Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis
Corresponding Author
Ermelinda De Meo MD, PhD
Neuroimaging Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Address correspondence to Dr Meo, Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. E-mail: [email protected]
Search for more papers by this authorMassimo Filippi MD
Neuroimaging Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Neurology Unit, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Neurorehabilitation Unit, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Neurophysiology Service, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Search for more papers by this authorMaria Trojano MD
Department of Basic Medical Sciences, Neurosciences, and Sense Organs, Aldo Moro Polyclinic, University of Bari, Bari, Italy
Search for more papers by this authorGiancarlo Comi MD
Vita-Salute San Raffaele University, Milan, Italy
Search for more papers by this authorFrancasco Patti MD
Department of Medical and Surgical Sciences and Advanced Technologies, G. F. Ingrassia Section of Neuroscience, Multiple Sclerosis Center, University of Catania, Catania, Italy
Search for more papers by this authorVincenzo Brescia Morra MD
Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy
Search for more papers by this authorGiuseppe Salemi MD
Department of Experimental Biomedicine and Neuroscience, Palermo, Italy
Search for more papers by this authorGiacomo Lus MD
University of Campania Luigi Vanvitelli, Naples, Italy
Search for more papers by this authorEleonora Cocco MD
Multiple Sclerosis Center, ASSL Cagliari, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Search for more papers by this authorMattia Fonderico MD
NEUROFARBA Department, University of Florence, Florence, Italy
Search for more papers by this authorValentina Torri Clerici MD
IRCCS Istituto Neurologico Carlo Besta Neurological Institute, Scientific Institute for Research and Health Care, Milan, Italy
Search for more papers by this authorGiorgia Teresa Maniscalco MD
Multiple Sclerosis Center and Neurological Clinic/Stroke Unit, A. Cardarelli Hospital, Naples, Italy
Search for more papers by this authorPaola Valentino MD
MaterDomini University Hospital, Catanzaro, Italy
Search for more papers by this authorAntonio Bertolotto MD
Regional Multiple Sclerosis Reference Center, Torino, Italy
Search for more papers by this authorAlessandra Lugaresi MD
UOSI Multiple Sclerosis Rehabilitation, Scientific Institute for Research and Health Care–ISNB, Bologna, Italy
Search for more papers by this authorRoberto Bergamaschi MD
Multiple Sclerosis Center, Scientific Institute for Research and Health Care, Mondino Foundation, Pavia, Italy
Search for more papers by this authorMarco Rovaris MD
Centro SM Multiple Sclerosis Center, Don Carlo Gnocchi Foundation, Milan, Italy
Search for more papers by this authorPatrizia Sola MD
Center for Demyelinating Diseases, Department of Neuroscience, University Hospital/OCSAE, UO Neurology, University of Modena and Reggio Emilia, Modena, Italy
Search for more papers by this authorGioacchino Tedeschi MD
University of Campania Luigi Vanvitelli, Naples, Italy
Search for more papers by this authorIlaria Pesci MD
Multiple Sclerosis Center, UO Neurology, Di Vaio Hospital, Fidenza, Italy
Search for more papers by this authorUmberto Aguglia MD
Great Metropolitan Hospital of Reggio Calabria, Reggio di Calabria, Italy
Search for more papers by this authorPaola Cavalla MD
Multiple Sclerosis Center and Neurology Unit I, Department of Neuroscience and Mental Health, City Health and Science University Hospital of Torino, Turin, Italy
Search for more papers by this authorDavide Maimone MD
Multiple Sclerosis Center, UOC Neurology, ARNAS Garibaldi, Catania, Italy
Search for more papers by this authorFranco Granella MD
Unit of Neurosciences, Department of Medicine and Surgery, University of Parma, Parma, Italy
Search for more papers by this authorMarika Vianello MD
Multiple Sclerosis Center, Neurology Unit, Ca Foncello Regional Hospital, Treviso, Italy
Search for more papers by this authorMarta Simone MD
Child Neuropsychiatric Unit, Department of Biomedical Science and Human Oncology, University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorEmilio Portaccio MD
NEUROFARBA Department, University of Florence, Florence, Italy
Search for more papers by this authorMaria Pia Amato MD
NEUROFARBA Department, University of Florence, Florence, Italy
Don Carlo Gnocchi Scientific Institute for Research and Health Care Foundation, Florence, Italy
Search for more papers by this authorCorresponding Author
Ermelinda De Meo MD, PhD
Neuroimaging Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Address correspondence to Dr Meo, Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. E-mail: [email protected]
Search for more papers by this authorMassimo Filippi MD
Neuroimaging Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Neurology Unit, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Neurorehabilitation Unit, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Neurophysiology Service, San Raffaele Scientific Institute, Scientific Institute for Research and Health Care, Milan, Italy
Search for more papers by this authorMaria Trojano MD
Department of Basic Medical Sciences, Neurosciences, and Sense Organs, Aldo Moro Polyclinic, University of Bari, Bari, Italy
Search for more papers by this authorGiancarlo Comi MD
Vita-Salute San Raffaele University, Milan, Italy
Search for more papers by this authorFrancasco Patti MD
Department of Medical and Surgical Sciences and Advanced Technologies, G. F. Ingrassia Section of Neuroscience, Multiple Sclerosis Center, University of Catania, Catania, Italy
Search for more papers by this authorVincenzo Brescia Morra MD
Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy
Search for more papers by this authorGiuseppe Salemi MD
Department of Experimental Biomedicine and Neuroscience, Palermo, Italy
Search for more papers by this authorGiacomo Lus MD
University of Campania Luigi Vanvitelli, Naples, Italy
Search for more papers by this authorEleonora Cocco MD
Multiple Sclerosis Center, ASSL Cagliari, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Search for more papers by this authorMattia Fonderico MD
NEUROFARBA Department, University of Florence, Florence, Italy
Search for more papers by this authorValentina Torri Clerici MD
IRCCS Istituto Neurologico Carlo Besta Neurological Institute, Scientific Institute for Research and Health Care, Milan, Italy
Search for more papers by this authorGiorgia Teresa Maniscalco MD
Multiple Sclerosis Center and Neurological Clinic/Stroke Unit, A. Cardarelli Hospital, Naples, Italy
Search for more papers by this authorPaola Valentino MD
MaterDomini University Hospital, Catanzaro, Italy
Search for more papers by this authorAntonio Bertolotto MD
Regional Multiple Sclerosis Reference Center, Torino, Italy
Search for more papers by this authorAlessandra Lugaresi MD
UOSI Multiple Sclerosis Rehabilitation, Scientific Institute for Research and Health Care–ISNB, Bologna, Italy
Search for more papers by this authorRoberto Bergamaschi MD
Multiple Sclerosis Center, Scientific Institute for Research and Health Care, Mondino Foundation, Pavia, Italy
Search for more papers by this authorMarco Rovaris MD
Centro SM Multiple Sclerosis Center, Don Carlo Gnocchi Foundation, Milan, Italy
Search for more papers by this authorPatrizia Sola MD
Center for Demyelinating Diseases, Department of Neuroscience, University Hospital/OCSAE, UO Neurology, University of Modena and Reggio Emilia, Modena, Italy
Search for more papers by this authorGioacchino Tedeschi MD
University of Campania Luigi Vanvitelli, Naples, Italy
Search for more papers by this authorIlaria Pesci MD
Multiple Sclerosis Center, UO Neurology, Di Vaio Hospital, Fidenza, Italy
Search for more papers by this authorUmberto Aguglia MD
Great Metropolitan Hospital of Reggio Calabria, Reggio di Calabria, Italy
Search for more papers by this authorPaola Cavalla MD
Multiple Sclerosis Center and Neurology Unit I, Department of Neuroscience and Mental Health, City Health and Science University Hospital of Torino, Turin, Italy
Search for more papers by this authorDavide Maimone MD
Multiple Sclerosis Center, UOC Neurology, ARNAS Garibaldi, Catania, Italy
Search for more papers by this authorFranco Granella MD
Unit of Neurosciences, Department of Medicine and Surgery, University of Parma, Parma, Italy
Search for more papers by this authorMarika Vianello MD
Multiple Sclerosis Center, Neurology Unit, Ca Foncello Regional Hospital, Treviso, Italy
Search for more papers by this authorMarta Simone MD
Child Neuropsychiatric Unit, Department of Biomedical Science and Human Oncology, University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorEmilio Portaccio MD
NEUROFARBA Department, University of Florence, Florence, Italy
Search for more papers by this authorMaria Pia Amato MD
NEUROFARBA Department, University of Florence, Florence, Italy
Don Carlo Gnocchi Scientific Institute for Research and Health Care Foundation, Florence, Italy
Search for more papers by this authorAbstract
Objective
This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset pediatric multiple sclerosis.
Methods
Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease-modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated.
Results
A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease-modifying treatment exposure were independent predictors for long-term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long-term disability.
Interpretation
These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022;91:483–495
Potential Conflicts of Interest
Nothing to report.
Supporting Information
| Filename | Description |
|---|---|
| ana26322-sup-0001-Tables.docxWord 2007 document , 40.8 KB | SUPPLEMENTARY TABLE 1. Main Clinical and Demographic Features of the Study Cohort Grouped by Age at Disease Onset and Diagnostic Criteria Adopted (Poser vs McDonald) SUPPLEMENTARY TABLE 2. Cox Models of Time to Expanded Disability Status Scale 3, 4, and 6, and to Conversion to Secondary Progressive Multiple Sclerosis (MS) from Birth or MS Onset, Comparing Early vs Late Onset Pediatric MS Patients (the Latter as Reference Group), Stratified for the Diagnostic Criteria Adopted (Poser vs McDonald) SUPPLEMENTARY TABLE 3. Univariate Cox Models of Time from Multiple Sclerosis Onset to Expanded Disability Status Scale 3, 4, and 6 in Early and Late Onset Pediatric Multiple Sclerosis Patients, Stratified for the Diagnostic Criteria Adopted (Poser vs McDonald) SUPPLEMENTARY TABLE 4. Multivariate Cox Regression Models of Prognostic Factors of Time from Disease Onset to Reach Disability Milestones (Expanded Disability Status Scale 3, 4, and 6) in Early and Late Onset Pediatric Multiple Sclerosis Patients, Stratified for the Diagnostic Criteria Adopted (Poser vs McDonald) |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Renoux C. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356: 2603–2613.
- 2Chabas D, Castillo-Trivino T, Mowry EM, et al. Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype? Neurology 2008; 71: 1090–1093.
- 3Ruggieri M, Polizzi A, Pavone L, Grimaldi LM. Multiple sclerosis in children under 6 years of age. Neurology 1999; 53: 478–484.
- 4Weygandt M, Hummel HM, Schregel K, et al. MRI-based diagnostic biomarkers for early onset pediatric multiple sclerosis. Neuroimage Clin 2015; 7: 400–408.
- 5Huppke B, Ellenberger D, Rosewich H, et al. Clinical presentation of pediatric multiple sclerosis before puberty. Eur J Neurol 2014; 21: 441–446.
- 6Ghassemi R, Antel SB, Narayanan S, et al. Lesion distribution in children with clinically isolated syndromes. Comparative study. Ann Neurol 2008; 63: 401–405.
- 7Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 2009; 72: 232–239.
- 8Wong YYM, de Mol CL, van der Vuurst de Vries RM, et al. Real-world validation of the 2017 McDonald criteria for pediatric MS. Neurol Neuroimmunol Neuroinflamm 2018; 6: e528.
- 9Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17: 162–173.
- 10McLaughlin KA, Chitnis T, Newcombe J, et al. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. J Immunol 2009; 183: 4067–4076.
- 11Fadda G, Brown RA, Longoni G, et al. MRI and laboratory features and the performance of international criteria in the diagnosis of multiple sclerosis in children and adolescents: a prospective cohort study. Lancet Child Adolesc Health 2018; 2: 191–204.
- 12Hacohen Y, Brownlee W, Mankad K, et al. Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort. Mult Scler J 2020; 26: 1372–1380.
- 13Waldman A, Ness J, Pohl D, et al. Pediatric multiple sclerosis: clinical features and outcome. Neurology 2016; 87: S74–S81.
- 14Benson LA, Healy BC, Gorman MP, et al. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord 2014; 3: 186–193.
- 15Gorman MP, Healy BC, Polgar-Turcsanyi M, Chitnis T. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch Neurol 2009; 66: 54–59.
- 16Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011; 76: 1989–1995.
- 17Chabas D, Ness J, Belman A, et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology 2010; 74: 399–405.
- 18Trojano M, Bergamaschi R, Amato MP, et al. The Italian multiple sclerosis register. Neurol Sci 2019; 40: 155–165.
- 19Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013; 19: 1261–1267.
- 20Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.
- 21Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria”. Ann Neurol 2005; 58: 840–846.
- 22Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–286.
- 23Kalincik T, Cutter G, Spelman T, et al. Defining reliable disability outcomes in multiple sclerosis. Brain 2015; 138: 3287–3298.
- 24Poser CM, Paty DW, Scheinberg L. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.
- 25McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.
- 26Baroncini D, Simone M, Iaffaldano P, et al. Risk of persistent disability in patients with pediatric-onset multiple sclerosis. JAMA Neurol 2021; 78: 726–735.
- 27Tintoré M, Arrambide G. Early onset multiple sclerosis: the role of gender. J Neurol Sci 2009; 286: 31–34.
- 28Bove R, Chitnis T. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler J 2014; 20: 520–526.
- 29Bove R, Chitnis T. Sexual disparities in the incidence and course of MS. Clin Immunol 2013; 149: 201–210.
- 30Paus T. Mapping brain maturation and cognitive development during adolescence. Trends Cogn Sci 2005; 9: 60–68.
- 31De Bellis MD, Keshavan MS, Beers SR, et al. Sex differences in brain maturation during childhood and adolescence. Cereb Cortex 2001; 11: 552–557.
- 32Yeo SS, Jang SH, Son SM. The different maturation of the corticospinal tract and corticoreticular pathway in normal brain development: diffusion tensor imaging study. Front Hum Neurosci 2014; 8:573. https://doi.org/10.3389/fnhum.2014.00573.
- 33Geertsen SS, Willerslev-Olsen M, Lorentzen J, Nielsen JB. Development and aging of human spinal cord circuitries. J Neurophysiol 2017; 118: 1133–1140.
- 34Chitnis T, Aaen G, Belman A, et al. Improved relapse recovery in paediatric compared to adult multiple sclerosis. Brain 2020; 143: 2733–2741.
- 35Young B, Waubant E, Lulu S, Graves J. Puberty onset and pediatric multiple sclerosis activity in boys. Mult Scler Relat Disord 2019; 27: 184–187.
- 36Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Mult Scler J 2016; 22: 193–200.
- 37Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016; 16: 626–638.
- 38McKay KA, Hillert J, Manouchehrinia A. Long-term disability progression of pediatric-onset multiple sclerosis. Neurology 2019; 92: e2764–e2773.
- 39Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770–782.
- 40Mowry EM, Pesic M, Grimes B, et al. Demyelinating events in early multiple sclerosis have inherent severity and recovery. Neurology 2009; 72: 602.
- 41Tremlett H, Yousefi M, Devonshire V, et al. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology 2009; 73:1616.
- 42Jokubaitis VG, Spelman T, Kalincik T, et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol 2016; 80: 89–100.
- 43Brownlee WJ, Altmann DR, Prados F, et al. Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis. Brain 2019; 142: 2276–2287.
- 44Amato MP, Krupp LB, Charvet LE, et al. Pediatric multiple sclerosis: cognition and mood. Neurology 2016; 87: S82–S87.
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