Presentation-Paediatric onset multiple sclerpsis

Paediatric onset multiple sclerosis Melinda Magyari

Abstract Pediatric onset multiple sclerosis (POMS) provides specific diagnostic challenges for the neurologist, with an early and accurate diagnosis crucial to the long-term prognosis of the patient. POMS must first be differentiated from other similar yet distinct demyelinating diseases, and then an effective treatment must be initiated in a timely manner to achieve maximum benefit for the patient.

In this ParadigMS Foundation presentation, Professor Melinda Magyari shares her experiences on the diagnosis and treatment of POMS patients. She also provides an overview the clinical trial landscape to assess and develop treatments for this patient cohort. This workshop is yet another excellent educational resource from ParadigMS, designed for neurologists aiming to further their knowledge and skill in relation to the diagnosis, care and management of pediatric MS patients.

Pediatric-onset multiple sclerosis (POMS) Multiple Sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS, commonly diagnosed in young adults, but can also affect children Clinical onset before the age of 18 (16) years Incidence of 0.5 and 1.66 /100 000 children.

Between 3 and 10% of MS >16 years and < 1% under 10 years of age Focal or multifocal acute demyelinating presentation CNS: central nervous system

Clinical presentation of POMS Female to male ratio 1:1 in prepubertal presentation, increasing to 2:1 post-puberty Common symptoms are sensory, cerebellar, visual (ON), brainstem, pyramidal More frequent polyfocal presentation at onset 70% The 2017 McDonald criteria have good specificity of 95% and sensitivity of 71%.

Waldman A, et al. Neurology. 2016 Aug 30;87(9 Suppl 2):S74-81; Yeh EA, et al. Nat Rev Neurol.2009;5(11):621–31; Reinhardt K, et al. Eur J Neurol. 2014 Apr;21(4):654-9; Boesen MS, et al.

Mult Scler. 2018 Jul;24(8):1077-1086

ON: optic neuritis; POMS: pediatric-onset multiple sclerosis

Aspects of POMS compared with the adult form Relapsing remitting onset with high relapse rate (98%), rarely progressive onset Frequent brainstem/cerebellar involvement and acute polysymptomatic/ADEM-like onset Better remission after first clinical event The pattern of MRI has some peculiar aspects in pediatric MS MRI lesions more pronounced inflammatory pattern and enhanced capability to recover CSF oligoclonal bands are less frequent in POMS Early with cognitive and behavioral deficits Disability milestones are reached after a longer interval, but at a lower age compared to adults Ghezzi A, et al. Mult Scler Demyelinating Disord. 2, 5 (2017). https://doi.org/10.1186/s40893-017-0022-6 ; Renoux C, et al. N Engl J Med. 2007 Jun 21;356(25):2603-13; Gorman MP, et al. Arch Neurol. 2009 Jan;66(1):54-9; Amato MP, et al. Neurology. 2014 Oct 14;83(16):1432-8

ADEM: acute disseminated encephalomyelitis; MRI: magnetic resonance imaging; POMS: paediatric-onset multiple sclerosis

Diagnosis of CIS and MS in children Pediatric CIS, all of the following is required

Evidence of dissemination of CNS inflammatory activity distributed in more than one CNS location (dissemination in space; DIS) and over time (dissemination in time; DIT)

• A monofocal or polyfocal, clinical CNS event with presumed inflammatory demyelinating cause

Exclusion of MS mimics, particularly antibody mediated demyelinating diseases, infections, leukodystrodystrophies, inflammatory vasculopathies

• No encephalopathy (i.e. no alteration in consciousness or behavior) that cannot be explained by fever

• Absence of a prior clinical history of CNS demyelination

• The diagnosis of MS based on baseline MRI features are not met CIS: clinically isolated syndrome; CNS: central nervous system; MRI: magnetic resonance imaging Thompson AJ, et al. Lancet Neurol. 2018 Feb;17(2):162-173; Alroughani R, Boyko A. BMC Neurol. 2018 Mar 9;18(1):27. doi: 10.1186/s12883-018-1026-3

Diagnostic criteria for pediatric MS One of the following is required • ≥ 2 clinical CNS events (non-encephalopathic),with presumed inflammatory cause, separated by > 30 days and involving more than one CNS area • One typical MS episode associated with MRI findings consistent with 2010 McDonald criteria for DIS and in a follow-up MRI with ≥ 1 new enhancing or non-enhancing lesion consistent with DIT • One ADEM attack followed by a non-encephalopathic clinical event, ≥ 3months after onset, that is associated with new MRI lesions that fulfill 2010 Revised McDonald DIS criteria.

• A first, single, acute event (e.g. a CIS) not meeting ADEM criteria and MRI findings are consistent with the 2010 McDonald Criteria for DIS and DIT (applied only to children ≥12 years old) The presence of CSF specific oligoclonal bands can substitute for radiological evidence of DIT ADEM: acute disseminated encephalomyelitis; CIS: clinically isolated syndrome; CNS: central nervous system; CSF: cerebrospinal fluid; DIS: dissemination in space; DIT: dissemination in time; MRI: magnetic resonance imaging Krupp LB, et al. Mult Scler. 2013 Sep;19(10):1261-7; Alroughani R, Boyko A. BMC Neurol. 2018 Mar 9;18(1):27. doi: 10.1186/s12883-018-1026-3

Diagnostic challenges in children A first demyelinating event may represent another acquired demyelinating syndrome Exclude both inflammatory / non-inflammatory mimics including NMOSD and MOGAD Cortical lesions, central vein sign, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. Acute disseminated encephalomyelitis (ADEM) typically monophasic Some children can have recurrent clinical episodes or MRI evidence of new lesions AQP: aquaporin; MOGAD: myelin oligodendrocyte glycoprotein antibody disease; MRI: magnetic resonance imaging; NMOSD: neuromyelitis optica spectrum disorder; RRMS: relapsing-remitting MS Alroughani R, Boyko A. BMC Neurol. 2018 Mar 9;18(1):27. doi: 10.1186/s12883-018-1026-3 Cortese R, et al. Neurology. 2023 Jan 17;100(3):e308-e323

Different acquired demyelinating syndrome presentations

ADEM acute disseminated encephalomyelitis, AQP4-NMOSD aquaporin-4 neuromyelitis optica spectrum disorder, CSF cerebrospinal fluid, F:M female:male, LETM longitudinal extensive transverse myelitis, MOGAD myelin oligodendrocyte glycoprotein antibody spectrum disorder, MS multiple sclerosis, OCB oligoclonal bands, ON optic neuritis, POMS pediatric-onset multiple sclerosis Jakimovski D, et al. CNS Drugs. 2022 Jan;36(1):45-59

MS Typical MS-based hyperintensities within the periventricular region, juxtacortical region, and in the cerebellum Neuromyelitis optica spectrum disease (NMOSD) Longitudinal extensive transverse myelitis involving the brainstem and extend over the entire cervical portion of the spinal cord

MOGAD Bilateral optic neuritis, optic nerve edema, contrast enhancement Cervical spinal cord lesion spanning over 2.5 vertebral levels

ADEM Multiple, diffuse, ‘fluffy,’ poorly defined T2 hyperintense lesions involving both grey and white matter in supra- and infratentorial region ADEM acute disseminated encephalomyelitis; MOGAD myelin oligodendrocyte glycoprotein antibody spectrum disorder Jakimovski D, et al. CNS Drugs. 2022 Jan;36(1):45-59

Treatment of MS in children Management of relapses • i.v. methylprednisolone, 20mg/kg/day to 30mg/kg/day (maximum 1g) for 3 to 5 days • Oral methylprednisolone at a dose of 500 mg for 5 days

Disease-modifying therapy Treatment goal • reduce relapses • disability progression, •

accrual of new MRI lesions

• no evidence of disease activity /NEDA

DMT approved for adult MS are applied in POMS Evidence on effectiveness and safety from observational studies

Le Page E, et al. Lancet. 2015 Sep 5;386(9997):974-81

DMT: disease-modifying therapy; MRI: magnetic resonance imaging; NEDA: no evidence of disease activity; POMS: pediatric onset MS Ziemssen T, et al. J Neurol. 2016 Jun;263(6):1053-65; Bevan CJ, Cree BA. JAMA Neurol. 2014 Mar;71(3):269-70

Recommendations for DMT in POMS

International Pediatric Multiple Sclerosis Study Group Prompt initiation of a first-line DMT with moderate efficacy • Relapse rate is high in initial phases and correlated with a poor prognosis • Brain tissue shows more active inflammation in childhood • Despite the apparent clinical recovery from relapses due to better neuronal plasticity, cognitive impairment is frequent • Postponing treatment may have a negative impact on social activities and school performance

Heterogeneities across Europe concerning treatment DMT: disease-modifying therapy; POMS: pediatric onset MS Chitnis T, et al. Mult Scler. 2012 Jan;18(1):116-27

First line therapy with DMT with moderate efficacy

Safety and efficacy of teriflunomide in pediatric MS (TERIKIDS)

• The IPMSSG guidelines recommend early initiation of DMTs with either an INTERFERON- β or GLATIRAMER ACETATE based on evidence from open-label multi-center studies • TERIFLUNOMIDE approved by EMA indication in pediatric patients aged ≥ 10 years in 2021, but not recommended in some countries

DMT: disease-modifying therapy; EMA: European Medicines Agency; IPMSSG: International Pediatric Multiple Sclerosis Study Group; Chitnis T, et al. Mult Scler. 2012 Jan;18(1):116-27; Banwell B, et al. Neurology. 2006 Feb 28;66(4):472-6; Tenembaum SN, J Child Neurol. 2013 Jul;28(7):849-56

Second line DMT with high efficacy • PARADIGMS study with FINGOLIMOD was associated with a lower rate of relapse and reduced accumulation of lesions on MRI over a 2-year period versus IFN beta-1a • In 2018, the FDA and the EMA approved the indication of fingolimod in children with relapsing MS Chitnis T, Arnold DL, Banwell B, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiplesclerosis.N Engl J Med2018 DMT: disease-modifying therapy; EMA: European Medicines Agency; FDA: Food and Drug Administration Chitnis T, et al. N Engl J Med. 2018 Sep 13;379(11):1017-1027

Evidence from observational studies Natalizumab A large real-world NATALIZUMAB study 101 patients with POMS 45 treatment naive, 67 switched from first line injectables, 7 from immunosuppressants Significant reduction of ARR from 2.3 to 0.1 during the follow op mean of 3 years Free of any clinical or MRI activity 58% No significant occurrences of AEs The pharmacokinetic/pharmacodynamic properties and the real-world efficacy/safety data are similar to those in adults AE: adverse event; ARR: annualized relapse rate; MRI: magnetic resonance imaging; POMS: pediatric onset multiple sclerosis Ghezzi A, et al. BMC Neurol. 2015 Sep 25;15:174. doi: 10.1186/s12883-015-0433-y; Alroughani R, et al. Pediatr Neurol. 2017 May;70:56-60.

Experience with Rituximab from observational studies US POMS cohort In 56 patients 62% reduction in relapses when compared with first-line injectables SWEDISH POMS cohort 14 patients, median period of 23.6 months; stable disease was observed in 13/14 patients (93%) Side effects were similar with infusion-related reactions being the most common, followed by rashes and fever

POMS: pediatric onset multiple sclerosis Krysko KM, et al. Ann Neurol. 2020;88(1):42–55; Salzer J, et al. J Neurol. 2016 Feb;263(2):322-326

Experience with B cell depleting DMT Rituximab

Ocrelizumab

US - 56 POMS

TURKISH-Istambul POMS

62% reduction in relapses when compared with first-line injectables

Mean age at Ocrelizumab initiation 16.1 (±1.3)

SWEDISH POMS cohort- 14 patients,

Median follow-up 24 m Decrease in ARR

Median period of 23.6 months; stable disease was observed in 13/14 patients (93%) Side effects were similar with infusion-induced reactions being the most common, followed by rashes and fewer ARR: annualized relapse rate; DMT: disease-modifying therapy; POMS: pediatric onset multiple sclerosis Krysko KM, et al. Ann Neurol. 2020;88(1):42–55; Salzer J, et al. J Neurol. 2016 Feb;263(2):322-326

Ongoing clinical trials with high efficacy DMT A Study To Evaluate Safety And Efficacy Of Ocrelizumab In Comparison With Fingolimod In Children And Adolescents With RelapsingRemitting Multiple Sclerosis (Operetta 2) 2022-2025 233 participants (10-17 years)

A Study of Ocrelizumab in Children and Adolescents With Relapsing-Remitting Multiple Sclerosis 2020-2027 Non-randomized Open label Clinical Trial Estimated Enrollment : 36 participants

Annualized relapse rate (primary)

Outcome measures Serum Concentration of Ocrelizumab during treatment according to bodyweight

N of new or enlarging T2- lesions

Levels of CD19+ B-cell Count in Blood

N of T1 Gd lesions

Developmental Milestones

Outcome measures

Incidence and severity of adverse events

Adverse events

Considerations on future treatment of POMS The rapidly evolving DMT landscape presents significant challenges for the development and testing of new treatments in children, including the need to recruit sufficient numbers in randomized trials, the time and cost involved, and the risk that trials conducted using older medications may become obsolete by the time they are completed Current treatment algorithms in POMS remain reliant on adult MS protocols Convincing evidence has increasingly emerged to support the biological rationale that effective DMTs in adult patients with MS are equally efficacious in children Based on existing evidence of the beneficial effect of high efficacy treatments to reduce disease activity and progression, it is essential to consider the window of opportunity in children with MS to initiate early effective treatment, as this has the potential to improve their long-term outcomes DMT: disease-modifying treatment; POMS: pediatric onset multiple sclerosis Abdel-Mannan OA, et al. Neurol Neuroimmunol Neuroinflamm. 2021 May 21;8(4):e1008

DMT considerations

Duignan S, et al. Dev Med Child Neurol. 2019 Sep;61(9):1039-1049

Monitoring of treatment IPMSSG guidelines 6-monthly MRI Re-baseline MRI 6 months after initiation of a new therapy to avoid prematurely defining treatment failure

TREATMENT FAILURE relapses and MRI activity (new T2 lesions) in fully compliant patients and on full-dose treatment for a time that is sufficient for the drug to be considered effective Treatment failure with injectable DMT, 25% to 64% across studies Long term safety Assessment of psychosocial and cognitive problems should be a multidisciplinary task Address the child's functioning at home, school, and among peers, and the effect on the family

DMT: DMT: disease-modifying treatment; IPMSSG: International Paediatric Multiple Sclerosis Study Group; MRI: magnetic resonance imaging Ghezzi A, et al. Neurology. 2016 Aug 30;87(9 Suppl 2):S97-S102; Duignan S, et al. Dev Med Child Neurol. 2019 Sep;61(9):10391049

The POMS cohort had slower disability progression than the adult-onset cases but reached disability milestones at a younger age Time from birth to EDSS 3

Time from MS onset to EDSS 3

EDSS: Expanded Disability Status Scale McKay KA, et al. Neurology. 2019 Jun 11;92(24):e2764-e2773

Time from birth to EDSS 6

Time from MS onset to EDSS 6

Prognostic factors Longer time to EDSS 6 but at earlier age Early treatment Disability status EDSS at treatment start

EDSS: Expanded Disability Status Scale Kopp TI, et al. Mult Scler Relat Disord. 2020 May;40:101956. doi: 10.1016/j.msard.2020.101956

Concluding remarks Early and accurate diagnosis of POMS is crucial.

Other antibody-mediated demyelinating diseases should be excluded.

Despite variations in treatment approaches throughout Europe, it is crucial to emphasize the significance of initiating early treatment with the most effective medications, determined through a benefit-risk evaluation.

Several clinical safety and efficacy trials are currently underway.

To address recruitment challenges of POMS in phase III trial designs, it is necessary to make efforts during the trial planning process.

Real-world evidence serves as a valuable complement to randomized controlled trials.

POMS: pediatric onset multiple sclerosis