Early Predictors of 9-Year Disability in Pediatric Multiple Sclerosis
Ermelinda De Meo MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Search for more papers by this authorRaffaello Bonacchi MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorLucia Moiola MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorBruno Colombo MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorFrancesca Sangalli MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorChiara Zanetta MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorMaria Pia Amato MD
Department NEUROFARBA, Section of Neurosciences, University of Florence, Florence, Italy
IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
Search for more papers by this authorVittorio Martinelli MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorMaria Assunta Rocca MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorCorresponding Author
Massimo Filippi MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
Address correspondence to Prof Massimo Filippi, Full Professor of Neurology, Vita-Salute San Raffaele University, Chair, Neurology Unit, Chair, Neurorehabilitation Unit, Director, Neurophysiology Service, Director, MS Center, Director, Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy. E-mail: [email protected]
Search for more papers by this authorErmelinda De Meo MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Search for more papers by this authorRaffaello Bonacchi MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorLucia Moiola MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorBruno Colombo MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorFrancesca Sangalli MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorChiara Zanetta MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorMaria Pia Amato MD
Department NEUROFARBA, Section of Neurosciences, University of Florence, Florence, Italy
IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
Search for more papers by this authorVittorio Martinelli MD
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorMaria Assunta Rocca MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Search for more papers by this authorCorresponding Author
Massimo Filippi MD
Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, Milan, Italy
Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
Address correspondence to Prof Massimo Filippi, Full Professor of Neurology, Vita-Salute San Raffaele University, Chair, Neurology Unit, Chair, Neurorehabilitation Unit, Director, Neurophysiology Service, Director, MS Center, Director, Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy. E-mail: [email protected]
Search for more papers by this authorAbstract
Objective
The purpose of this study was to assess early predictors of 9-year disability in pediatric patients with multiple sclerosis.
Methods
Clinical and magnetic resonance imaging (MRI) assessments of 123 pediatric patients with multiple sclerosis were obtained at disease onset and after 1 and 2 years. A 9-year clinical follow-up was also performed. Cox proportional hazard and multivariable regression models were used to assess independent predictors of time to first relapse and 9-year outcomes.
Results
Time to first relapse was predicted by optic nerve lesions (hazard ratio [HR] = 2.10, p = 0.02) and high-efficacy treatment exposure (HR = 0.31, p = 0.005). Predictors of annualized relapse rate were: at baseline, presence of cerebellar (β = −0.15, p < 0.001), cervical cord lesions (β = 0.16, p = 0.003), and high-efficacy treatment exposure (β = −0.14, p = 0.01); considering also 1-year variables, number of relapses (β = 0.14, p = 0.002), and the previous baseline predictors; considering 2-year variables, time to first relapse (2-year: β = −0.12, p = 0.01) entered, whereas high-efficacy treatment exposure exited the model. Predictors of 9-year disability worsening were: at baseline, presence of optic nerve lesions (odds ratio [OR] = 6.45, p = 0.01); considering 1-year and 2-year variables, Expanded Disability Status Scale (EDSS) changes (1-year: OR = 26.05, p < 0.001; 2-year: OR = 16.38, p = 0.02), and ≥ 2 new T2-lesions in 2 years (2-year: OR = 4.91, p = 0.02). Predictors of higher 9-year EDSS score were: at baseline, EDSS score (β = 0.58, p < 0.001), presence of brainstem lesions (β = 0.31, p = 0.04), and number of cervical cord lesions (β = 0.22, p = 0.05); considering 1-year and 2-year variables, EDSS changes (1-year: β = 0.79, p < 0.001; 2-year: β = 0.55, p < 0.001), and ≥ 2 new T2-lesions (1-year: β = 0.28, p = 0.03; 2-year: β = 0.35, p = 0.01).
Interpretation
A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first 2 years of disease contribute to predict 9-year prognosis in pediatric patients with multiple sclerosis. ANN NEUROL 2021;89:1011–1022
Potential Conflicts of Interests
Nothing to report.
Supporting Information
| Filename | Description |
|---|---|
| ana26052-sup-0001-tables.docxWord 2007 document , 19.6 KB | Table S1 Supporting information |
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.
- 2Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain 2004; 127: 1942–1947.
- 3Banwell B, Ghezzi A, Bar-Or A, et al. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol 2007; 6: 887–902.
- 4Mikaeloff Y, Caridade G, Assi S, et al. Prognostic factors for early severity in a childhood multiple sclerosis cohort. Pediatrics 2006; 118: 1133–1139.
- 5Iaffaldano P, Simone M, Lucisano G, et al. Prognostic indicators in pediatric clinically isolated syndrome. Ann Neurol 2017; 81: 729–739.
- 6Gorman 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.
- 7Benson 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.
- 8Waubant E, Chabas D, Okuda DT, et al. Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol 2009; 66: 967–971.
- 9Minneboo A, Barkhof F, Polman CH, et al. Infratentorial lesions predict long-term disability in patients with initial findings suggestive of multiple sclerosis. Arch Neurol 2004; 61: 217–221.
- 10Swanton JK, Fernando KT, Dalton CM, et al. Early MRI in optic neuritis: the risk for disability. Neurology 2009; 72: 542–550.
- 11Tintore M, Rovira A, Arrambide G, et al. Brainstem lesions in clinically isolated syndromes. Neurology 2010; 75: 1933–1938.
- 12Brownlee WJ, Altmann DR, Alves Da Mota P, et al. Association of asymptomatic spinal cord lesions and atrophy with disability 5 years after a clinically isolated syndrome. Mult Scler 2017; 23: 665–674.
- 13Arrambide G, Rovira A, Sastre-Garriga J, et al. Spinal cord lesions: a modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor. Mult Scler 2018; 24: 301–312.
- 14Di Filippo M, Anderson VM, Altmann DR, et al. Brain atrophy and lesion load measures over 1 year relate to clinical status after 6 years in patients with clinically isolated syndromes. J Neurol Neurosurg Psychiatry 2010; 81: 204–208.
- 15Krupp 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.
- 16Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.
- 17Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17: 162–173.
- 18Kalincik T, Cutter G, Spelman T, et al. Defining reliable disability outcomes in multiple sclerosis. Brain 2015; 138: 3287–3298.
- 19Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: 2059–2069.
- 20Ruet A, Arrambide G, Brochet B, et al. Early predictors of multiple sclerosis after a typical clinically isolated syndrome. Mult Scler 2014; 20: 1721–1726.
- 21Tintoré M, Rovira A, Rio J, et al. Is optic neuritis more benign than other first attacks in multiple sclerosis? Ann Neurol 2005; 57: 210–215.
- 22Tintore M, Rovira À, Río J, et al. Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain 2015; 138: 1863–1874.
- 23Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131: 808–817.
- 24Davion JB, Lopes R, Drumez É, et al. Asymptomatic optic nerve lesions: an underestimated cause of silent retinal atrophy in MS. Neurology 2020; 94: e2468–e2478.
- 25London F, Zéphir H, Drumez E, et al. Optical coherence tomography: a window to the optic nerve in clinically isolated syndrome. Brain 2019; 142: 903–915.
- 26Zimmermann HG, Knier B, Oberwahrenbrock T, et al. Association of Retinal Ganglion Cell Layer Thickness with Future Disease Activity in patients with clinically isolated syndrome. JAMA Neurol 2018; 75: 1071–1079.
- 27Ghezzi A, Comi G, Grimaldi LM, et al. Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS. Neurol Neuroimmunol Neuroinflamm 2019; 6:e591.
- 28Killestein J, Polman CH. Determinants of interferon β efficacy in patients with multiple sclerosis. Nat Rev Neurol 2011; 7: 221–228.
- 29Davis MD, Ashtamker N, Steinerman JR, Knappertz V. Time course of glatiramer acetate efficacy in patients with RRMS in the GALA study. Neurol neuroimmunol Neuroinflamm 2017; 4:e327.
- 30Absinta M, Rocca MA, Moiola L, et al. Brain macro- and microscopic damage in patients with paediatric MS. J Neurol Neurosurg Psychiatry 2010; 81: 1357–1362.
- 31Weier K, Fonov V, Aubert-Broche B, et al. Impaired growth of the cerebellum in pediatric-onset acquired CNS demyelinating disease. Mult Scler 2016; 22: 1266–1278.
- 32De Meo E, Meani A, Moiola L, et al. Dynamic gray matter volume changes in pediatric multiple sclerosis: a 3.5 year MRI study. Neurology 2019; 92: e1709–e1723.
- 33Simmonds DJ, Hallquist MN, Asato M, Luna B. Developmental stages and sex differences of white matter and behavioral development through adolescence: a longitudinal diffusion tensor imaging (DTI) study. Neuroimage 2014; 92: 356–368.
- 34Zecca C, Disanto G, Sormani MP, et al. Relevance of asymptomatic spinal MRI lesions in patients with multiple sclerosis. Mult Scler 2016; 22: 782–791.
- 35Okuda DT, Mowry EM, Cree BA, et al. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology 2011; 76: 686–692.
- 36Sombekke MH, Wattjes MP, Balk LJ, et al. Spinal cord lesions in patients with clinically isolated syndrome: a powerful tool in diagnosis and prognosis. Neurology 2013; 80: 69–75.
- 37Okuda DT, Siva A, Kantarci O, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLoS One 2014; 9:e90509.
- 38Freedman MS. Induction vs. escalation of therapy for relapsing multiple sclerosis: the evidence. Neurol Sci 2008; 29: S250–S252.
- 39Harding K, Williams O, Willis M, et al. Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis. JAMA Neurol 2019; 76: 536–541.
- 40Cree BA, Gourraud PA, Oksenberg JR, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol 2016; 80: 499–510.
- 41Martinez-Lapiscina EH, Arnow S, Wilson JA, et al. Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study. Lancet Neurol 2016; 15: 574–584.
- 42Rothman A, Murphy OC, Fitzgerald KC, et al. Retinal measurements predict 10-year disability in multiple sclerosis. Ann Clin Transl Neurol 2019; 6: 222–232.
- 43Minneboo A, Uitdehaag BM, Jongen P, et al. Association between MRI parameters and the MS severity scale: a 12 year follow-up study. Mult Scler 2009; 15: 632–637.
- 44Saidha S, Al-Louzi O, Ratchford JN, et al. Optical coherence tomography reflects brain atrophy in multiple sclerosis: a four-year study. Ann Neurol 2015; 78: 801–813.
- 45Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–399.
- 46Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–285.
- 47Brownlee WJ, Altmann DR, Prados F, et al. Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis. Brain 2019; 142: 2276–2287.
- 48Goodin DS, Traboulsee A, Knappertz V, et al. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83: 282–287.
- 49Filippi M, Wolinsky JS, Sormani MP, et al. Enhancement frequency decreases with increasing age in relapsing-remitting multiple sclerosis. Neurology 2001; 56: 422–423.
- 50Brown RA, Narayanan S, Arnold DL. Imaging of repeated episodes of demyelination and remyelination in multiple sclerosis. Neuroimage Clin 2014; 6: 20–25.
- 51Ghassemi R, Brown R, Narayanan S, et al. Arnold DL. Normalization of white matter intensity on T1-weighted images of patients with acquired central nervous system demyelination. J Neuroimag 2015; 25: 184–190.
- 52Ghassemi R, Brown R, Banwell B, et al. Quantitative measurement of tissue damage and recovery within new T2w lesions in pediatric- and adult-onset multiple sclerosis. Mult Scler 2015; 21: 718–725.
- 53Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14: 183–193.
- 54Caggiula M, Batocchi AP, Frisullo G, et al. Neurotrophic factors and clinical recovery in relapsing-remitting multiple sclerosis. Scand J Immunol 2005; 62: 176–182.
- 55Steinman L. Immunology of relapse and remission in multiple sclerosis. Annu Rev Immunol 2014; 32: 257–281.
- 56Rotstein DL, Healy BC, Malik MT, et al. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol 2015; 72: 152–158.
Citing Literature
