Diagnosis of MS and related disorders in children

Diagnosis of MS and related disorders in children

Cheryl HemingwayGreat Ormond Street Hospital

for Children

Cheryl HemingwayGreat Ormond Street Hospital

for Children

Disclosures

• I have received educational and travel grant grants and consulted for the following:– Merck Serono– Bayer Schering– Biogen-Idec– Alexion

• This presentation may refer to medicines which may not be licenced for this specific use in the paediatric populations

Objectives

• Review the spectrum of ADS and the IPMSSG criteria for diagnosis of MS

• Through cases illustrate the key features of ADS and the differential diagnoses

• Discuss some of the current challenges and new phenotypes

Diagnosis of MS

• MS remains a clinical diagnosis • No specific biomarker• Misdiagnosis – missing common mimic

and inappropriate application of criteria

Solomon et al. Neurology. 2016 Sep 87

Acquired demyelinating syndromes

Banwell et al., 2007 Lancet Neurology 6:887‐902Krupp et al., 2013 Mult Scler. 19(10):1261‐7. 

MultiphasicADEM

Relapsing NMO/

NMOSDMultiple sclerosis

clinically isolated syndrome

Other Relapsing:Antibody mediated; ADEMON; CRION

Time to diagnosis 2007 vs 2012

van Pelt E D et al. J Neurol Neurosurg Psychiatry 10.1136

Early treatmentPotential window of therapeutic opportunity for disease‐modifying therapy

TimeDisease onset

Disability

Natural course of diseaseLater treatment

Later interventionTreatmentat diagnosis

Intervention at diagnosis

Cohen JA, et al. J Neuroimmunol 1999;98(1):29–36Jeffery DR. J Neurol Sci 2002;197(1−2):1−8

Adapted from Trapp BD, et al. Curr Opin Neurol 1999;12(3):295–302 Trapp BD, et al. Neuroscientist 1999;5:48–57

Trapp BD, et al. N Engl J Med 1998;338(5):278–285

Incidence of ADS• Paucity of population data

– Canada 0.9/100 000/y1

– Dutch 0.66/100 000/y2

– UK 1.1/100 000/y3

• Surveillance study in UK 2009‐2010– first onset CNS Inflammatory Demyelination <16y– 4095 clinicians surveyed; 90% return; 222+ notifications 

• 2007 IPMSSG consensus definitions allowed uniformity in research, revised 2012 and 2010 McDonald MRI criteria

1: Banwell et al. Neurology. 2009 Jan 20;72(3):232‐92: Ketelslegers et al. J Neurol 2012 259;1929‐19353: Absoud et al Mult Scler. 2012.

ADS Spectrum

All CIS (83) : ADEM (40)= 2.1:1

n=125

Absoud et al Mult Scler. 2012

= 25)(n= 38)

= 36)(n= 26)

7 year old with status epilepticus in PICU

13m with right “stroke”and irritabilityCT

T2

ADC

23m with pontine “astrocytoma”

T2

T1‐Gd

ADC

16y with“tumour”

9y focal seizure dx: pilocytic astrocytoma

7y odd behaviour and fever

Dx: Herpes encephalitis

11y seizures and behavioural change

Dx VGKC + LE

4y sleepy, movement disorder

Dx: Mg transport defect

Case 1• In 2011 at 5y of age - left sided weakness

no encephalopathy• EBV+ and OCB+ • Vitamin D deficient (15nmol/l)• AQP4 and MOG antibody negative

Dec 2011

McDonald 2010 MRI criteria -can be used in children

Age of Onset of POMS

Harding et al JNNP 2013

Predictors for MS diagnosis at onset

• Children diagnosed with MS were 38 times as likely to have one or more brain lesions as compared to children with monophasic illness and 45 times as likely if they also had CSF OCB

• Children diagnosed with MS were 3.3 times as likely to have remote EBV infection as compared to children with monophasic illness

• Children with vitamin D sufficiency were 66% less likely to be diagnosed with MS

Banwell, et al Lancet Neurol 2011: 10; 436‐445

Follow–up MRI booked..

Oct 2012

Dec 2011

10 months later…

• New onset right sided weakness - again no encephalopathy

Paediatric multiple sclerosis1. Two clinical events (without encephalopathy) both

consistent with attacks typical of MS, separated by more than 30 days, and affecting more than one area of the brain, optic nerves, or spinal cord.

2. A first clinical event consistent with multiple sclerosis in a patient between 12–18 years who fulfills the 2010 McDonald MRI DIS and DIT criteria on baseline MRI.

3. One clinical event (without encephalopathy) typical of multiple sclerosis and MRI demonstrating at least one new T2 lesion on a scan more than 30 days after

4. An event that fulfills criteria initially for ADEM, followed by a second non-acute disseminated encephalomyelitis event (>3 months from symptom onset) associated with new MRI lesions with 2010 McDonald DIS criteria.

Disability progression

Clinical threshold

RelapsesDisability 

Inflammatory phase

Degenerative phase

Adapted from Trapp BD et al. Neuroscientist. 1999;5(1):48‐57. 

MS-2 main pathological phases

Relapse rate

Treatment algorithm

• Ghezzi et al. Neurology 2016; S2:S97-102

Dec 2014

May 2015

Oct 2012

Dec 2011

Proposed Definition of Inadequate Treatment Response

• On full dose of therapy for > 6 months• At least one of:

– Increase in relapse rate or new T2 or contrast enhancing lesions on MRI obtained pre-treatment

– > 2 confirmed relapses in 12 months or less

• Fully compliant on treatment

Chitnis et al. Multiple Sclerosis Journal 2012;18:116-127

Natalizumab in Paediatric MS

Ghezzi et al BMC Neurol 2015

Time for EDSS 6.0

POMS=30.8y

AOMS=20.4y POMS=45.4y

AOMS=53.9y

Harding et al JNNP 2013Welsh database

September 2016…

• Remains on interferon i.m. weekly injection• EDSS – currently 1.0, cognitive changes

Case 2• 11y old girl – September 2015 – 3/52 episode of persistent retching and vomiting (hyponatraemia of 118nmol/l)

• GIT investigation‐ normal• CT Head – normal• Vomiting stopped 

October 2015

• October 2015 -ascending weakness leading to quadriplegia over 1 week

• Dx: transverse myelitis

• Rx: IVMP• Routine bloods

normal and negative

October 2015 January 2016

AQP4+

Aquaporin-4 antibodies • Directly influenced the diagnosis and management of patients with NMO/SD

• 0.71‐4.52% paediatricpatients with a first episode of demyelination are AQP4‐Ab +

• Identified in patients who previously did not fulfill clinical criteria for NMO

(1Banwell et al. 2011. Lancet Neurology 2Hacohen et al. 2014 JNNP

Revised criteria - NMOSD

Aquaporin 4 +At least 1 core characteristic• Optic neuritis • Acute myelitis • Area postrema syndrome:

nausea/vomiting/hiccups • Other brain stem syndrome

– Symptomatic narcolepsy or acute diencephalicsyndrome with MRI lesion(s)

• Symptomatic cerebral syndrome with MRI lesion(s)

• No better clinical explanation

Aquaporin 4 – or unavailableAt least 2 core characteristics• 1 of ON, myelitis, or area

postrema syndrome• Dissemination in space• Additional MRI requirements

– AP syndrome: dorsal medulla lesion

– Myelitis: LETM – ON: normal brain MRI OR

>1/2 ON OR chiasm lesion • No better clinical explanation

Wingerchuk et al. Neurology 2015;85(2):177-89

Paediatric NMO

• The clinical features, MRI abnormalities and AQP4-Ab seropositivity reported in children are similar to the adult phenotype

• Children with NMO may have a less clinically severe disease, and may take longer to reach disability than adults with NMO

• Many children are left with visual or motor deficits after a single NMO attack- disability is attack related

• Area postrema syndrome is still under-recognised.

Case 3• 6y old girl ‐ presented May 2013 with bilateral optic neuritis, irritability, lethargy and ataxia

• MRI

• Initial diagnosis: ADEM

What is ADEM?• Acute Disseminated Encephalomyelitis • A first polyfocal, presumed inflammatory clinical CNS event

• Must include encephalopathy that cannot be explained by fever

• Frequently follows infection • Brain MRI is abnormal during the acute (three‐month) phase.

MRI in ADEM• Diffuse, poorly demarcated, large T2 lesions involving predominantly the cerebral white matter 

• T1 hypointense lesions in the white matter are rare 

• Deep grey matter lesions (e.g. thalamus or basal ganglia) can be present

ADEM – clinical features

All CIS : ADEM = 2.1:1

n=125

Absoud et al Mult Scler. 2012

11m later…• March 2014 ‐left optic neuritis, lethargy and ataxia 

• OCB: negative• MRI• Revised diagnosis: MDEM

March 2014May 2013

What is MDEM?• A new ADEM event 3 months or more after initial events– with re‐emergence of prior clinical and MRI findings 

– or new findings clinically and on MRI

May 2013

May 2013

March 2014

March 2014

June 2014

April 2015

Dx: RRMSRx: Interferon β1a

Paediatric multiple sclerosis1. Two clinical events (without encephalopathy) both

consistent with attacks typical of MS, separated by more than 30 days, and affecting more than one area of the brain, optic nerves, or spinal cord.

2. A first clinical event consistent with multiple sclerosis in a patient between 12–18 years who fulfills the 2010 McDonald MRI DIS and DIT criteria on baseline MRI.

3. One clinical event (without encephalopathy) typical of multiple sclerosis and MRI demonstrating at least one new T2 lesion on a scan more than 30 days after

4. An event that fulfills criteria initially for ADEM, followed by a second non-acute disseminated encephalomyelitis event (>3 months from symptom onset) associated with new MRI lesions with 2010 McDonald DIS criteria.

May 2013

May 2013

March 2014

March 2014

June 2014

April 2015

MOG+

Revised diagnosis – MOG antibody + associated demyelination

Started on azathioprine and is doing well

MOG Ab Demyelination

Case 4

• 13y girl• 2/52 hx of reluctance to walk, backache,

urinary symptoms• 1/7 hx of abnormal vision• Afebrile, not encephalopathic• Bilateral optic neuritis • Unstable gait

Initial investigationsCSF

Opening pressure 56cm

CSF OCB Negative

Culture No growth

Cells WBC 180 RBC<1

Protein and glucose Normal

Neopterin 75

16S, meningococcal, pneumococcal, HSV, adenovirus, enterovirus, VZV, parechovirus PCR

Negative

Bloods

Urea and electrolytes Normal

FBC, CRP Normal

ACE Normal

ANA, dsDNA, C3, C4 Normal

Viral screen Negative

Anti-DNAaseB, ASOT 180

EBV, CMV, HSV PCR Negative

Borrelia, myco serology Negative

Normal

Prolactin, DHEAS, Normal

Aldosterone, Renin Normal

Thyroid function Normal

ESR 44Ferritin 337LFT, Amylase Normal

Bone profile, lactate Normal

Initial diagnosis – NMOSD• AQP4 negative• Then blood returned MOG antibody positive

Revised diagnosis – NMOSD with MOG antibody + associated 

demyelination

Case 5• 6y f‐ 2006 ‐ progressive deterioration over 3/7‐headache, vomiting, off legs, seizure

• PICU – IPPV• Diagnosis: ADEM• Some recovery

1 month later..• bilateral ON• Isolated spinal lesions• Diagnosis: ADEM • Some remaining deficit after rehabilitation

9 years later..

• Right optic neuritis

• Blood MOG +

Revised diagnosis: ADEM‐ON

ADEM-ON• Initial presentation fulfills criteria for ADEM• ON diagnosed 1 month after ADEM with

objective evidence of visual loss• Supportive criteria

– OCB not detected in CSF– Aquaporin 4 – negative– Initial MRI – typical brain or cord T2 lesions

consistent with ADEM, with resolution on subsequent images and no new lesion

MOG antibodies: Relapsing phenotypes

• MDEM Baumann et al., MSJ 2016 Epub

• AQP4 negative NMOSDKitley et al., 2014 JAMA Neurol 71(3):276-83.

• ADEM-ONHuppke et al 2013 Mult Scler 19(7):941-6.

Myelin oligodendrocyte glycoprotein

• Exclusively expressed in CNS

• Minor component of myelin (0.05%)

• Abs to MOG have been shown to induce or contribute to demyelination in various animal models 

Hemmer B. et al. Nature Reviews Neuroscience  2002; 3:291‐301 

MOG Ab and ADS• More in paediatric than adult ADS

• All presentations, but in paedsmore in ADEM

• Levels can be transient

• Relapsing phenotype

Reindl, M. et al. (2013)Nat. Rev. Neurol. doi:10.1038/nrneurol.2013

1Matthias Baumann et al. Mult Scler 20162 Hacohen et al Mult Sclerosis 2015

Copyright © by SAGE Publications

MDEM and MOG

• 8/8 patients MOG +1

• 9/9 patientsMOG +2

MOG vs AQP4 Ab vs MS

• Younger• OCB negative• Distinct MRI from MS and often from AQP4

1 2 3 40

20

40

60

MRI Score

Num

ber o

f pat

ient

s

1 2 3 40

20

40

60

MSNon-MS

MRI Score

Num

ber o

f pat

ient

s

1 Not MS2 Not typical of MS 3 Some MS features 4 Typical MS

First Scan Subsequent scans

Blinded radiological analysis

Hacohen et al (submitted)

Summary

• Misdiagnosis and in particular late diagnosis remains common

• Making an accurate diagnosis is NB – Predict outcome– Choose appropriate, timely treatment– Recruit appropriate patients for trials

• MOG – has distinct phenotypes, although pathogenicity and best treatment options are still being determined