943777 research-article20202020 MSJ0010.1177/1352458520943777Multiple Sclerosis JournalR Geraldes, M Juryńczyk MULTIPLE SCLEROSIS MSJ JOURNAL Short Report The role of pontine lesion location in Multiple Sclerosis Journal 2021, Vol. 27(6) 968­–972 differentiating multiple sclerosis from vascular DOI: 10.1177/ https://doi.org/10.1177/1352458520943777 1352458520943777 https://doi.org/10.1177/1352458520943777 risk factor-related small vessel disease © The Author(s), 2020. Article reuse guidelines: sagepub.com/journals- Ruth Geraldes , Maciej Juryńczyk, Giordani Rodrigues dos Passos, Alexander Pichler, permissions Karen Chung, Marloes Hagens, Serena Ruggieri , Cristina Auger, Jaume Sastre-Garriga , Christian Enzinger, Declan Chard , Frederik Barkhof , Claudio Gasperini , Alex Rovira, Gabriele DeLuca and Jacqueline Palace; on behalf of the MAGNIMS study group Abstract Correspondence to: J Palace Background: Differentiating multiple sclerosis (MS) from vascular risk factor (VRF)-small vessel dis- Nuffield Department of ease (SVD) can be challenging. Clinical Neurosciences, Level 3, West Wing, John Objective and Methods: In order to determine whether or not pontine lesion location is a useful dis- Radcliffe Hospital, Headley criminator of MS and VRF-SVD, we classified pontine lesions on brain magnetic resonance imaging Way, Oxford OX3 9DU, UK. (MRI) as central or peripheral in 93 MS cases without VRF, 108 MS patients with VRF and 43 non-MS jacqueline.palace@ndcn. ox.ac.uk cases with VRF. Ruth Geraldes Results: MS without VRF were more likely to have peripheral pons lesions (31.2%, 29/93) than non-MS Maciej Juryńczyk Giordani Rodrigues dos with VRF (0%, 0/43) (Exp(B) = 29.8; 95% confidence interval (CI) = (1.98, 448.3); p = 0.014) but there Passos were no significant differences regarding central pons lesions between MS without VRF (5.4%, 5/93) and Gabriele DeLuca Jacqueline Palace non-MS with VRF patients (16.3%, 7/43) (Exp(B) = 0.89; 95% CI = (0.2, 3.94); p = 0.87). The presence Nuffield Department of of peripheral pons lesions discriminated between MS and VRF-SVD with 100% (95% CI = (91.8, 100)) Clinical Neurosciences, Oxford, UK specificity. The proportion of peripheral pons lesions in MS with VRF (30.5%, 33/108) was similar to that Alexander Pichler seen in MS without VRF (31.2%, 29/93, p = 0.99). Central lesions occurred in similar frequency in MS Christian Enzinger Department of Neurology, with VRF (8.3%, 9/108) and non-MS with VRF (16.3%, 7/43, p = 0.15). Medical University of Graz, Graz, Austria/Division of Conclusion: Peripheral pons lesion location is a good discriminator of MS from vascular lesions. Neuroradiology, Vascular & Interventional Radiology, Medical University of Graz, Keywords: Multiple sclerosis, cerebral small vessel disease, imaging, differential diagnosis Graz, Austria Karen Chung NMR Research Unit, Date received: 28 December 2019; revised: 25 June 2020; accepted: 28 June 2020. Queen Square Multiple Sclerosis Centre, University College London Institute of Introduction determine the specificity of pontine lesions in these Neurology, London, UK Lesions located at the periphery of the pons have been locations for MS and VRF-SVD. Marloes Hagens MS Center Amsterdam, described in multiple sclerosis (MS),1 and in theory, Department of Neurology, due to a rich vascularization, this area is less prone to Amsterdam UMC, Vrije Universiteit Amsterdam, vascular risk factor (VRF)-related small vessel dis- Materials and methods Amsterdam, The ease (SVD). On the contrary, the central pons is sup- Netherlands Serena Ruggieri plied by perforating end-arterioles and is prone to Study design and cohorts Claudio Gasperini ischaemic hypoxia and demyelination which under- A multicentre, cross-sectional (2006–2017) compara- Multiple Sclerosis Center, Department of lies T2 magnetic resonance imaging (MRI) hyperin- tive study assessed people with MS (2010 McDonald Neurosciences, San tensities seen in this area in patients with VRF-SVD.2 criteria3) without VRF (N = 93, mean Camillo-Forlanini Hospital, Rome, Italy However, these assumptions are based on limited age = 47.2 ± 8.2 years, 63.4% females), with VRF Cristina Auger observations and the role of these markers in discrim- (N = 108, mean age = 48.5 ± 8.5 years, 62.0% females) Alex Rovira inating MS from SVD-related lesions has not been and a non-MS group with VRF (N = 43, mean Section of Neuroradiology, Department of Radiology, tested so far. We aim to explore whether VRFs and age = 58.5 ± 13.8 years, 61.7% females). The MS Hospital Universitari Vall MS associate with pontine lesions in different loca- patients were seen in five MAGNIMS network cen- d’Hebron, Universitat Autonoma de Barcelona, tions, defined as either central or peripheral, and to tres (www.magnims.eu) (Amsterdam, Barcelona, Barcelona, Spain 968 journals.sagepub.com/home/msj R Geraldes, M Juryńczyk et al. Jaume Sastre-Garriga Servei de Neurologia/ Neuroimmunologia, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain Declan Chard NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK/National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, UK Frederik Barkhof MS Center Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands/NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK/National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, UK Figure 1. (a) Pons lesions were classified as central if they were present with a 1.0 cm radius of the midpoint (midpoint of a line from the basilar groove to the posterior median sulcus, as seen on axial sections) of the pons, or peripheral if beyond that circle. If crossing the circle line, lesions would be considered central if more than ¾ of the lesion is inside the circle.a,b (b) Examples of the patterns of pons lesion location in MS without VRF and non-MS with VRF cases are shown, white arrows pointing to peripheral and central pons lesions, respectively. (c) Proportion of peripheral and central pons lesions in MS only, MS with VRF and VRF only groups. aConsidering that pontine anterior–posterior length did not differ between 10 MS only and 10 VRF only cases, the authors used an absolute cut-off instead of a discriminatory cut-off. A discriminatory threshold, independent of pontine size, may be preferable in cohorts with significant pontine size variability. bRaters blinded to clinical information, were given a mixture of MS with and without VRF and non-MS with VRF, and were instructed to ignore the supratentorial areas. journals.sagepub.com/home/msj 969 Multiple Sclerosis Journal 27(6) Graz, London, Rome) and the non-MS cases derived adjusting for age and site, were made using a general- from brain imaging studies on diabetic cohorts from ized linear model with methods for bias reduction and two of these centres (Amsterdam and Barcelona). The maximum penalized likelihood; results are presented VRF cases were asymptomatic because patients with as odds ratios (exponential coefficients EXP(B)) and transient ischemic attack (TIA) and stroke were 95% confidence intervals (CI). A p value < 0.05 was excluded, and the MS cases were imaged outside of considered statistically significant. The specificity relapse and did not have new relevant symptoms at (number of true negative cases/number of false posi- the time of MRI although the detailed chronic symp- tive cases + true negative cases) of peripheral pontine toms of each MS patient was not available. lesions for MS and of central pontine lesions for VRF- SVD was assessed by comparing MS without VRF Cases with known brain lesions unrelated to either and non-MS with VRF cases. Specificity and 95% CI MS or SVD were excluded. Anonymized clinical data were calculated using MEDCALC statistical soft- were collected: sex, age and disease duration at the ware. All other analyses were performed with SPSS time of MRI scan, presence of the following VRFs version 25, R software version 3.6.2, and GraphPad (yes/no): (1) arterial hypertension (HT) (ever); (2) Prism version 7. dyslipidaemia (ever); (3) diabetes mellitus (DM); and (4) self-reported smoking status – yes, if patients smoked more than 10 cigarettes a day for at least Results 6 months. Cases were considered to be in the VRF The VRF profile of the non-MS cases was as fol- group when one or more of the above VRFs were lows: 100% with DM, 41.9% ever-smokers, 23.3% present. with HT, 25.6% with dyslipidaemia; 37.2% with more than one VRF; and in the MS with VRF: 78.7% ever-smokers, 40.7% with HT, 23.1% with Visual scoring dyslipidaemia, and 9.2% with DM; 25.9% with Investigators (R.G., M.J., G.R.d.P.) were blinded to more than one VRF. The non-MS with VRF group clinical information, performed visual assessment of was older (N = 43, mean age = 58.5 ± 13.8 years) the brain MRIs (3T) using the following sequences: than the MS without VRF group (N = 93, mean 2D/3D T2-weighted fluid-attenuated inversion recov- age = 47.2 ± 8.2 years) (p < 0.001), but age did not ery and or 2D T2-weighted fast spin echo differ between MS without and MS with VRF (Supplemental Table 1). The total number of infraten- (N = 108, mean age = 48.5 ± 8.5 years) (p = 0.51). torial lesions – defined as any lesion in the brainstem or cerebellum – was counted. When present, pontine Moderate agreement (0.5) was found for the total lesions were classified as central if they were present exact number of infratentorial lesions and substantial with a 1.0 cm radius of the pons midpoint or periph- for pontine lesion location (0.61). Infratentorial eral if beyond that circle, as depicted in Figure 1(a). lesions were more commonly seen in people with MS without VRF (52.7%, 49/93, per patient: median All MRI and clinical data sets had initially been col- number = 1, IQR = 2) and with MS with VRF (50.9%, lected, anonymized and stored at the contributing 55/108, per patient: median number = 1, IQR = 2) sites in accordance with the local research ethics compared to non-MS with VRF cases (20.9%, 9/43, regulations. per patient: median number = 0, IQR = 0), p = 0.001. Peripheral pontine lesions (Figure 1(b)) were observed Statistical analysis in 31.2% (29/93) MS without VRF patients and in Agreement was measured as previously reported.4 none of non-MS with VRF cases (p < 0.0001), thus The number of infratentorial lesions and the propor- showing 100% specificity for MS (95% CI = (91.78, tion of cases with peripheral and central pontine 100)) (Figure 1(c)). lesions were compared between MS without VRF, MS with VRF, and non-MS with VRF. Variables are Central pontine lesions (Figure 1(b)) were seen in presented as median and interquartile range (IQR). 16.3% (7/43) of non-MS with VRF cases and only in Chi-square or Fisher’s exact test and nonparametric 5.4% (5/93) of MS without VRF cases (p = 0.02) tests were applied as appropriate. Considering poten- (Figure 1(c)), showing a 94.6% (95% CI = (87.9, tial differences between MAGNIMS sites, a ‘site’ fac- 98.2)) specificity for VRF-SVD. The proportion of torial variable was built. Comparisons between MS central pontine lesions was not different in MS with without VRF and non-MS with VRF regarding the VRF cases (8.3%, 9/108) compared with MS without presence of central and peripheral pons lesions, VRF (5.4%, 5/93), (p = 0.57). 970 journals.sagepub.com/home/msj R Geraldes, M Juryńczyk et al. VRFs in MS did not impact the presence of peripheral Table 1), suggesting that they may be applicable in pontine lesions which were seen in 30.5% (33/108) of the clinical setting. The fact that extra-pontine areas MS with VRF and in 31.2% (29/93) of MS without were not masked while scoring pons lesions is a limi- VRF (p = 0.99). The proportion of central pontine tation although the scorers were aware that mixed lesions in MS with VRF (8.3% (9/108)) did not sig- lesion groups were included making it impossible for nificantly differ from non-MS with VRF (16.3%, them to be sure whether patients had VRF or not. 7/43), p = 0.15 (Figure 1(c)). Despite the limitations, our data suggest that periph- eral pontine lesions may have a different pathogene- In a model including age and site as covariates, MS sis from central lesions, some of which may be without VRF were more likely to have peripheral related to vascular disease. In clinical practice, new pons lesions than non-MS with VRF (Exp(B) = 29.8; lesions in MS are assumed to be related to disease 95% CI = (1.98, 448.3); p = 0.014). Using the same activity, and differentiating new vascular from model, there were no significant differences regard- inflammatory lesions would be useful in decisions ing central pons lesions between MS without VRF around escalating disease-modifying treatments. and VRF patients (Exp(B) = 0.89; 95% CI = (0.2, Prospective studies are warranted to confirm pontine 3.94); p = 0.87). lesion location as a discriminator of MS from vascu- lar to determine the impact of specific VRF on lesion accumulation in MS. Discussion Differentiating MS lesions from SVD lesions on MRI Acknowledgements may be challenging, especially in cases with atypical The authors are grateful to Adriana Roca-Fernández clinical presentations5 and where both MS and VRFs for her support with the statistical analysis. Statistical are present. analysis was conducted by Dr R.G., MD, Nuffield Department of Clinical Neurosciences, John Radcliffe Presence of infratentorial (brainstem and cerebellum) Hospital, Oxford, UK. lesions is one of the criteria required to demonstrate dissemination in space according to the McDonald Declaration of Conflicting Interests diagnostic criteria for MS,6 but few studies have The author(s) declared the following potential con- described the characteristics of brainstem lesions. flicts of interest with respect to the research, author- Half of our MS cohort showed one or more lesions in ship and/or publication of this article: R.G. has this location. The frequency of brainstem lesions has received travel expenses from Bayer, Biogen, Merck, been reported to range from 6% to 82% in MS case Teva, Novartis and Wolfson College; has also received series with specific clinical symptoms and a tendency honoraria for advisory work and as an invited speaker for lesions to occur closer to the ventricular surface for Biogen, Novartis and the EAN. M.J. reports no or the periphery of the pons especially where cranial disclosures. G.R.d.P. has received scholarships from nerves emerge.1,7–10 We have directly compared pon- the ECTRIMS, the World Federation of Neurology tine lesions locations in MS and SVD-VRF cases and and Novartis; funding for research from Biogen, have shown that the presence of peripheral pons Novartis and Roche; travel grants from Roche, lesions (seen in about one-third of people with MS) is Sanofi-Genzyme and Teva; and fees for editorial con- a useful discriminator for MS from VRF-associated tent from Bayer, Merck Serono and Roche. A.P. lesions. Furthermore, the presence of concomitant reports no disclosures. K.C. has received honoraria VRF in MS does not appear to associate with for speaking at meetings, and advisory work or sup- increased peripheral pons lesions, further suggesting port to attend meetings from Teva, Biogen Idec and the specificity of this finding. Central pontine lesions Roche. M.H. reports no disclosures. S.R. reports no can be seen both in MS and with VRF-related SVD. disclosures. C.A. has received honoraria for speaking In our study, there was a poor age and VRF matching at meeting from Novartis. J.S.-G. reports, in the last between MS (mainly smokers) and non-MS groups 36 months, grants and personal fees from Genzyme; (all diabetic), and the frequency of central pontine personal fees from Biogen, Bayer, Merck, Almirall, lesions in age-matched healthy controls and age- and Bial, Novartis, Roche, TEVA and Celgene; he is VRF-matched asymptomatic and symptomatic director of Revista de Neurologia, for which he does patients with VRF needs to be further explored. not receive any compensation; and serves on the edi- Nevertheless, our findings seem to be consistent torial board of Multiple Sclerosis Journal, for which despite the heterogeneity of MRI protocols across he receives a compensation. C.E. has received fund- centres, which were not systematically different ing for travel and speaker honoraria from Biogen, between MS and VRF groups (see Supplementary Bayer, Genzyme, Merck, Novartis, Shire and Teva; journals.sagepub.com/home/msj 971 Multiple Sclerosis Journal 27(6) research support from Biogen, Merck and Teva; and Jaume Sastre-Garriga https://orcid.org/0000-0002 has served on scientific advisory boards for Bayer, -1589-2254 Biogen, Merck, Novartis, Roche and Teva. D.C. has, Declan Chard https://orcid.org/0000-0003-3076 in the last 3 years, received honoraria from EXCEMED -2682 for faculty-led education work. He is a consultant for Frederik Barkhof https://orcid.org/0000-0003 Biogen and Hoffmann-La Roche. He has received -3543-3706 research funding from the International Progressive Claudio Gasperini https://orcid.org/0000-0002 MS Alliance, the MS Society and the National -3959-4067 Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Supplemental Material Research Centre. F.B. serves as a consultant for Supplemental material for this article is available Biogen, Bayer, Genzyme, Jansen Research, Merck, online. Novartis, Roche, Synthon BV and Teva. C.G. has received compensation for consulting from Bayer and Biogen, and speaker’s fees for lectures from Biogen, Bayer, Genzyme, Merck, Novartis and References Teva. A.R. serves on scientific advisory boards for 1. Nakashima I, Fujihara K, Kimpara T, et al. Linear Novartis, Sanofi-Genzyme, SyntheticMR, Bayer, pontine trigeminal root lesions in multiple sclerosis. Roche, Biogen, Neurodiem and OLEA Medical; and Arch Neurol 2001; 58: 101–104. has received speaker honoraria from Bayer, Sanofi- 2. 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