BACKGROUND: Early infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume. METHODS: We investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions. RESULTS: We found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9-321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002). CONCLUSIONS: Diffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions.

2nd Department of Neurology Faculty of Medicine Comenius University Bratislava Slovakia

Advanced Clinical Imaging Technology Siemens Healthcare AG Lausanne Switzerland

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Katerinska 30 Praha 2 Prague Czech Republic

Department of Radiology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Radiology Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Signal Processing Laboratory Lausanne Switzerland

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Barkhof F, Scheltens P, Comi GP. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis intraoperative EEG monitoring view project cortical graphs and brain disconnection in multiple sclerosis view project. 1997. PubMed

Minneboo A, Barkhof F, Polman CH, Uitdehaag BMJ, Knol DL, Castelijns JA. Infratentorial lesions predict long-term disability in patients with initial findings suggestive of multiple sclerosis. Arch Neurol. 2004;61:217–221. doi: 10.1001/archneur.61.2.217. PubMed DOI

Tintore M, Rovira A, Arrambide G, Mitjana R, Río J, Auger C, et al. Brainstem lesions in clinically isolated syndromes. Neurology . 2010 ;75(21):1933–8. PubMed

Silveira F, Sánchez F, Miguez J, Contartese L, Gómez A, Patrucco L, et al. New MRI lesions and topography at 6 months of treatment initiation and disease activity during follow up in relapsing remitting multiple sclerosis patients. Neurol Res. 2020;42:148–152. doi: 10.1080/01616412.2019.1710415. PubMed DOI

Dekker I, Sombekke MH, Balk LJ, Moraal B, Geurts JJG, Barkhof F, et al. Infratentorial and spinal cord lesions: cumulative predictors of long-term disability? Mult Scler J. 2019;1:11. doi: 10.1177/1352458519864933. PubMed DOI PMC

Arrambide G, Rovira A, Sastre-Garriga J, Tur C, Castilló J, Río J, et al. Spinal cord lesions: a modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor. Mult Scler J. 2018;24:301–312. doi: 10.1177/1352458517697830. PubMed DOI

Kohler M, Kohler E, Vrech C, Pappolla A, Miguez J, Patrucco L, et al. Aggressive multiple sclerosis in Argentina: data from the nationwide registry RelevarEM. J Clin Neurosci. 2021;89:360–364. doi: 10.1016/j.jocn.2021.05.047. PubMed DOI

Weier K, Mazraeh J, Naegelin Y, Thoeni A, Hirsch JG, Fabbro T, et al. Biplanar MRI for the assessment of the spinal cord in multiple sclerosis. Mult Scler J. 2012;18:1560–1569. doi: 10.1177/1352458512442754. PubMed DOI

Weier K, Penner IK, Magon S, Amann M, Naegelin Y, Andelova M, et al. Cerebellar abnormalities contribute to disability including cognitive impairment in multiple sclerosis. PLoS One. 2014;9(1):e86916. doi: 10.1371/journal.pone.0086916. PubMed DOI PMC

Lycklama G, Thompson A, Filippi M, Miller D, Polman C, Fazekas F, et al. Spinal-cord MRI in multiple sclerosis. Lancet Neurol. 2003;2:555–562. doi: 10.1016/S1474-4422(03)00504-0. PubMed DOI

Hua LH, Donlon SL, Sobhanian MJ, Portner SM, Okuda DT. Thoracic spinal cord lesions are influenced by the degree of cervical spine involvement in multiple sclerosis. Spinal Cord. 2015;53:520–525. doi: 10.1038/sc.2014.238. PubMed DOI

Bonek R, Orlicka KMZ. Demyelinating lesions in the cervical cord in multiple sclerosis 10 years after onset of the disease. Correlation between MRI parameters and clinical course. Neurol Neurochir Pol. 2007;41(3):229–233. PubMed

Bellenberg B, Busch M, Trampe N, Gold R, Chan A, Lukas C. 1H-magnetic resonance spectroscopy in diffuse and focal cervical cord lesions in multiple sclerosis. Eur Radiol. 2013;23(12):3379–3392. doi: 10.1007/s00330-013-2942-7. PubMed DOI

Lukas C, Sombekke MH, Bellenberg B, Hahn HK, Popescu V, Bendfeldt K, et al. Relevance of spinal cord abnormalities to clinical Disability in Multiple sclerosis: MR Imaging Findings in a Large Cohort of Patients. Radiol n Radiol. 2013;269:542–552. PubMed

Andelova M, Uher T, Krasensky J, Sobisek L, Kusova E, Srpova B, et al. Additive effect of spinal cord volume, diffuse and focal cord pathology on disability in multiple sclerosis. Front Neurol. 2019;10:820. doi: 10.3389/fneur.2019.00820. PubMed DOI PMC

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173. doi: 10.1016/S1474-4422(17)30470-2. PubMed DOI

Gass A, Rocca MA, Agosta F, Ciccarelli O, Chard D, Valsasina P, et al. MRI monitoring of pathological changes in the spinal cord in patients with multiple sclerosis. Lancet Neurol. 2015;14(4):443–454. doi: 10.1016/S1474-4422(14)70294-7. PubMed DOI

Tsagkas C, Naegelin Y, Amann M, Papadopoulou A, Barro C, Chakravarty MM, et al. Central nervous system atrophy predicts future dynamics of disability progression in a real-world multiple sclerosis cohort. Eur J Neurol. 2021;28(12):4153–4166. doi: 10.1111/ene.15098. PubMed DOI PMC

Bischof A, Papinutto N, Keshavan A, Rajesh A, Kirkish G, Zhang X, et al. Spinal cord atrophy predicts progressive disease in relapsing multiple sclerosis. Ann Neurol. 2022;91:268–281. doi: 10.1002/ana.26281. PubMed DOI PMC

Uher T, Krasensky J, Vaneckova M, Sobisek L, Seidl Z, Havrdova E, et al. A novel Semiautomated pipeline to measure brain atrophy and lesion burden in multiple sclerosis: a long-term comparative study. J Neuroimaging. 2017;27(6):620–629. doi: 10.1111/jon.12445. PubMed DOI

Nijeholt GJ LÀ, Barkhof F, Scheltens P, Castelijns JA, Adèr H, Van Waesberghe JH, et al. MR of the spinal cord in multiple sclerosis: relation to clinical subtype and disability. Am J Neuroradiol. 1997;18(6):1041–1048. PubMed PMC

Nijeholt GJ LÀ, MAA VW, Castelijns JA, JHTM VW, Polman C, Scheltens P, et al. Brain and spinal cord abnormalities in multiple sclerosis: correlation between MRI parameters, clinical subtypes and symptoms. Brain. 1998;121(Pt 4):687–697. doi: 10.1093/brain/121.4.687. PubMed DOI

Schmitter D, Roche A, Maréchal B, Ribes D, Abdulkadir A, Bach-Cuadra M, et al. An evaluation of volume-based morphometry for prediction of mild cognitive impairment and Alzheimer’s disease. NeuroImage Clin. 2015;7:7–17. doi: 10.1016/j.nicl.2014.11.001. PubMed DOI PMC

Fartaria MJ, Kober T, Granziera C, Bach CM. Longitudinal analysis of white matter and cortical lesions in multiple sclerosis. NeuroImage Clin. 2019;23:101938. doi: 10.1016/j.nicl.2019.101938. PubMed DOI PMC

Bot JC, Barkhof F, Polman CH, Lycklama à Nijeholt GJ, de Groot V, Bergers E, Ader HJ CJ. Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination. Neurology. 2004;27 62(2):226–233. doi: 10.1212/WNL.62.2.226. PubMed DOI

Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler. 2003;9:260–274. doi: 10.1191/1352458503ms914oa. PubMed DOI

Qiu W, Raven S, James I, Luo Y, Wu J, Castley A, et al. Spinal cord involvement in multiple sclerosis: a correlative MRI and high-resolution HLA-DRB1 genotyping study. J Neurol Sci. 2011;300:114–119. doi: 10.1016/j.jns.2010.09.006. PubMed DOI

Droby A, Fleischer V, Carnini M, Zimmermann H, Siffrin V, Gawehn J, et al. The impact of isolated lesions on white-matter fiber tracts in multiple sclerosis patients. NeuroImage Clin. 2015;8:110–116. doi: 10.1016/j.nicl.2015.03.003. PubMed DOI PMC

Nijeholt GJ L à, Bergers E, Kamphorst W, Bot J, Nicolay K, Castelijns JA, et al. Post-mortem high-resolution MRI of the spinal cord in multiple sclerosis a correlative study with conventional MRI, histopathology and clinical phenotype. Brain. 2001;124:154–166. doi: 10.1093/brain/124.1.154. PubMed DOI

Bot JCJ, Blezer ELA, Kamphorst W, Nijeholt GJ LÀ, Ader HJ, Castelijns JA, et al. The spinal cord in multiple sclerosis: relationship of high-spatial- resolution quantitative MR imaging findings to histopathologic results. Radiology. 2004;233:531–540. doi: 10.1148/radiol.2332031572. PubMed DOI

Bergers E, Bot JCJ, De Groot CJA, Polman CH, Nijeholt GJ L à, Castelijns JA, et al. Axonal damage in the spinal cord of MS patients occurs largely independent of T2 MRI lesions. Neurology. 2002;59:1766–1771. doi: 10.1212/01.WNL.0000036566.00866.26. PubMed DOI

Sombekke MH, Lukas C, Bart ; J, Crusius A, Tejedor D, Killestein J, et al. HLA-DRB1*1501 and Spinal Cord Magnetic Resonance Imaging Lesions in Multiple Sclerosis. Arch Neurol. 2009;66(12):1531–6. PubMed

Ganesvaran G, Greer JM, Pender MP. Prominent brainstem and cerebellar involvement in multiple sclerosis with psoriasis. Mult Scler. 2009;15:763–766. doi: 10.1177/1352458509103612. PubMed DOI

Greer JM, Csurhes PA, Muller DM, Pender MP. Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. J Immunol. 2008;180(9):6402–10. PubMed

Biberacher V, Boucard CC, Schmidt P, Engl C, Buck D, Berthele A, et al. Atrophy and structural variability of the upper cervical cord in early multiple sclerosis. Mult Scler. 2015;21:875–884. doi: 10.1177/1352458514546514. PubMed DOI

Miller DH. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain. 2002. 10.1093/brain/awf177. PubMed

Azevedo CJ, Overton E, Khadka S, Buckley J, Liu S, Sampat M, et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e102. PubMed PMC

Henry RG, Shieh M, Okuda DT, Evangelista A, Gorno-Tempini ML, Pelletier D. Regional grey matter atrophy in clinically isolated syndromes at presentation. J Neurol Neurosurg Psychiatry. 2008;79:1236–1244. doi: 10.1136/jnnp.2007.134825. PubMed DOI PMC

Dekker I, Schoonheim MM, Venkatraghavan V, Eijlers AJC, Brouwer I, Bron EE, et al. The sequence of structural, functional and cognitive changes in multiple sclerosis. NeuroImage Clin. 2021;29:102550. doi: 10.1016/j.nicl.2020.102550. PubMed DOI PMC

Wagenknecht N, Becker B, Scheld M, Beyer C, Clarner T, Hochstrasser T, et al. Thalamus degeneration and inflammation in two distinct multiple sclerosis animal models. J Mol Neurosci. 2016;60(1):102–114. doi: 10.1007/s12031-016-0790-z. PubMed DOI

Tsagkas C, Parmar K, Pezold S, Barro C, Chakravarty MM, Gaetano L, et al. Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance. Hum Brain Mapp. 2021;42(8):2399–2415. doi: 10.1002/hbm.25375. PubMed DOI PMC

Eshaghi A, Prados F, Brownlee WJ, Altmann DR, Tur C, Cardoso MJ, et al. Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol. 2018;83(2):210–222. doi: 10.1002/ana.25145. PubMed DOI PMC

Magon S, Tsagkas C, Gaetano L, Patel R, Naegelin Y, Amann M, et al. Volume loss in the deep gray matter and thalamic subnuclei: a longitudinal study on disability progression in multiple sclerosis. J Neurol. 2020;267(5):1536–1546. doi: 10.1007/s00415-020-09740-4. PubMed DOI

Combès B, Kerbrat A, Ferré JC, Callot V, Maranzano J, Badji A, et al. Focal and diffuse cervical spinal cord damage in patients with early relapsing–remitting MS: a multicentre magnetisation transfer ratio study. Mult Scler. 2019;25(8):1113–23. PubMed

Oh J, Saidha S, Chen M, Smith SA, Prince J, Jones C, et al. Spinal cord quantitative MRI discriminates between disability levels in multiple sclerosis. Neurology. 2013;80(6):540-7. PubMed PMC

Von Meyenburg J, Wilm BJ, Weck A, Petersen J, Gallus E, Mathys J, et al. Spinal cord diffusion-tensor imaging and motor-evoked potentials in multiple sclerosis patients: microstructural and functional asymmetry. Radiology. 2013;267:869–879. doi: 10.1148/radiol.13112776. PubMed DOI

Eden D. Spatial distribution of multiple sclerosis lesions in the cervical spinal cord. Brain. 2019;142(3):633–646. doi: 10.1093/brain/awy352. PubMed DOI PMC