Paediatric Neurology Update 2018

Paediatric Immune-mediated
CNS Demyelinating Disorders
& Auto-antibodies
Dr Heng Hock Sin
Paediatric Neurologist
Sabah Women and
Children’s Hospital
 Contents
• Overview of ‘classical’ immune-mediated CNS
demyelinating disorders
– ADEM
– Clinically isolated syndromes: Transverse myelitis,
optic neuritis
– Multiple sclerosis
– Neuromyelitis optica

• AQP4-antibody & NMO spectrum disorder

• MOG-antibody associated disease
Immune-mediated / Inflammatory
Demyelination
 Clinical Presentations of
Immune-mediated CNS Demyelination
• Acquired neurologic deficits corresponding to
the areas of CNS involvement

– Acute-onset; monophasic
– Chronic / relapsing / progressive

– Monofocal VS Polyfocal
International Pediatric Multiple Sclerosis Study Group

Neurology 2007; 68 (Suppl 2):S7-S12

Multiple Sclerosis Journal 2013 ; 19(10): 1261-1267
 Paediatric Immune-mediated
CNS Demyelinating Disorders
• Acute Disseminated Encephalomyelitis
(ADEM)
• Clinically Isolated Syndrome (CIS)
– Transverse myelitis
– Optic neuritis
– Others
• Multiple Sclerosis (MS)
• Neuromyelitis Optica (NMO)
 Paediatric Immune-mediated
CNS Demyelinating Disorders
• Course of disease :
– Monophasic disorder: ADEM, optic neuritis,
transverse myelitis, or
– Relapsing demyelinating syndrome: multiple
sclerosis, NMO

• A subgroup of patients does not fit into any

disorders by IPMSSG definitions
 Paediatric Immune-mediated
CNS Demyelinating Disorders

 Aetiology: Multi-factorial
 Immune-mediated inflammation triggered by
certain environmental factors in genetically
susceptible individuals

 Until recently, no specific or sensitive

biomarkers for diagnosis (except for NMO)
Acute Disseminated Encephalomyelitis
(ADEM)
• Clinical syndrome characterized by:
– new-onset polyfocal neurologic symptoms
including encephalopathy
– neuro-imaging evidence of multifocal
demyelination

• Typically a monophasic disease

 ADEM: Epidemiology
• Rare. Incidence: 0.3-0.6 per 100,000 per year
• Strong predilection to early childhood (mean
age: 5 - 8 yrs)

• May be:
– Para-infectious
• influenza , enterovirus, measles, Mycoplasma etc.
– Post-vaccination
• rabies, smallpox, measles vaccine
 ADEM: Clinical features
• Acute onset of encephalopathy & polyfocal
neurologic deficits

• Sometimes assoc. prodromal symptoms: fever,

malaise, headache, nausea & vomiting

• In para-infectious cases, symptoms begin 2 -

21 d after the infectious event
 ADEM: Clinical features
• The neurologic deficits are determined by the location
of the lesions:

– Uni- or bilateral pyramidal signs

– acute hemiplegia
– ataxia
– cranial nerve palsies
– visual loss (optic neuritis)
– seizures
– spinal cord syndrome
– impairment of speech
– Sensory disturbance
– Respiratory failure (brainstem lesion)
 ADEM: Clinical features
• Rapidly progressive
– over hours to maximal deficits within days

• Wide variation in severity:

– Subtle symptoms  Respiratory failure & coma

• The symptoms may be fluctuating (not > 3

months)
 ADEM: Diagnosis

• Based on the clinical & radiological features

• Exclusion of other aetiologies

• No specific biomarker
 Diagnostic Criteria
(IPMSSG Consensus Definition 2013)

1. A first polyfocal clinical CNS event with

presumed inflammatory demyelinating cause
2. Encephalopathy:
– Alteration in consciousness or behaviour unexplained by fever,
systemic illness, or post-ictal symptoms

3. Brain MRI abnormalities consistent with

demyelination during the acute (3 month) phase
4. No new clinical or MRI findings after 3 months
of onset
 ADEM: Differential Diagnoses
• CNS infections
• CNS vasculitis / autoimmune disorders
• Stroke
• Intra-cerebral malignancies /macrophage
activation synd.
• Metabolic disorders: Mitochondrial dis., organic
aciduria, leucodystrophies
• Acute necrotizing encephalopathy
• Biotin-thiamine-responsive basal ganglia dis.
• Extrapontine myelinolysis
• Neurosarcoidosis, e.t.c.
 ADEM: Brain & spinal MRI
• T2 weighted / FLAIR:
– Diffuse or multiple, poorly demarcated & large
(>1-2 cm) hyper-intense lesions involving
predominantly the cerebral white matter
– Deep grey matter (thalami, basal ganglia),
cerebellum & brain stem lesions
– Spinal cord lesions (1/3 of patients)

• Variable gadolinium enhancement (30%)

 MRI Findings of ADEM

A, B. Axial T2: Bilateral diffuse, multifocal, C. Coronal FLAIR:

poorly marginated, large asymmetric lesions Asymmetric
of white matter, basal ganglia, and cortical involvement of
gray matter thalami
 ADEM: Investigations
• CSF analysis:

– To rule out CNS infection

– Non-specific findings in ADEM

• ↑ in CSF protein & mild pleocytosis
• CSF oligoclonal bands: Rare
 ADEM: Treatment
• Treatment is based on expert opinion &
observational studies
– No RCTs

• Immunosuppressive therapies:
– High-dose corticosteroids
– IVIG
– Plasma exchange
 ADEM: Treatment
• Steroids
– IV methylprednisolone (30 mg/kg/d, max. 1 g/d)
for 5 days

– Followed by oral steroid taper over 4 - 6 wks

– Shorter duration: ↑risk of relapse
 Prognosis
• Full recovery in majority
– Improvement within days following treatment;
recovery to baseline within weeks
• Mortality: 1-3%
• Long-term sequelae:
– Cognitive impairment, focal motor & sensory
deficits, urinary symptoms e.t.c.
• Relapses or further demyelinating events: rare
 ADEM: Relapse or further CNS
demyelinating event
• Following ADEM, any further CNS
demyelinating event may indicate a chronic or
relapsing CNS demyelinating disorder

• Multiphasic ADEM: 2 episodes of ADEM

separated by 3 months, but no further events
(IPMSSG definition 2013)

• ADEM-MS, ADEM-NMOSD, ADEM-ON

 Clinically Isolated Syndrome (CIS)
• 1st acute clinical episode of CNS symptoms with a
presumed inflammatory demyelinating cause

• Monofocal or polyfocal

• No encephalopathy (distinguish from ADEM)

• MRI features do not meet the diagnostic criteria

of multiple sclerosis
 Clinically Isolated Syndrome

• Clinically heterogeneous entity

• Example:
– Optic neuritis
– transverse myelitis
– Brainstem / cerebellar / cerebral WM
demyelination
 Clinically Isolated Syndrome

• Could be the 1st presentation of a relapsing

CNS demyelinating disorder

• Treatment: Short course of high-dose steroid

– IV methylprednisolone 30 mg/kg/day for 3-5 days
 Multiple Sclerosis (MS)
• A chronic inflammatory demyelinating syndrome
of the CNS

• Children follow relapsing-remitting MS disease

course - recurrence of CNS demyelinating events

• Most children recover well from initial relapses

but suffer cumulative disabilities in long-term
 MS: Epidemiology
• Incidence: Geographical variation - more
common in temperate countries

• Predominantly affects adult female

• Risk factors: HLA DRB1*1501, ↓Vit. D, EBV-

IgG +ve
 MS: Clinical Features
• The 1st MS event is typically one of the CISs

– motor dysfunction, sensory symptoms, visual loss,

ataxia, brainstem syndromes, urinary & bladder
symptoms

– ADEM is rare; more common in children

• CSF: Oligoclonal bands (up to 90%)

 MS: Diagnosis

• The diagnosis requires clinical or radiological

evidence of relapsing demyelinating events
separated in time & space

– Dissemination in time (DIT)

– Dissemination in space (DIS)
 Dissemination in Time

Polman et al. Diagnosis Criteria for Multiple Sclerosis: 2010 Revisions to the
McDonald Criteria. Ann Neurol 2011;69:292-302
 Dissemination in Space

Polman et al. Diagnosis Criteria for Multiple Sclerosis: 2010 Revisions to the
McDonald Criteria. Ann Neurol 2011;69:292-302
 MS: Diagnostic Criteria
(IPMSSG Consensus Definition 2013)

Either one of the below:

• 2 or more CIS separated by >30 days & involving

more than 1 area of the CNS

• One CIS associated with MRI findings consistent

with criteria of dissemination in space (DIS) and
in which a follow up MRI shows at least one new
lesion consistent with dissemination in time (DIT)
criteria
 MS: Diagnostic Criteria (cont.)
• 1 ADEM attack followed by 1 CIS (≥ 3 months
after symptom onset) that is associated with
new MRI lesions consistent with criteria of DIS

• A CIS whose MRI findings are consistent with

criteria for DIS and DIT (applies only to
children ≥12 years old)
 Treatment
• Treatment of attacks: Steroids

• Long-term disease modifying therapies

– Interferon-β , glatiramer acetate
– 2nd line treatment

• Supportive
 Neuromyelitis Optica (NMO)
• ‘Devic’s disease’
• Previously considered a subtype of MS

• Sequential or concomitant optic neuritis &

transverse myelitis
– Symptoms are usually severe
– Either as a monophasic event, or a remitting-
relapsing syndrome
 Neuromyelitis Optica (NMO)
• Rare in children
– Paediatric onset: 3-5% of all cases
• Mean age of onset: 12 yr
• Female preponderance

• Disease specific autoantibody - NMO IgG

targeting against the aquaporin-4 (AQP4)
water channel was identified in patients with
relapsing NMO in 2004
 Aquaporin-4
• Water channel protein of cell membrane

• Highly expressed on the foot processes

of astrocytes at the blood-brain barrier

• Mainly found in optic nerves, spinal cord

& certain brain areas
 NMO: Spinal MRI
• Spinal MRI:
– long-segment lesion
extending > 3 vertebrae

 Longitudinally
extensive transverse
myelitis (LETM)

• Not specific for pediatric

NMO
 Revised Diagnostic Criteria for
Neuromyelitis Optica
Wingerchuk et al. Neurology 2006

• All of below:
1. Optic neuritis
2. Acute myelitis
3. At least 2 of 3 supportive criteria:
• Contiguous spinal cord MRI lesion extending over 3
vertebral segments
• Brain MRI not meeting diagnostic criteria for MS
• Anti-aquaporin-4 IgG seropositive status
 NMO: Treatment
• The treatment of acute event is the same as in
ON & TM:
– Corticosteroid: 1st line therapy
– Plasma exchange, IVIG

• In relapsing NMO:
– Long-term oral steroids + other
immunosuppresants e.g. azathioprine, MMF,
rituximab e.t.c.
– May be worsened by disease modifying drugs for
MS
 Case Scenario
• 13 yr boy , previously
well
– Presented with acute
onset of limb
weakness &
encephalopathic

– Treated as ADEM
– Full recovery
After 8 months….
• Came back with loss of vision both eyes but no
encephalopathic.

First brain MRI

 Diagnosis?
• Multiphasic ADEM?

• Multiple sclerosis?

• ADEM-ON?
 NMO Spectrum Disorder
• Identification of anti-AQP4-ab positive
patients with features beyond the 2016
criteria  NMO spectrum disorder (NMOSD)

– Limited form – single or recurrent LETM; recurrent

or simultaneous bilateral ON

– ON or TM associated with brain lesions typical of

NMO
 NMO Spectrum Disorder
• Disease can involve CNS areas beyond optic
nerves & spinal cord

– ADEM-like phenotype (10%)

– Brainstem lesion: prolonged vomiting ± hiccups,
cranial nerve dysfunction
– Rarely diencephalic impairment: endocrine
disorders
 NMOSD: MRI Findings
• Brain lesions

– More common in children

– Tend to localise to areas of high AQP4 expression

• Around the 3rd & 4th ventricles, diencephalon,
hypothalamus, dorsal brainstem / area postrema

– Destructive lesions on follow-up MRI

 Revised NMOSD diagnostic criteria
Wingerchuk et al. Neurology 2015

• Core clinical characteristics

1. Optic neuritis
2. Acute myelitis
3. Area postrema syndrome
4. Acute brainstem syndrome
5. Symptomatic narcolepsy or acute diencephalic
syndrome
6. Symptomatic cerebral syndrome with typical
brain lesions
 Revised NMOSD diagnostic criteria
Wingerchuk et al. Neurology 2015

• NMOSD with AQP4-IgG

1. > 1 core clinical characteristics
2. Positive AQP4-IgG
3. Exclusion of alternative diagnosis

• NMOSD without AQP4-IgG or unknown

antibody status
 > 2 core clinical characteristics, with additional
clinical & radiological criteria
 NMOSD: Disease Course
• Untreated, further relapse in > 90% of anti-AQP4
positive patients

• May be associated with other autoimmune

diseases

• 10-40% remain seronegative for AQP4-ab

– Myelin oligodendrocyte glycoprotein (MOG) antibody
has been found in a subgroup of patients (7-20%)
Myelin Oligodendrocyte Glycoprotein
(MOG) Antibody
• MOG: Myelin protein solely expressed at the
surface of myelin sheath & oligodendrocyte
membrane
• MOG-Ab has been shown to induce
demyelination in animal models
• Pathogenic in human?
 Myelin Oligodendrocyte Glycoprotein
(MOG) Antibody
• Have been associated with variety of
monophasic or relapsing acquired
demyelinating syndromes

– A subgroup of patients with NMOSD without

AQP4-ab
– Multiphasic ADEM, relapsing ON, paed MS, ADEM
follow by ON (ADEM-ON)
 MOG-Ab Associated Disease
• Compared with AQP4-ab positive NMOSD,
patients with positive MOG-ab tend to have:

– Nearly equal female : male ratio

– Fewer severe attacks, recover better & longer
attack interval
– Disseminated brain lesions resembling ADEM
 Y Hacohen et al. Diagnostic algorithm for relapsing acquired
demyelinating syndromes in children. Neurology 2017;89:1–10

• Total 110 children: 56.4% MS , 25.4% NMOSD, 12.7%

MDEM, 5.5% RON

• 82.9% of non-MS patients were +ve to either AQP4-Ab or

MOG-Ab

• 30.7% of NMOSD cases were AQP4-Ab +ve

• 83.3% of AQP4-Ab negative NMOSD cases were MOG-Ab
+ve

• MOG-Ab were found in 100% of MDEM cases & 33.3% of

RON cases

• No patients had Ab to both antigens

 YYHacohen
Hacohen et
et al.
al. Diagnostic
Diagnostic algorithm
algorithm for
for relapsing
relapsing
acquired demyelinating
acquired demyelinating syndromes
syndromes inin children.
children.
Neurology 2017;89:1–10
Neurology 2017;89:1–10

MOG-antibody VS AQP4-antibody

• Children with MOG-Ab were:

– younger
– lower disability
– longer time to relapse
– more cerebellar peduncle lesions
 MRI pattern in
MOG-Ab positive
patients

Y Hacohen et al. Diagnostic

algorithm for relapsing acquired
demyelinating syndromes in
children. Neurology 2017;89:1–10
Y Hacohen et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology 2017;89:1–10
 Conclusion
• Recognition of specific auto-antibodies & brain
MRI pattern in CNS demyelinating disorders has
lead to delineation of new disease entities e.g.
NMOSD & the emerging MOG-ab related disease

• Children with relapsing / recurrent demyelinating

events need urgent referral for early workup &
treatment to improve outcome

• Up-to-date radiological & immunology service is

essential to support the diagnostic pathway
Thank You