Pediatric Multiple Sclerosis:
Updates in Diagnosis and Treatment
Pediatric MS Diagnosis:
Application of Revised Criteria
Child Neurology Society Annual Meeting 2016
Amy T. Waldman, M.D., M.S.C.E.
Clinical Director, Inflammatory Brain Program, Children’s Hospital of Philadelphia
Assistant Professor of Neurology, Perelman School of Medicine at the University of
Pennsylvania
Disclosures
• Research Funding
– I am currently supported by a K23 award, National Institute for
Neurologic Disorders and Stroke, National Institutes of Health,
and The Children’s Hospital of Philadelphia
– I have received funding in the past from the National Multiple
Sclerosis Society (NMSS) and American Academy of Neurology
Foundation (now American Brain Foundation)
– I have received funding from private foundations, including the
Lynn Saligman League, Butterflies of Hope, and The Calliope
Joy Foundation
– I am a site principal investigator for a pediatric MS clinical trial
sponsored by Novartis
– I am collaborating with Biogen on the validation of an outcome
measure in children
Objectives
1. Review the rationale for diagnostic criteria
2. Discuss the International Pediatric MS
Study Group (IPMSSG) and McDonald
criteria for pediatric MS
3. Present the impact of such definitions on
the field of pediatric demyelination
4. Introduce the broadening spectrum of
neuroinflammatory disorders
Diagnostic criteria
• MS is a clinical diagnosis
• Inflammatory diseases are further defined by paraclinical
(MRI, laboratory) data
– Example: optic neuritis
• Identification of a clinical phenotype guides evaluation and
treatment
– Confirmation of a diagnosis allows for prompt treatment
– Earlier treatment impacts prognosis
• Aids in research studies
– Inclusion and exclusion criteria
– Helps to validate clinical observations
• Suitability of adult criteria for children was previously
unknown
IPMSSG: Consensus Definitions for
Pediatric Demyelinating Disorders
• Originally published in 2007, revised in 2013
• Goal: operationalize a “classification system to facilitate
prospective research studies”
• Use consistent terminology
• Future directions: to be tested in future research and
modified accordingly
• Recognized that there would be exceptions to the
proposed definitions
Krupp LB et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders.
Neurology 2007; 68: S7–S12.
Krupp LB et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis
and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.
Mult Scler 2013;19:1261.
Case 1
• CC: numbness
• HPI: 14 year old presented with
bilateral leg numbness
– Initially noted in the thighs 3 days
prior to admission
– Then developed back pain and
truncal numbness
– No trouble walking, but legs “feel like
spaghetti”
– No changes in bowel/bladder
function
• Examination:
– Impaired sensation below T8-T9 but
able to distinguish sharp and dull
Case 1 - continued
Diagnosis?
A. Clinically isolated syndrome – monofocal
B. Clinically isolated syndrome – polyfocal
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
Diagnosis?
A. Clinically isolated syndrome – monofocal
B. Clinically isolated syndrome – polyfocal
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
IPMSSG definitions: Pediatric MS
•
•
•
•
2 or more nonencephalopathic (e.g. not ADEM-like), clinical CNS events with
presumed inflammatory cause
– Separated by more than 30 days and involving more than one area of the
CNS
1 nonencephalopathic episode typical of MS which is associated with MRI
findings consistent with 2010 Revised McDonald criteria for:
– Dissemination in space (DIS), AND
– A follow-up MRI shows at least one new enhancing or nonenhancing lesion
consistent with dissemination in time (DIT) MS criteria
1 ADEM attack followed by a nonencephalopathic clinical event
– Three or more months after symptom onset, AND
– New MRI lesions fulfill 2010 Revised McDonald DIS criteria
A first, single, acute event that does not meet ADEM criteria and whose MRI
findings are consistent with the 2010 Revised McDonald criteria for DIS and DIT
– Applies only to children ≥12 years old
2010 McDonald Criteria

Goal: permit confirmation of DIS and DIT in
patients with a first attack and a single MRI

Dissemination in space:
≥ 1 clinically-silent T2 lesion in at least
2 of 4 CNS regions:
1. Periventricular
2. Juxtacortical
3. Infratentorial
4. Spinal cord

Periventricular
Juxtacortical
Dissemination in time:
–A new T2 and/or gadolinium enhancing
lesion(s) on f/u MRI, with reference to baseline
irrespective of timing of baseline scan
–Simultaneous presence of asymptomatic
gadolinium enhancing and nonenhancing
lesions at any time
Infratentorial
Spinal Cord
Swanton JK et al. Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis
related to the prevalence of multiple sclerosis? A global comparison. J Neurol Neurosurg Psychiatry 2006; 77(9):1070-1072
Swanton JK et al. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre
retrospective study. Lancet Neurol 2007; 6(8):677-686.
IPMSSG definitions:
Clinically Isolated Syndrome
• A monofocal or polyfocal, clinical CNS event with
presumed inflammatory demyelinating cause
• Absence of a prior clinical history of CNS
demyelinating disease
– e.g. absence of past optic neuritis (ON), transverse myelitis (TM) and
hemispheric or brain-stem related syndromes)
• No encephalopathy (i.e. no alteration in consciousness
or behavior) that cannot be explained by fever
• The diagnosis of MS based on baseline magnetic
resonance imaging (MRI) features (2010 McDonald
criteria) are not met
Case 2
• CC: eye “looks lazy”
• HPI: 4 year old presented with a 1day history of:
– Eye deviation: L eye "looked lazy" - it
was deviated away from the midline
and he could not focus his gaze. He
would squint to try to focus and
preferentially closed his R eye, looking
with his L. He told his mom she had 4
eyes
– He was veering to one side while
walking down a narrow hallway.
• Examination:
– Elevator palsy (left)
– No motor, sensory, or cerebellar
abnormalities on exam
Case 2, continued
• MRI brain with and without contrast:
– Scattered, juxtacortical and periventricular foci of T2/FLAIR
hyperintense in bilateral centrum semiovale, frontal, parietal, occipital
and left temporal lobes
– Foci of T2/FLAIR signal abnormality in right genu and left splenium of
corpus callosum.
– Areas of T2 prolongation posterior to right putamen, in left pons and
left cerebellum.
– Enhancing focus in left posterior frontal subcortical white matter
• MRI C- and T-spine with and without contrast: normal
• LP:
– WBC 0, RBC 4, Protein 15, Glucose 50
– Oligoclonal bands 7
• Labs:
– Vitamin D 32 (normal 25-80 ng/dL)
– Epstein Barr Virus serology: evidence of prior infection
Diagnosis?
A. Acute disseminated encephalomyelitis
B. Clinically isolated syndrome
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
Diagnosis?
A. Acute disseminated encephalomyelitis
B. Clinically isolated syndrome
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
IPMSSG definitions: Pediatric MS
•
•
•
•
2 or more nonencephalopathic (e.g. not ADEM-like), clinical CNS events with
presumed inflammatory cause
– Separated by more than 30 days and involving more than one area of the
CNS
1 nonencephalopathic episode typical of MS which is associated with MRI
findings consistent with 2010 Revised McDonald criteria for:
– Dissemination in space (DIS), AND
– A follow-up MRI shows at least one new enhancing or nonenhancing lesion
consistent with dissemination in time (DIT) MS criteria
1 ADEM attack followed by a nonencephalopathic clinical event
– Three or more months after symptom onset, AND
– New MRI lesions fulfill 2010 Revised McDonald DIS criteria
A first, single, acute event that does not meet ADEM criteria and whose MRI
findings are consistent with the 2010 Revised McDonald criteria for DIS and DIT
– Applies only to children ≥12 years old
Case summary
• We frequently encounter cases that challenge our
current application of diagnostic criteria
– IPMSSG definitions updated in 2012
• Webinar for open discussions
– See Network of Pediatric MS Centers website
at www.usnpmsc.org
• Future
– More data needed on the diagnosis, treatment,
and prognosis of many pediatric inflammatory
diseases
– Clinical phenotyping necessary!
Is it MS?
• A child with optic nerve and spinal cord
disease with negative Aquaporin-4 IgG
antibodies
• A child with ADEM who later develops
recurrent optic neuritis
• A child with multiple attacks of optic
neuritis
• A child with monolimb weakness and
cranial nerve abnormalities
Newly defined disorders needing
further validation
• A child with optic nerve and spinal cord disease with
negative Aquaporin-4 IgG antibodies
– NMO Spectrum Disorder with negative AQ4-IgG
• A child with ADEM who later develops recurrent optic
neuritis
– ADEM followed by monophasic or recurrent ON
• A child with multiple attacks of optic neuritis
– Chronic relapsing inflammatory optic neuropathy
• A child with monolimb weakness and cranial nerve
abnormalities
– Acute flaccid myelitis
Conclusions
• Consensus definitions have been applied to pediatric
demyelinating disease cohorts
– Stronger prognostic data for families
• Clinical and MRI predictors aid clinicians in differentiating
children with relapsing disease from monophasic
illnesses
• Areas for future research include
– Further defining ADEM-ON, CRION, acute flaccid myelitis, and
other demyelinating diseases
– Identifying pathologic antibodies
– Determining how the age of onset affects immunopathogenesis
Acknowledgements
Co-presenters
Jayne Ness
Tim Lotze
CHOP MS Center
Brenda Banwell
Gihan Tennekoon
Sona Narula
Sarah Hopkins
Laura Adang
Erin Prange
Beth Kunzelman
Sarah Stoney
HUP MS Center
Joseph Berger
Clyde Markowitz
Dina Jacobs
Eric Williamson
Salim Chahin
Vision Lab
Grant Liu
Amy Lavery
Geraldine Liu
Krystle Karoscik
Robert Avery
Collaborators
Emmanuelle Waubant
Ben Greenberg
Leslie Benson
Jennifer Graves
Funding
NIH (NINDS)
American Brain Foundation
National MS Society
In loving memory of Peter H. Berman, M.D.
Additional Slides
Case 3
• CC: hand numbness,
weakness
• HPI: 10 year old presented
with 24 hours of
paresthesias in the UE and
LE, weakness, and vomiting
– Right hand numbness, tingling,
and weakness, needing
assistance for ADLs
– Progressed to similar
symptoms in her leg
– Blurry vision in the left eye
Case 3 - continued
• Exam:
–
–
–
–
Sleepy but arousable, normal speech, following commands
Visual acuity – hand motions only in the left eye
Weakness of the right hand and leg
Decreased sensation to light touch, pinprick right UE and LE
• Evaluation:
– LP: routine studies were reportedly normal, HSV, CMV, VZV,
Enterovirus PCR negative, Oligoclonal bands 0
– Serum AQP4-IgG negative (sent to LabCorp)
• Treatment
– IV methylprednisolone 30 mg/kg/day x 5 days
– Oral taper x 6 weeks
Diagnosis?
A. Acute disseminated encephalomyelitis
B. Clinically isolated syndrome – polyfocal
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
Case 3 - continued
• One day after the steroid taper
ended, the patient developed
tingling in the right hand and
returned to the OSH ED
• Follow-up imaging revealed
new diffuse juxtacortical white
matter lesions with ring
enhancement
– Cervicomedullary junction lesion
still present, no longer enhancing
Diagnosis?
A. Acute disseminated encephalomyelitis
B. Clinically isolated syndrome – polyfocal
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
Diagnosis?
A. Acute disseminated encephalomyelitis
B. Clinically isolated syndrome – polyfocal
C. Multiple sclerosis
D. Neuromyelitis optica spectrum disorder
E. Acute flaccid myelitis
Revised classification of NMO
• Clinical phenotyping and the identification of the
aquaporin-4 antibody have improved diagnostic
and therapeutic strategies in NMO
• Proposed diagnostic criteria uses NMO
spectrum disorder (NMOSD) as a unifying term:
– NMOSD with AQP4-IgG
– NMOSD without AQP4-IgG
Weinshenker BG, Diagnostic criteria for neuromyelitis optica 2014 update. Presented
at ECTRIMS, Boston, MA 2014.
NMOSD with AQP4-IgG
• At least 1 core clinical characteristic
–
–
–
–
–
Optic neuritis
Acute myelitis
Area postrema syndrome (nausea/vomiting/hiccups)
Other brain stem syndrome
Symptomatic narcolepsy or acute diencephalic syndrome with
MRI lesion(s)
– Symptomatic cerebral syndrome with MRI lesion(s)
• Positive test for AQP4-IgG
• No better explanation
Weinshenker BG, Diagnostic criteria for neuromyelitis optica 2014 update.
Presented at ECTRIMS, Boston, MA 2014.
NMOSD without AQP4-Ig
(or unavailable)
• At least 2 core clinical characteristics all satisfying:
– 1 of ON, myelitis, or area postrema syndrome
– Dissemination in space
• Isolated recurrent ON or recurrent TM do not qualify
– Additional MRI requirements
• AP syndrome: dorsal medulla lesion
• Myelitis: LETM
• ON: normal brain MRI OR >1/2 ON OR chiasm lesion
– Negative test(s) for AQP4-IgG using best available
assay, or testing unavailable
• No better explanation for the clinical syndrome
Weinshenker BG, Diagnostic criteria for neuromyelitis optica 2014 update.
Presented at ECTRIMS, Boston, MA 2014.
Pediatric NMOSD
• Same criteria as adult NMOSD
• Longitudinally extensive
transverse myelitis may be seen
in pediatric MS
– Caution when applying diagnostic
criteria
• Children have a higher
incidence of cerebral
presentations
Child with pediatric MS
Case 3 summary
• Working diagnosis: NMOSD without AQP4-IgG
– NMO AQP4-IgG resent from serum and CSF, both negative
• Why isn’t this MS?
– Dissemination in space: ≥ 1 clinically-silent T2 lesion in at least
2 of 4 CNS regions:
1.Periventricular
2.Juxtacortical
3.Infratentorial
4.Spinal cord
– Dissemination in time:
• A new T2 and/or gadolinium enhancing lesion(s) on f/u MRI,
with reference to baseline irrespective of timing of baseline
scan
• Simultaneous presence of asymptomatic gadolinium
enhancing and nonenhancing lesions at any time
However, McDonald DIS and DIT criteria are
applicable for children ≥12 years old!
ADEM followed by ON:
proposed diagnostic criteria
1. Initial presentation fulfills IPMSSG criteria for
ADEM
2. ON diagnosed after ADEM with objective
evidence of loss of visual function
3. The ON occurs after a symptom-free interval of
four weeks and not as part of the ADEM or
recurrent ADEM
4. Diagnostic criteria for pediatric MS are not
fulfilled
Huppke P, Rostasy K, Karenfort M, et al.
Mult Scler 2013:19(7):941-946.
ADEM followed by ON:
proposed diagnostic criteria (cont’d)
5. Oligoclonal bands are not detected in the CSF
– a pleocytosis may be present
6. MRI reveals typical brain or spinal cord T2
lesions consistent with ADEM initially; however,
subsequent imaging shows resolution or nearcomplete resolution of lesions and new brain or
spinal cord lesions do not appear during the
ON attacks
Huppke P, Rostasy K, Karenfort M, et al.
Mult Scler 2013:19(7):941-946.
Chronic Relapsing Inflammatory Optic
Neuropathy – proposed diagnostic criteria
1. History: ON and at least one relapse;
2. Clinical: objective evidence for loss of visual
function;
3. Laboratory: NMO-IgG seronegative;
4. Imaging: contrast enhancement of the acutely
inflamed optic nerves;
5. Treatment: response to immunosuppressive
treatment and relapse on withdrawal or dose
reduction of immunosuppressive treatment.
Petzold A, Plant GT. J Neurol 2013.
Acute flaccid myelitis
• Confirmed Case
1. Acute onset of focal limb weakness, AND
2. An MRI showing a spinal cord lesion largely restricted to
gray matter and spanning one or more spinal segments.
• Probable Case
1. Acute onset of focal limb weakness, AND
2. Cerebrospinal fluid (CSF) with pleocytosis (white blood
cell count >5 cells/mm3, adjusting for presence of red
blood cells by subtracting 1 white blood cell for every
500 red blood cells present).
http://www.cdc.gov/acute-flaccid-myelitis/hcp/case-definition.html