Table 1. Selected works studying gray matter lesions in MS and their diagnostic and prognostic relevance (physical and cognitive disability).

Study	Patients	Follow up	Parameters Evaluated	Main outcome
Filippi et al. 2010	80 CIS	4 y	CLs, T2-WM lesions, Gad+ lesions	The accuracy of MRI diagnostic criteria for MS is increased when considering the presence of CLs on baseline scans from patients at presentation with CIS suggestive of MS.
Calabrese et al. 2012	86 patients with CIS.	3 y	CL and WM lesion number, new MRI activity, CSF examination.	The association of intrathecal Ig synthesis and CLs is highly predictive of an earlier CIS conversion to MS as well as of a higher disease activity.
Popescu et al. 2011	One RRMS.	Case Report	MRI, CSF and histological examination.	Pathologic evidence of RRMS patient presenting with inflammatory solitary cortical enhancing lesion.
Calabrese et al. 2009	4 RRMS	Case Report	CLs and T2-WM lesions	CLs were observed by DIR before the MRI evidence of inflammatory lesions in the white matter
Absinta et al. 2012	32 patients with migraine, 15 RRMS, 20 healthy controls.	Cross-sectional	T2-WM lesion and CL count and volume.	No CLs identified in migraine patients. The application of DIR imaging seems to be useful in the diagnostic workup of patients with WM hyperintensities of unknown etiology, including those with migraine.
Giorgio et al. 2011	15 radiologically isolated syndrome.	Cross-sectional	T2-WM lesion and CL count and volume, normalized brain and cortical volume	CLs are identified in subject with RIS (40%) and are frequent in subjects with IgOBs and dissemination in time. CLs are therefore associated with important markers of evolution to MS.
Popescu et al. 2011	19 autopsied NMO patients	Cross-sectional	Histological examination.	Lack of cortical demyelination in patients with NMO is a feature that might help distinguishing NMO from MS.
Calabrese et al. 2012 in press	30 NMO patients, 30 RRMS patients, 30 healthy controls.	Cross-sectional	CL and T2-WM lesion count, global and regional cortical thickness.	No CLs identified in patients with NMO and no significant differences found in cortical thickness between NMO a controls. MRI analysis of the cortex may be a potential diagnostic tool, especially in ambiguous cases.
Absinta et al. 2011	24 pediatric and 15 adult MS.	Cross-sectional	WM lesions and CLs number and volume, GM and WM volumes.	CL are rare in patients with MS in comparison with adult patients.
Calabrese et al. 2010	76 RRMS, 31 SPMS	3 y	CL and T2-WM lesion number and volume, T2-WM lesion volume, GM volume	CL volume correlates with EDSS and EDSS changes over time and it is an independent predictor of EDSS accumulation and GM volume change in SP and RRMS patients.
Calabrese et al. 2009	48 benign MS, 96 early not disabling RRMS.	1 y	CL and T2-WM lesion number and volume,	Benign MS have lower CL number compared with early RRMS patients. At one-year follow-up a significant increase of CL number and volume is observed only in early patients with RRMS.
Calabrese et al. 2012	35 pediatric and 57 adult MS	3 y	CL and T2-WM lesion number and volume, GM volume	Focal (CLs) and diffuse (atrophy) GM damage are strictly associated with the biologic onset of MS, and proceed linearly and partly independently of WM pathology.
Calabrese et al. 2012	32 RRMS with epilepsy, 60 RRMS without epilepsy.	3 y	CL and T2-WM lesion number and volume, regional cortical thickness, new CLs and WM lesions; neuropsychological evaluation	Cortical pathology, psysical and cognitive decline are more severe and evolving in MS patients with epilepsy compared with patients without epilepsy.
Roosendal et al. 2009	9 RRMS, 4 SPMS, 7 healthy controls	3-y	CL and T2-WM lesion number and volume, neuropsychological evaluation	CLs increase significantly over a 3 y time period, are most frequent in SP patients and are associated with cognitive impairment.
Mike et al. 2011	20 RRMS, 20 SPMS	Cross-sectional	CLs number and volume, T2-WM volume, EDSS, cognitive testing.	Routinely detectable cortical lesions were related to physical disability and cognitive impairment better than T2-WM lesions
Calabrese et al. 2009	70 RRMS	Cross-sectional	CL and T2-WM lesion number and volume, GM volume. neuropsychological evaluation	Cognitively impaired patients have a higher CL number and volume, decreased normalized cortical volume compared with cognitively preserved patients.

Abbreviations: CLs, cortical lesions; CSF, Cerebro-spinal-fluid; DIR, Double inversion recovery; Gad*, gadolinium enhancing lesions; GM, gray matter; IgGOB, IgG oligoclonali bands; MRI, magnetic resonance imaging, MS, Multiple Sclerosis; NMO, Neuromyelitis optica; RIS, radiologically isolated syndrome; RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; T2-WM, T2 white matter; WM, white matter