diagnosis of ms and related disorders in children - cheryl hemingway
TRANSCRIPT
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