Enhancing Mood, Cognition, and Quality of Life in Pediatric Multiple Sclerosis

Springer Science and Business Media LLC - Tập 23 - Trang 317-329 - 2021
Cristina Fernandez-Carbonell1, Leigh E. Charvet2, Lauren B. Krupp2
1Cohen’s Children Medical Center, Northwell Health, New York, USA
2NYU Langone Pediatric Multiple Sclerosis Center, New York, USA

Tóm tắt

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease.

Tài liệu tham khảo

Ghezzi A, Deplano V, Faroni J, Grasso MG, Liguori M, Marrosu G, et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler. 1997;3(1):43–6. Boiko A, Vorobeychik G, Paty D, Devonshire V, Sadovnick D, University of British Columbia MSCN. Early onset multiple sclerosis: a longitudinal study. Neurology. 2002;59(7):1006–10. Chitnis T, Glanz B, Jaffin S, Healy B. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult Scler. 2009;15(5):627–31. Harding KE, Liang K, Cossburn MD, Ingram G, Hirst CL, Pickersgill TP, et al. Long-term outcome of paediatric-onset multiple sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2013;84(2):141–7. Benson LA, Healy BC, Gorman MP, Baruch NF, Gholipour T, Musallam A, et al. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years. Mult Scler Relat Disord. 2014;3(2):186–93. Verhey LH, Shroff M, Banwell B. Pediatric multiple sclerosis: pathobiological, clinical, and magnetic resonance imaging features. Neuroimaging Clin N Am. 2013;23(2):227–43. Chitnis T, Aaen G, Belman A, Benson L, Gorman M, Goyal MS, et al. Improved relapse recovery in paediatric compared to adult multiple sclerosis. Brain. 2020;143(9):2733–41. McKay KA, Hillert J, Manouchehrinia A. Long-term disability progression of pediatric-onset multiple sclerosis. Neurology. 2019;92(24):e2764–73. Charvet LE, O’Donnell EH, Belman AL, Chitnis T, Ness JM, Parrish J, et al. Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network. Mult Scler. 2014;20(11):1502–10. Waubant E, Banwell B, Wassmer E, Sormani MP, Amato MP, Hintzen R, et al. Clinical trials of disease-modifying agents in pediatric MS: opportunities, challenges, and recommendations from the IPMSSG. Neurology. 2019;92(22):e2538–49. Chitnis T, Arnold DL, Banwell B, Bruck W, Ghezzi A, Giovannoni G, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. 2018;379(11):1017–27. Deiva K. Pediatric onset multiple sclerosis. Revue Neurologique. 2020;176(1–2):30–6. Banwell B, Bar-Or A, Arnold DL, Sadovnick D, Narayanan S, McGowan M, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol. 2011;10(5):436–45. Salzer J, Hallmans G, Nystrom M, Stenlund H, Wadell G, Sundstrom P. Vitamin D as a protective factor in multiple sclerosis. Neurology. 2012;79(21):2140–5. Steinberg SC, Faris RJ, Chang CF, Chan A, Tankersley MA. Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study. Clin Drug Investig. 2010;30(2):89–100. Fraser C, Hadjimichael O, Vollmer T. Predictors of adherence to glatiramer acetate therapy in individuals with self-reported progressive forms of multiple sclerosis. J Neurosci Nurs. 2003;35(3):163–70. Thannhauser JE, Mah JK, Metz LM. Adherence of adolescents to multiple sclerosis disease-modifying therapy. Pediatr Neurol. 2009;41(2):119–23. Giovannoni G, Southam E, Waubant E. Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler. 2012;18(7):932–46. Halpern R, Agarwal S, Borton L, Oneacre K, Lopez-Bresnahan MV. Adherence and persistence among multiple sclerosis patients after one immunomodulatory therapy failure: retrospective claims analysis. Adv Ther. 2011;28(9):761–75. Costello K, Kennedy P, Scanzillo J. Recognizing nonadherence in patients with multiple sclerosis and maintaining treatment adherence in the long term. Medscape J Med. 2008;10(9):225. Yeh EA, Grover SA, Powell VE, Alper G, Banwell BL, Edwards K, et al. Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial. Qual Life Res. 2017;26(9):2333–49. Gianfrancesco MA, Stridh P, Rhead B, Shao X, Xu E, Graves JS, et al. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017;88(17):1623–9. Duan S, Lv Z, Fan X, Wang L, Han F, Wang H, et al. Vitamin D status and the risk of multiple sclerosis: a systematic review and meta-analysis. Neurosci Lett. 2014;570:108–13. Brenton JN, Koenig S, Goldman MD. Vitamin D status and age of onset of demyelinating disease. Mult Scler Relat Disord. 2014;3(6):684–8. Ueda P, Rafatnia F, Baarnhielm M, Frobom R, Korzunowicz G, Lonnerbro R, et al. Neonatal vitamin D status and risk of multiple sclerosis. Ann Neurol. 2014;76(3):338–46. Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67(5):618–24. Graves JS, Barcellos LF, Shao X, Noble J, Mowry EM, Quach H, et al. Genetic predictors of relapse rate in pediatric MS. Mult Scler. 2016;22(12):1528–35. Graves JS, Barcellos LF, Krupp L, Belman A, Shao X, Quach H, et al. Vitamin D genes influence MS relapses in children. Mult Scler. 2019;26:894–901. Soilu-Hanninen M, Aivo J, Lindstrom BM, Elovaara I, Sumelahti ML, Farkkila M, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(5):565–71. Aivo J, Lindsrom BM, Soilu-Hanninen M. A randomised, double-blind, placebo-controlled trial with vitamin D3 in MS: subgroup analysis of patients with baseline disease activity despite interferon treatment. Mult Scler Int. 2012;2012:802796. Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest. 2011;40(6):627–39. Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects of adjunct low-dose vitamin d on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int. 2012;2012:452541. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518–22. Farez MF. Salt intake in multiple sclerosis: friend or foe? J Neurol Neurosurg Psychiatry. 2016;87(12):1276. Cortese M, Yuan C, Chitnis T, Ascherio A, Munger KL. No association between dietary sodium intake and the risk of multiple sclerosis. Neurology. 2017;89(13):1322–9. Azary S, Schreiner T, Graves J, Waldman A, Belman A, Guttman BW, et al. Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry. 2018;89(1):28–33. Pakpoor J, Seminatore B, Graves JS, Schreiner T, Waldman AT, Lotze TE, et al. Dietary factors and pediatric multiple sclerosis: a case-control study. Mult Scler. 2017;24:1067–76. McDonald J, Graves J, Waldman A, Lotze T, Schreiner T, Belman A, et al. A case-control study of dietary salt intake in pediatric-onset multiple sclerosis. Mult Scler Relat Disord. 2016;6:87–92. Nourbakhsh B, Graves J, Casper TC, Lulu S, Waldman A, Belman A, et al. Dietary salt intake and time to relapse in paediatric multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(12):1350–3. Evans E, Piccio L, Cross AH. Use of vitamins and dietary supplements by patients with multiple sclerosis: a review. JAMA Neurol. 2018;75:1013. Sedel F, Papeix C, Bellanger A, Touitou V, Lebrun-Frenay C, Galanaud D, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4(2):159–69. Tourbah A, Lebrun-Frenay C, Edan G, Clanet M, Papeix C, Vukusic S, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: a randomised, double-blind, placebo-controlled study. Mult Scler. 2016;22(13):1719–31. Cree BAC, Cutter G, Wolinsky JS, Freedman MS, Comi G, Giovannoni G, et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020;19(12):988–97. Chaudhary P, Marracci GH, Bourdette DN. Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2006;175(1–2):87–96. Yadav V, Marracci G, Lovera J, Woodward W, Bogardus K, Marquardt W, et al. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005;11(2):159–65. Spain R, Powers K, Murchison C, Heriza E, Winges K, Yadav V, et al. Lipoic acid in secondary progressive MS: a randomized controlled pilot trial. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e374. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–73. Leocani L, Nuara A, Houdayer E, Schiavetti I, Del Carro U, Amadio S, et al. Sativex ((R)) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol. 2015;262(11):2520–7. Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(17):1556–63. Brook JS, Lee JY, Brook DW. Trajectories of marijuana use beginning in adolescence predict tobacco dependence in adulthood. Subst Abus. 2015;36(4):470–7. Feinstein A, Meza C, Stefan C, Staines WR. Discontinuing cannabis improves depression in people with multiple sclerosis: a short report. Mult Scler. 2021;27(4):636–9. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology. 2013;80(6):548–52. Chitnis T, Graves J, Weinstock-Guttman B, Belman A, Olsen C, Misra M, et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol. 2016;3(12):897–907. Brenton JN, Woolbright E, Briscoe-Abath C, Qureshi A, Conaway M, Goldman MD. Body mass index trajectories in pediatric multiple sclerosis. Dev Med Child Neurol. 2019;61(11):1289–94. Riccio P, Rossano R, Larocca M, Trotta V, Mennella I, Vitaglione P, et al. Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: a pilot study. Exp Biol Med (Maywood). 2016;241(6):620–35. Yadav V, Marracci G, Kim E, Spain R, Cameron M, Overs S, et al. Low-fat, plant-based diet in multiple sclerosis: a randomized controlled trial. Mult Scler Relat Disord. 2016;9:80–90. Hempel S, Graham GD, Fu N, Estrada E, Chen AY, Miake-Lye I, et al. A systematic review of modifiable risk factors in the progression of multiple sclerosis. Mult Scler. 2017;23(4):525–33. Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G, Ramagopalan SV. Smoking and multiple sclerosis: an updated meta-analysis. PLoS ONE. 2011;6(1):e16149. Hawkes CH. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler. 2007;13(5):610–5. Holt PG. Immune and inflammatory function in cigarette smokers. Thorax. 1987;42(4):241–9. Makrygiannakis D, Hermansson M, Ulfgren AK, Nicholas AP, Zendman AJ, Eklund A, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008;67(10):1488–92. O’Gorman C, Lucas R, Taylor B. Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms. Int J Mol Sci. 2012;13(9):11718–52. Morabia A, Bernstein MS, Antonini S. Smoking, dietary calcium and vitamin D deficiency in women: a population-based study. Eur J Clin Nutr. 2000;54(9):684–9. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Vitamin D deficiency in postmenopausal, healthy women predicts increased cardiovascular events: a 16-year follow-up study. Eur J Endocrinol. 2012;167(4):553–60. Hernan MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol. 2001;154(1):69–74. Ramanujam R, Hedstrom AK, Manouchehrinia A, Alfredsson L, Olsson T, Bottai M, et al. Effect of smoking cessation on multiple sclerosis prognosis. JAMA Neurol. 2015;72(10):1117–23. Manouchehrinia A, Tench CR, Maxted J, Bibani RH, Britton J, Constantinescu CS. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain. 2013;136(Pt 7):2298–304. Poorolajal J, Bahrami M, Karami M, Hooshmand E. Effect of smoking on multiple sclerosis: a meta-analysis. J Public Health (Oxf). 2017;39(2):312–20. Mikaeloff Y, Caridade G, Tardieu M, Suissa S, group Ks. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain. 2007;130(10):2589–95. Lavery AM, Collins BN, Waldman AT, Hart CN, Bar-Or A, Marrie RA, et al. The contribution of second hand tobacco smoke exposure to pediatric multiple sclerosis risk. Mult Scler. 2019;25(4):515–22. Schulz D, Kopp B, Kunkel A, Faiss JH. Cognition in the early stage of multiple sclerosis. J Neurol. 2006;253(8):1002–10. Amato MP, Krupp LB, Charvet LE, Penner I, Till C. Pediatric multiple sclerosis: cognition and mood. Neurology. 2016;87(9 Suppl 2):S82–7. Julian L, Serafin D, Charvet L, Ackerson J, Benedict R, Braaten E, et al. Cognitive impairment occurs in children and adolescents with multiple sclerosis: results from a United States network. J Child Neurol. 2013;28(1):102–7. Wallach AI, Waltz M, Casper TC, Aaen G, Belman A, Benson L, et al. Cognitive processing speed in pediatric-onset multiple sclerosis: baseline characteristics of impairment and prediction of decline. Mult Scler. 2019;26:1938–47. Amato MP, Goretti B, Ghezzi A, Lori S, Zipoli V, Moiola L, et al. Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up. Neurology. 2010;75(13):1134–40. Amato MP, Goretti B, Ghezzi A, Hakiki B, Niccolai C, Lori S, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology. 2014;83(16):1432–8. Till C, Ghassemi R, Aubert-Broche B, Kerbrat A, Collins DL, Narayanan S, et al. MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. Neuropsychology. 2011;25(3):319–32. MacAllister WS, Christodoulou C, Troxell R, Milazzo M, Block P, Preston TE, et al. Fatigue and quality of life in pediatric multiple sclerosis. Mult Scler. 2009;15(12):1502–8. Weisbrot D, Charvet L, Serafin D, Milazzo M, Preston T, Cleary R, et al. Psychiatric diagnoses and cognitive impairment in pediatric multiple sclerosis. Mult Scler. 2014;20(5):588–93. Aaen G, Waltz M, Vargas W, Makhani N, Ness J, Harris Y, et al. Acquisition of early developmental milestones and need for special education services in pediatric multiple sclerosis. J Child Neurol. 2018;34:148–52. Mikaeloff Y, Caridade G, Billard C, Bouyer J, Tardieu M. School performance in a cohort of children with CNS inflammatory demyelination. Eur J Paediatr Neurol. 2010;14(5):418–24. Goretti B, Portaccio E, Ghezzi A, Lori S, Moiola L, Falautano M, et al. Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis. Mult Scler. 2012;18(3):329–34. Johnen A, Elpers C, Riepl E, Landmeyer NC, Kramer J, Polzer P, et al. Early effective treatment may protect from cognitive decline in paediatric multiple sclerosis. Eur J Paediatr Neurol. 2019;23(6):783–91. Margoni M, Rinaldi F, Riccardi A, Franciotta S, Perini P, Gallo P. No evidence of disease activity including cognition (NEDA-3 plus) in naive pediatric multiple sclerosis patients treated with natalizumab. J Neurol. 2019;267:100–5. Krupp BB, Chitnis T, Deiva K, Gärtner J, Ghezzi A, Huppke P, Waubant E, Pearce GL, Stites T, K-Laflamme A, Karan R. Fingolimod treatment improved quality of life in paediatric patients with multiple sclerosis: PARADIGMS study. Mult Scler. 2018;24:518. Kampman MT, Steffensen LH, Mellgren SI, Jorgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler. 2012;18(8):1144–51. Achiron A, Givon U, Magalashvili D, Dolev M, Liraz Zaltzman S, Kalron A, et al. Effect of Alfacalcidol on multiple sclerosis-related fatigue: a randomized, double-blind placebo-controlled study. Mult Scler. 2015;21(6):767–75. Ashtari F, Toghianifar N, Zarkesh-Esfahani SH, Mansourian M. High dose Vitamin D intake and quality of life in relapsing-remitting multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Neurol Res. 2016;38(10):888–92. Rolf L, Muris AH, Bol Y, Damoiseaux J, Smolders J, Hupperts R. Vitamin D3 supplementation in multiple sclerosis: symptoms and biomarkers of depression. J Neurol Sci. 2017;378:30–5. Weinstock-Guttman B, Baier M, Park Y, Feichter J, Lee-Kwen P, Gallagher E, et al. Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids. 2005;73(5):397–404. Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 2016;15(10):2136–46. Friedman DB, Becofsky K, Anderson LA, Bryant LL, Hunter RH, Ivey SL, et al. Public perceptions about risk and protective factors for cognitive health and impairment: a review of the literature. Int Psychogeriatr. 2015;27(8):1263–75. Fitzgerald KC, Tyry T, Salter A, Cofield SS, Cutter G, Fox R, et al. Diet quality is associated with disability and symptom severity in multiple sclerosis. Neurology. 2018;90(1):e1–11. Amato MP, Goretti B, Viterbo RG, Portaccio E, Niccolai C, Hakiki B, et al. Computer-assisted rehabilitation of attention in patients with multiple sclerosis: results of a randomized, double-blind trial. Mult Scler. 2014;20(1):91–8. Rosti-Otajarvi EM, Hamalainen PI. Neuropsychological rehabilitation for multiple sclerosis. Cochrane Database Syst Rev. 2014;2:CD009131. Chiaravalloti ND, Moore NB, Nikelshpur OM, DeLuca J. An RCT to treat learning impairment in multiple sclerosis: the MEMREHAB trial. Neurology. 2013;81(24):2066–72. Filippi M, Riccitelli G, Mattioli F, Capra R, Stampatori C, Pagani E, et al. Multiple sclerosis: effects of cognitive rehabilitation on structural and functional MR imaging measures–an explorative study. Radiology. 2012;262(3):932–40. Sastre-Garriga J, Alonso J, Renom M, Arevalo MJ, Gonzalez I, Galan I, et al. A functional magnetic resonance proof of concept pilot trial of cognitive rehabilitation in multiple sclerosis. Mult Scler. 2011;17(4):457–67. Goverover Y, Chiaravalloti ND, O’Brien AR, DeLuca J. Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007 to 2016. Arch Phys Med Rehabil. 2018;99(2):390–407. Cerasa A, Gioia MC, Valentino P, Nistico R, Chiriaco C, Pirritano D, et al. Computer-assisted cognitive rehabilitation of attention deficits for multiple sclerosis: a randomized trial with fMRI correlates. Neurorehabil Neural Repair. 2013;27(4):284–95. Thaut MH, Peterson DA, McIntosh GC, Hoemberg V. Music mnemonics aid verbal memory and induce learning—related brain plasticity in multiple sclerosis. Front Hum Neurosci. 2014;8:395. Sigmundsdottir L, Longley WA, Tate RL. Computerised cognitive training in acquired brain injury: a systematic review of outcomes using the International Classification of Functioning (ICF). Neuropsychol Rehabil. 2016;26(5–6):673–741. Charvet LE, Yang J, Shaw MT, Sherman K, Haider L, Xu J, et al. Cognitive function in multiple sclerosis improves with telerehabilitation: results from a randomized controlled trial. PLoS ONE. 2017;12(5):e0177177. Grover SA, Aubert-Broche B, Fetco D, Collins DL, Arnold DL, Finlayson M, et al. Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis. Neurology. 2015;85(19):1663–9. Grover SA, Sawicki CP, Kinnett-Hopkins D, Finlayson M, Schneiderman JE, Banwell B, et al. Physical activity and its correlates in youth with multiple sclerosis. J Pediatr. 2016;179:197-203 e2. Stephens S, Shams S, Lee J, Grover SA, Longoni G, Berenbaum T, et al. Benefits of physical activity for depression and fatigue in multiple sclerosis: a longitudinal analysis. J Pediatr. 2019;209:226-32 e2. Sikes EM, Richardson EV, Motl RW. A qualitative study of exercise and physical activity in adolescents with pediatric-onset multiple sclerosis. Int J MS Care. 2019;21(2):81–91. Rocca MA, Filippi M, Deiva K. Promoting physical activity to control multiple sclerosis from childhood. Neurology. 2015;85(19):1644–5. Langeskov-Christensen M, Bisson EJ, Finlayson ML, Dalgas U. Potential pathophysiological pathways that can explain the positive effects of exercise on fatigue in multiple sclerosis: a scoping review. J Neurol Sci. 2017;373:307–20. Heine M, van de Port I, Rietberg MB, van Wegen EE, Kwakkel G. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2015;9:CD009956. Cruickshank TM, Reyes AR, Ziman MR. A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease. Medicine (Baltimore). 2015;94(4):e411. Latimer-Cheung AE, Pilutti LA, Hicks AL, Martin Ginis KA, Fenuta AM, MacKibbon KA, et al. Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. Arch Phys Med Rehabil. 2013;94(9):1800 e3-1828. Andreasen AK, Stenager E, Dalgas U. The effect of exercise therapy on fatigue in multiple sclerosis. Mult Scler. 2011;17(9):1041–54. Motl RW, Gosney JL. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Mult Scler. 2008;14(1):129–35. Kjolhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training: a systematic review. Mult Scler. 2012;18(9):1215–28. Sa MJ. Exercise therapy and multiple sclerosis: a systematic review. J Neurol. 2014;261(9):1651–61. Ensari I, Motl RW, Pilutti LA. Exercise training improves depressive symptoms in people with multiple sclerosis: results of a meta-analysis. J Psychosom Res. 2014;76(6):465–71. Morrison JD, Mayer L. Physical activity and cognitive function in adults with multiple sclerosis: an integrative review. Disabil Rehabil. 2017;39(19):1909–20. Sandroff BM, Motl RW, Scudder MR, DeLuca J. Systematic, evidence-based review of exercise, physical activity, and physical fitness effects on cognition in persons with multiple sclerosis. Neuropsychol Rev. 2016;26(3):271–94. Veauthier C, Gaede G, Radbruch H, Wernecke KD, Paul F. Sleep disorders reduce health-related quality of life in multiple sclerosis (Nottingham health profile data in patients with multiple sclerosis). Int J Mol Sci. 2015;16(7):16514–28. Sarraf P, Azizi S, Moghaddasi AN, Sahraian MA, Tafakhori A, Ghajarzadeh M. Relationship between sleep quality and quality of life in patients with multiple sclerosis. Int J Prev Med. 2014;5(12):1582–6. Veauthier C, Radbruch H, Gaede G, Pfueller CF, Dorr J, Bellmann-Strobl J, et al. Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult Scler. 2011;17(5):613–22. Edwards KA, Molton IR, Smith AE, Ehde DM, Bombardier CH, Battalio SL, et al. Relative importance of baseline pain, fatigue, sleep, and physical activity: predicting change in depression in adults with multiple sclerosis. Arch Phys Med Rehabil. 2016;97(8):1309–15. Ghajarzadeh M, Sahraian MA, Fateh R, Daneshmand A. Fatigue, depression and sleep disturbances in Iranian patients with multiple sclerosis. Acta Med Iran. 2012;50(4):244–9. Veauthier C, Gaede G, Radbruch H, Gottschalk S, Wernecke KD, Paul F. Treatment of sleep disorders may improve fatigue in multiple sclerosis. Clin Neurol Neurosurg. 2013;115(9):1826–30. Cote I, Trojan DA, Kaminska M, Cardoso M, Benedetti A, Weiss D, et al. Impact of sleep disorder treatment on fatigue in multiple sclerosis. Mult Scler. 2013;19(4):480–9. Hughes AJ, Turner AP, Alschuler KN, Atkins DC, Beier M, Amtmann D, et al. Association between sleep problems and perceived cognitive dysfunction over 12 months in individuals with multiple sclerosis. Behav Sleep Med. 2018;16(1):79–91. van Geest Q, Westerik B, van der Werf YD, Geurts JJ, Hulst HE. The role of sleep on cognition and functional connectivity in patients with multiple sclerosis. J Neurol. 2017;264(1):72–80. Zafar AB, Ness J, Dowdy S, Avis K, Bashir K. Examining sleep, fatigue, and daytime sleepiness in pediatric multiple sclerosis patients. Mult Scler. 2012;18(4):481–8. Storm Van’s Gravesande K, Blaschek A, Calabrese P, Rostasy K, Huppke P, Kessler JJ, et al. Fatigue and depression predict health-related quality of life in patients with pediatric-onset multiple sclerosis. Mult Scler Relat Disord. 2019;36:101368. Storm Van’s Gravesande K, Calabrese P, Blaschek A, Rostasy K, Huppke P, Rothe L, et al. The Multiple Sclerosis Inventory of Cognition for Adolescents (MUSICADO): a brief screening instrument to assess cognitive dysfunction, fatigue and loss of health-related quality of life in pediatric-onset multiple sclerosis. Eur J Paediatr Neurol. 2019;23(6):792–800. van Kessel K, Moss-Morris R, Willoughby E, Chalder T, Johnson MH, Robinson E. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008;70(2):205–13. Mohr DC, Hart SL, Goldberg A. Effects of treatment for depression on fatigue in multiple sclerosis. Psychosom Med. 2003;65(4):542–7. Veauthier C, Hasselmann H, Gold SM, Paul F. The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue. EPMA J. 2016;7:25. Florea A, Maurey H, Le Sauter M, Bellesme C, Sevin C, Deiva K. Fatigue, depression, and quality of life in children with multiple sclerosis: a comparative study with other demyelinating diseases. Dev Med Child Neurol. 2019;62:241–4. Hebert D, Geisthardt C, Hoffman H. Insights and recommendations from parents receiving a diagnosis of pediatric multiple sclerosis for their child. J Child Neurol. 2019;34(8):464–71. Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses. 1986;21(2):193–200.