This presentation reviews clinical features, long term outcome and treatment of early and late onset multiple sclerosis.

1. Early and Late onset Multiple
Sclerosis
Dr Pramod Krishnan
Consultant Neurologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru
June 26th 2020

2. Introduction
Multiple Sclerosis (MS) can be divided based on the age of onset:
1. EOMS/ POMS (Early onset or Pediatric onset MS): onset < 18 years of age.
2. AOMS/ YOMS (Adult onset or Young onset MS): onset between 18-50 years
of age.
3. LOMS (Late onset MS): onset > 50 years of age.
4. VLOMS (Very late onset MS): onset > 60 years of age.
Krupp, L.B. et al. Neurology 2007, 68, S7–S12.
Lotti, C.B.C. et al. Arq. Neuropsiquiatr. 2017, 75, 451–456.
But, does this distinction matter?

3. Clinical features:
EOMS, AOMS and LOMS

4. Diagnostic criteria for Pediatric MS (any one of the following)
≥ 2 non-encephalopathic, clinical CNS events with presumed inflammatory cause, separated by
> 30 days and involving more than one CNS area.
One non-encephalopathic episode typical of MS which is associated with MRI findings
consistent with 2010 Revised McDonald criteria for dissemination in space (DIS) and in which a
follow-up MRI shows at least one new enhancing or non-enhancing lesion consistent with
dissemination in time (DIT) MS criteria.
One ADEM attack followed by a non-encephalopathic clinical event, three or more months after
symptom onset, that is associated with new MRI lesions that fulfill 2010 Revised McDonald DIS
criteria.
A first, single, acute event (e.g. a CIS) that does not meet ADEM criteria and whose MRI
findings are consistent with the 2010 revised McDonald Criteria for DIS and DIT (applied only
to children ≥12 years old).
Krupp LB, Tardieu M, Amato MP, et al. Mult Scler. 2013;19(10):1261–7.

5. • 3 to 10% of MS patients present < 16 years of age and < 1% under 10 years of age.
• 98% of POMS patients present with relapsing- remitting course (in AOMS: 84%).
• Relapses are more frequent in patients with POMS compared with AOMS.
• POMS patients experience a more aggressive disease onset with polyfocal
presentation and disabling clinical symptoms, and a higher relapse rate early in the
disease course.

6. Incidence and prevalence of pediatric MS: results from various national cohorts
• Most studies indicate that at least 5% of the total population with MS comprises of
pediatric patients.

7. Clinical features
Disablity milestone is reached at an earlier stage
Time from onset to confirmed disability is longer
Probably due to better plasticity enabling better
recovery from relapses
They take 10 years longer to reach secondary
progressive phase compared to AOMS
Slower disease progression over time
More favourable outcome after the first clinical event

8. • 137 children with MS and 96 matched control participants.
• Assays for IgG antibodies against EBV, CMV, VZV, HSV and parvovirus B19.
• Over 108 (86%) children with MS, were seropositive for remote EBV infection,
compared with 61 (64%) of controls (p=0.025).
• POMS patients did not differ from controls in seroprevalence of other viruses.
• POMS might be associated with exposure to EBV, suggesting a possible role for EBV
in MS pathobiology.
Lancet Neurol 2007; 6: 773–81

9. • Objective: To investigate the familial risk of MS in EOMS and LOMS.
• Results: 629 EOMS and 1148 LOMS, each matched to 10 controls from the general
population.
• The OR of MS for individuals with a first-degree relative diagnosed with EOMS was
10.86 (95% CI 6.87–17.17); and for LOMS was 8.08 (95% CI 6.12–10.67).
• Conclusions: No substantial differences in familial risk noted in EOMS and LOMS.

10. Odds ratios of multiple sclerosis in relatives of patients with early- or late-onset multiple sclerosis
• Familial risk constitutes both genetic and environmental risk factors shared by a family.
• The estimated recurrence risks for MS in Sweden are 17.3% for monozygotic twins and
2.6% for siblings.

11. • When the study group of patients with JMS was compared to healthy controls,
association of JMS with DR2(15) (DRB1*150. . .) alleles and DR2(15)-bearing
genotypes was found.
• Comparison of patients with JMS with family-based controls confirmed the JMS
association with DR2(15).
• TDT analysis provides strong evidence for linkage of DR2(15) and susceptibility
to JMS.

12. J Neurol Neurosurg Psychiatry 2013;84:141–147
• 111/3048 patients had onset <18
years of age (5.4%) with M: F ratio
of 2.9:1.
• 132/3048 patients had onset >50
years of age (6.7%).
• POMS cohort had mean follow up
of 25.3 years (SD 15.8), and the
adult cohort of 17.2 years (SD 12).

13. Index event and initial disease course
• In 110/111 patients, disease onset was relapsing, and only one patient
had a progressive disease course from onset.
• Of these 110 patients, 93 (83.8%) recovered completely from the index
event, but 17 (15.3%) had persistent neurological sequelae.
• Motor symptoms were the most common initial manifestation (52.8%)
followed by optic neuritis (26.4%).
• There was no significant variation in symptoms at presentation by
gender (p=0.86) or age group (p=0.11).
• Most patients (76.4%) presented with monoregional symptoms.

14. Kaplan–Meier survival curves for time to, and age at, disability end points for adult-onset cohort
(solid line) and paediatric-onset cohort (dotted line), with median times marked.

15. Kaplan–Meier survival curves for time to, and age at, disability end points for adult-onset cohort
(solid line) and paediatric-onset cohort (dotted line), with median times marked.

16. • Median time from onset to
diagnosis was longer in POMS
(5.8 years vs 2.0 years,
p<0.0001).
• Fewer AOMS patients
recovered from the initial
event: 61.9% vs 83.8%, p=0.06).
• In the first 5 years of disease,
POMS patients had fewer
relapses (median ARR 0.2 vs
0.4; p=0.05).
• Significantly longer time from
first to second event in the
POMS cohort (2.55 years vs
5.02 years, p=0.04).

17. • Incomplete recovery from initial event was significantly associated
with a shorter time to EDSS 4 (HR 2.44, 95% CI 1.20 to 4.95, p=0.01)

18. Cognitive impairment in EOMS/POMS
• POMS is associated with significant cognitive impairment.
• In a study of 63 patients, 19 (31%) fulfilled criteria for cognitive
impairment.
• Cognitive outcome in these patients can be heterogeneous, as cognitive
performance deteriorated in 42 of 56 cases (75%) after 2 years of follow-
up.
• In a 5-year longitudinal study, cognitive impairment index deterioration
was observed in 56% of patients, improvement in 25%, and stability in
18.8%.
Amato MP, Goretti B, Ghezzi A, et al. Neurology. 2010;75(13): 1134–40.
Amato MP, Goretti B, Ghezzi A, et al. Neurology. 2014;83(16):1432–8.

19. • Primary objective of this retrospective study was to identify the characteristics
of MS in patients aged ≥ 50 years from 4 centres in Northern Midwest USA.
• LOMS: 124/3700 MS patients had onset after age 50 (3.4%).
• VLOMS: 26 patients (21%) of LOMS had onset after ≥ 60 years, and 9 patients
(7%) after ≥70 years.

20. Clinical course classification by age groups
Clinical course classification before and after reclassification
based on careful questioning regarding a prior focal
neurological deficit.

21. • 5-year follow up data was available for 54
patients (44%).
• 50 (93%) had difficulty with ambulation.
• Course status was assessed in 39 (31%)
patients.
3 (8%)
22 (56%)
10 (26%)
4 (10%)

22. Summary
• LOMS is uncommon. 3.4% of MS patients in this series.
• Female predominance is less prominent 1.7: 1 (Vs 2-3:1).
• Relapsing and progressive courses were nearly equally common.
• The most common acute presentation was transverse myelitis.
• VLOMS comprises 1% of MS patients in this series.
• SPMS and PPMS are the common types in this age group.
• At 5 year follow up majority required support for ambulation.
• Most common disease course was static disease with residual deficits.

23. • Of the 742 patients with MS, 31 were LOMS patients (4.18%).
• Female predominance of 2:1
• Median age of initial symptoms: 54 years. 2 patients were > 60 years old (VLOMS).
• Initial neurological presentation: motor in 54.8%, cerebellar in 29.0%, sensory and
brainstem symptoms in 19.4% each, visual in 16.1% and vesical dysfunction in 3.2%.
• A multi-topographic involvement was described in 38.7%, and the most frequent
combination was motor and cerebellar.

24. No statistically significant differences between the two groups

25. Summary
• LOMS is uncommon (4.1%).
• Most common initial presentations
were motor and cerebellar.
• PPMS/ SPMS was 64.3%, RRMS
was 35.7%.
• CSF OCB was less useful in LOMS.
• No significant differences in the
disease course, disability between
LOMS and AOMS.

26. • Objective: to compare the risk of reaching sustained disability status assessed
by EDSS in LOMS and AOMS cohorts.
• They used EDSS score of 6.0 as endpoint, i.e. a status requiring a walking aid
to walk about 100 m with or without resting.
• LOMS: onset after age 40 years. AOMS: onset between 18-40 years.
• 671 RRMS patients: 143 (21.3%) had LOMS and 528 (78.7%) had AOMS.
Eur J Neurol 2018 Dec;25(12):1425-1431

27. Characteristics of patients with LOMS and AOMS

28. Factor LOMS (n=143) AOMS (n=528) P value
Median EDSS at follow up 4.0 (1.0-7.0) 2.5 (1.0-7.0) <0.001
MRI activity at 5 years 19 (15.4%) 159 (31.6%) <0.001
MRI activity at last f/u 12 (9.7%) 105 (20.9%) <0.001
Confirmed secondary progression 9 (6.3%) 17 (3.2%) NS
Disability, progression and MRI changes during Follow up
The Kaplan–Meier survival analysis showed that LOMS reached an EDSS
score of 6.0 sooner than AOMS (mean: 94.2 months in the LOMS group vs.
103.2 months in the AOMS group; logrank 8.8; P < 0.001)

29. Univarite analysis of variables for reaching EDSS of 6.0 in LOMS and AOMS patients.

30. Summary
• Patients with LOMS were more prone to rapidly reach an EDSS score
of 6.0, although patients with AOMS showed more brain MRI activity.
• This is probably due to declining remyelination and increasing
neurodegeneration with advancing age.
• Male gender was associated with an increased risk of attaining such
disability status.
• LOMS patients may therefore warrant more aggressive therapeutic
management.

31. • 2627 MS patients were studied.
• 127 (4.8%) were EOMS, 84 (3.20%) were LOMS and 2416 (91.93%) were AOMS.
• Mean disease durations: for EOMS 10.10 years, for AOMS 7.50 years, and for LOMS
5.30 years.
J. Clin. Med. 2020, 9, 1326

32. Parameter Whole sample EOMS AOMS LOMS
Number 2627 127 (4.8%) 2416 (91.93%) 84 (3.2%)
Females 2081 (79.2%) 101 (79.5%) 1921 (79.5%) 59 (70.2%)
Mean age at onset 30.2 years 14.5 age 29.4 years 53.8 years
Mean follow up 8.64 years 11.47 years 8.59 years 5.93 years
Initial symptoms Visual: 35.4%
Brainstem: 16.5%
Sensory: 15%
Motor: 12%
Sensory: 30.7%
Visual: 26.2%
Motor: 15.1%
Motor: 38.1%
Sensory: 31 %
Visual: 13.1%
Median EDSS at
first visit
2.0 (1.0-2.5) 2.0 (0.0-2.0) 2.0 (1.0-2.5) 2.25 (2.0-3.0)
Median EDSS at
last f/u
1.0 (0.0-2.5) 0.0 (0.0-2.0) 1.0 (0.0-2.5) 2.25 (0.75-5.0)
EDSS <3 at f/u 85% 95% 87%
Family history of
MS: first degree
250 (9.5%) 15 (11.8%) 27 (9.4%) 8 (9.5%)

33. Parameter Whole sample EOMS AOMS LOMS
Course RRMS: 2129 (81%)
SPMS: 415 (15.8%)
PPMS: 83 (3.2%)
109 (85.8%)
18 (14.2%)
0
1971 (81.6%)
377 (15.6%)
68 (2.8%)
49 (58.3%)
20 (23.8%)
15 (17.9%)
RRMS to SPMS 14.2% 15.6% 25.3%
Mean age at
SPMS onset
39.8 years 53 years 67 years
Disease onset
to SPMS onset
24.6 years 20.5 years 14 years
Predictors of
SPMS
High EDSS at
onset
Higher EDSS at onset,
younger age, short inter-
attack interval, spinal cord
lesions.
Spinal cord
lesions with
enhancement at
disease onset.
Relapses in
first 2 years
646 (24.6%) 46 (36.2%) 585 (24.2%) 15 (17.8%)
Autoimmune
comorbidity
440 (16.7%) 31 (24.4%) 402 (16.6%) 7 (8.3%)

34. Multivariate cox regression model to predict SPMS conversion in the groups.
EOMS
AOMS
LOMS

35. Summary
• Initial symptoms are usually visual in EOMS, sensory or visual in
AOMS and motor in LOMS.
• SPMS and PPMS are more commonly seen in LOMS.
• Progression from RRMS to SPMS is more likely in LOMS, and happens
much sooner from the time of disease onset.
• A high EDSS at onset, late age of onset, and spinal cord MRI lesions
predict this progression from RRMS to SPMS.

36. Treatment of EOMS and LOMS

37. Treatment of EOMS
• The available efficacy data for pediatric MS patients is scarce.
• Fingolimod is the only DMTs approved in POMS (>10 yrs, > 40 kg).
• Current POMS treatment strategies tend to favor lower-efficacy DMTs,
whereas current adult regimens move toward higher-efficacy DMTs.
• Current treatment guidelines for POMS are comprised of expert
opinion based on available retrospective observational, case series, and,
in some cases, prospective safety data.

38. Special issues in EOMS
• Effect of DMTs on the developing immune system is unknown.
• Effect of DMT on neurodevelopment.
• Body weight and surface area change significantly during treatment.
• Pubertal changes can affect MS activity and response to DMT.
• Complex social and emotional issues.
• Cost of treatment, in view of longer duration of treatment.
• Reduced autonomy over treatment decisions, choices.
Risk vs Cost Vs Benefit decision in EOMS is more complicated than in
AOMS

39. DMT Evidence Comment
Interferons Retrospective and open label
studies
P: Safety, tolerability similar to adults.
C: Efficacy unclear. Dosing unclear. Injection.
Glatiramer acetate Open label studies P: Safety, efficacy similar to adults.
C: Injection form.
Dimethyl Fumarate Retrospective reviews P: Oral. Safe. 120 mg BD vs 240 mg BD.
C: Side effects similar to adults. PML
Fingolimod Retrospective reviews P: Potentially safe and tolerable. Oral
C: Bradycardia, lymphopenia, infections, PML.
Teriflunomide No studies P: Oral.
C: No data in POMS.
Natalizumab Open label and retrospective P: highly effective, tolerable.
C: monitoring for risk of PML. Cost.
Alemtuzumab No studies No data. Can be chosen for highly active MS.
Rituximab Retrospective Effective. Risk of hypogammaglobulinemia.
Ocrelizumab No studies No data in children.
Cyclophosphamide Retrospective reviews Restricted to highly active or fulminant disease.
P: Pros. C: Cons

40. Treatment strategy: Escalation therapy
EOMS
Relapse: ≥2 clinical
or radiological
IFN Glatiramer acetate
DMF/
?Teriflunomide
FingolimodNatalizumabAlemtuzumab
Side effects/
Relapse
Side effects/
Relapse
MRI every 6-12 m MRI every 6-12 m
Rituximab

41. Drawbacks of escalation strategy
• 30% of POMS relapse in the first year of therapy.
• 44% opt to switch therapy in view of adverse effects.
• Non compliance rate of 37-47% due to injections, adverse effects and
low efficacy.
• Delaying escalation by 12-24 months means risk of enduring transient
or permanent neurologic deficits.
• Relapses have huge effects on academics, psychosocial health of
children and productivity of care givers.

42. Rationale for early initiation of therapy in EOMS
85-90% has an active relapsing MS course.
Relapse rate is high in initial phases of the disease and correlates with a bad prognosis.
Short duration between relapses and the subsequent accumulation of disability.
Although progression may be slower than in adults, moderate-to-severe disability is
reached at a younger age.
Brain tissue shows more active inflammation in childhood, so patients may benefit
from the anti-inflammatory effects of DMTs.
Despite the apparent clinical recovery from relapses due to better neuronal plasticity,
cognitive impairment is frequent.
Postponing treatment may negatively impact social activities and school performance.

43. Treatment strategy: High efficacy early therapy
(HEET)
• Start treatment with the most efficacious DMT suitable to a specific
patient.
• The goal of HEET is to stop disease activity early to prevent
deleterious neurodevelopmental deficits now, and disability progression
in the future.
• This will address the issue of early tissue level inflammation, axon loss,
increased relapse rate, and earlier age of disability in POMS.

44. Highly active therapy in pre-pubertal age
Natalizumab Fingolimod
• Tests: For TB, HBV, HCV,
HIV.
• Vaccination for VZV, measles,
mumps, rubella.
• 500-750 mg per meter squared
BSA (max of 1000 mg).
• Day 1, 15 and every 6 m.
• Monitor CD19 count,
lymphocyte count,
immunoglobulin levels every 6
months.
• Dose can be increased to 750
mg per meter squared BSA
and interval can be reduced to
4 months if required.
• For JCV negative patients.
• 3-6 mg/kg body weight
(max 300 mg).
• Every 28 days, or even
every 6 weeks.
• JCV antibody test every 3
months, LFT every 3
months.
• Antinatalizumab antibodies
after 6 month or if disease
activity is noted.
• If JCV is positive change to
Rituximab or another
highly active therapy within
8 weeks.
• Once daily oral.
• Convenient.
• First dose bradycardia.
• Rare serious
cardiovascular side
effects.
• PML.
• Rebound MS activity
on stopping.
Rituximab Natalizumab

45. Highly active therapy in post-pubertal age
• Can be treated similar to adults.
• Natalizumab: <50 kg- 3 mg/kg/body eight; > 50 kg- 6 mg/kg/body
weight.
• Rituximab or Ocrelizumab.
• Fingolimod.
• Alemtuzumab.

46. Treatment of LOMS
• Most studies do not include sufficient LOMS patients.
• Patients should be stratified based on disease activity to chose the
right DMT.
• In view of shorter duration to SPMS, faster accumulation of
disability, there should be low threshold for starting high efficacy
therapy.
• Risk of infections, cardiovascular adverse effects should be
considered while choosing therapy in LOMS.

47. Case discussion

48. Case 1: history
• 59 y/male; no comorbidities.
• In 2010, developed acute urinary retention and weakness of both
lower limbs (left weaker than the right).
• Partial recovery with IVMP.
• Not started on any DMTs.
• Son has RRMS since the age of 22 years, well controlled with
Dimethyl fumarate.

49. Relapse in 2014
• Developed left lower limb weakness of 1-week duration, with
marked difficulty in walking requiring support.
• Incomplete evacuation of urine which required catherization.
• Spasticity and brisk DTRs in the lower limbs.
• Left lower limb power was 3/5.
• Sensory examination was normal.
• He had extensor plantar response on both sides.

50. MRI cervical spine T2 sagittal: showed
hyperintensity in the cervical cord at C6-
7 vertebral level, and in the upper dorsal
cord.
MRI cervical T1 sagittal: showed
hypointense region in the cervical cord
at C6-7 vertebral level.

51. MRI cervical spine T2 sagittal: showed
hyperintensity in the cervical cord at C2-
3, C6-7 level, and in the upper dorsal
cord.
MRI cervical spine T1 post contrast
sagittal: showed contrast enhancement
in the lesion in the upper dorsal cord.

52. MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and juxtacortical regions
consistent with demyelination.
MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and subcortical regions
consistent with demyelination.

53. MRI brain T2F axial: showed multiple
hyperintense lesions in the subcortical
and juxtacortical white matter
consistent with demyelination.
MRI brain T2 sagittal: showed multiple
hyperintense lesions involving the
corpus callosum and periventricular
white matter (Dawson fingers).

54. Treatment
• He showed good improvement with IVMP.
• He was started on Dimethyl Fumarate 240 mg BD.
• During a follow up MRI in 2017, he was noted to have multiple new
MRI lesions.
• There was no clinical worsening.
• The family was concerned that the therapy was not effective.
• Dimethyl fumarate was changed to Teriflunomide 14 mg OD.

55. Relapse in 2018
• Developed acute unsteadiness of gait and urinary retention.
• New lesions were noted in the pons and cerebellar peduncle, and
in the cervical and dorsal cord.
• He improved with IVMP. He required more support to walk.
• Change of treatment was considered: Rituximab, Natalizumab
and Alemtuzumab. Family was undecided.
• Teriflunomide was continued.

56. Relapse in Jan 2019
• Acute bowel and urinary urgency, frequency and urge
incontinence.
• Unsteadiness of gait with inability to stand or walk even with
support.
• He had right lower limb weakness, with spasticity, power of 3/5
with extensor plantar response.
• Pre-existing left lower limb weakness worsened.
• New lesions were noted in the MRI brain and spine.

57. MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and subcortical regions
consistent with demyelination.
MRI brain T2F axial: showed multiple
hyperintense lesions in the subcortical
and juxtacortical white matter
consistent with demyelination.

58. MRI brain T2F axial: showed multiple
hyperintense lesions in the juxtacortical
white matter consistent with
demyelination.
MRI brain T2F axial: showed multiple
hyperintense lesions in the
periventricular and subcortical regions
consistent with demyelination.

59. MRI brain T2F axial: showed left cerebellar hemisphere hyperintense lesion consistent with
demyelination.

60. Treatment
• He opted for a highly active therapy and chose Alemtuzumab.
• It was successfully administered in April 2019.
• 12 mg/d for 5 days.
• Alemtuzumab infusion was uneventful except for high BP from day 3
onwards.
• Required multiple antihypertensives. BP returned to normal during
follow up and antihypertensives were discontinued.

61. Follow up.
• No clinical or radiological activity.
• Able to walk without support, but slow. Uses a walker for faster mobility.
• Urinary and bowel symptoms have subsided.
• Has significant spasticity of both lower limbs and mild weakness of left
lower limb.
• No adverse effects till now.

62. Case 2
• 18 year old boy, diagnosed as RRMS 3 years prior.
• Initial presentation was right LL weakness and bladder involvement.
• Started on treatment with Interferons.
• Had a relapse with left LL weakness, bladder and bowel involvement.
• Treatment was changed to dimethyl fumarate.
• MRI showed new T2 lesions on follow up.
• Had another relapse in the form of ataxia.
• Incomplete response to IVMP during each relapse.

63. • MRI brain T2F sagittal (top) showing hyperintense
lesions involving the corpus callosum and
periventricular regions.
• MRI Cervical spine T2 sagittal (right) showing patchy
hyperintense areas involving the entire cervical cord.

64. • MRI brain T2F axial showing hyperintense lesions involving the periventricular and subcortical regions
in both hemispheric regions.

65. • MRI brain T2F axial (left) showing hyperintense lesions involving the periventricular and subcortical
regions.
• MRI brain T2 coronal showing involvement of the midbrain and pons on both sides.

66. • MRI Cervical spine T2 axial showing multiple hyperintense areas along the entire extent of the cervical
cord.

67. Treatment
• Was treated with Lemtrada in August 2019.
• No relapses or new MRI lesions since then.
• Bowel and bladder symptoms have subsided.
• Ambulant without support. Minimal gait disturbance.
• Has mild degree of spasticity.
• No cerebellar signs.
• No adverse effects till date.

68. Developed erythematous, non
pruritic eruptions 3 -4 hours
after completion of infusion.
Patient was otherwise stable.
The rashes improved with
standard allergy therapies.
These rashes are likely due to
cytokine release due to lysis of
CD52 cells by Alemtuzumab.

69. Take home message
• EOMS and LOMS are uncommon.
• EOMS has more inflammatory component and LOMS is more likely
progressive due to prominent degenerative component.
• Motor and brainstem involvement is common in EOMS and LOMS.
• LOMS results in disability sooner than EOMS and AOMS.
• Disability occurs at an earlier age in EOMS.
• DMT data in EOMS is mainly derived from Adult MS studies.
• High efficacy therapy should be considered early in EOMS and LOMS.

70. THANK YOU