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