. As a consequence, new strategies have been proposed, including the use of a single-slab 3D DIR sequence 20, and the combination of DIR with other MR sequences, such as phase-sensitive inversion recovery (21), and 3D magnetization-prepared rapid acquisition with gradient-echo 22images. Another possibility for an additional gain in CL detection and characterization is likely to be achieved using ultra high-field MR scanners (23, 24).

 Using a 7.0 T scanner, Mainero et al. (24)identified three major cortical lesion patterns (type I: leukocortical; type II: intracortical, and type III/IV: subpial extending partly or completely through the cortical layers), similarly to those described by the histopathological analysis.

 In conclusion, as confirmed by several pathological and MRI studies, MS is a heterogeneous disease, characterized by the involvement both of the WM and the GM. The assessment of GM alterations, both in term of focal CL and diffuse damage (atrophy, functional changes, etc.), might improve our ability to early diagnose MS, increase our understanding of the pathophysiological mechanisms of the disease and might provide predictors to define patient’s prognosis.



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2. Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol. 2010;6:438-444

3. Filippi M, Rocca MA. MR imaging of gray matter involvement in multiple sclerosis: implications for understanding disease pathophysiology and monitoring treatment efficacy. AJNR Am J Neuroradiol. 2010;31:1171-1177

4. Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol. 2008;7:841-851

5. Peterson JW, Bo L, Mork S et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389-400

6. Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology. 2011;259:659-681

7. Geurts JJ, Pouwels PJ, Uitdehaag BM et al. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology. 2005;236:254-260

8. Calabrese M, De Stefano N, Atzori M et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol. 2007;64:1416-1422

9. Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302

10. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46:907-911

11. Pittock SJ, McClelland RL, Mayr WT et al. Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol. 2004;56:303-306

12. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452

13. Calabrese M, Filippi M, Rovaris M et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult Scler. 2009;15:36-41

14. Filippi M, Rocca MA, Calabrese M et al. Intracortical lesions: relevance for new diagnostic criteria for multiple sclerosis. Neurology. 2010;In press

15. Calabrese M, Rocca M, Atzori M et al. A three-year MRI study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 2010;67:376-383

16. Calabrese M, Rocca MA, Atzori M et al. Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study. Neurology. 2009;72:1330-1336

17. Calabrese M, Filippi M, Rovaris M et al. Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study. Neuroimage. 2008;42:1324-1328

18. Roosendaal SD, Moraal B, Pouwels PJ et al. Accumulation of cortical lesions in MS: relation with cognitive impairment. Mult Scler. 2009;15:708-714

19. Calabrese M, Agosta F, Rinaldi F et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol. 2009;66:1144-1150

20. Pouwels PJ, Kuijer JP, Mugler JP, 3rd et al. Human gray matter: feasibility of single-slab 3D double inversion-recovery high-spatial-resolution MR imaging. Radiology. 2006;241:873-879

21. Nelson F, Poonawalla AH, Hou P et al. Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging. AJNR Am J Neuroradiol. 2007;28:1645-1649

22. Nelson F, Poonawalla A, Hou P et al. 3D MPRAGE improves classification of cortical lesions in multiple sclerosis. Mult Scler. 2008;14:1214-1219

23. Kangarlu A, Bourekas EC, Ray-Chaudhury A, Rammohan KW. Cerebral cortical lesions in multiple sclerosis detected by MR imaging at 8 Tesla. AJNR Am J Neuroradiol. 2007;28:262-266

24. Mainero C, Benner T, Radding A et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology. 2009;73:941-948

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This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

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.