Actualização no diagnóstico e tratamento das doenças desmielinizantes na infância. Silvia Tenembaum

Transcription

1 Actualização no diagnóstico e tratamento das doenças desmielinizantes na infância Silvia Tenembaum

2 Acquired CNS inflammatory/demyelinating disorders: Background information More frequent in children than in adults and still underdiagnosed Clinically heterogeneous: mode of presentation, severity, rate of progression, and prognosis Difficulty of differential diagnosis and frequent misclassification: overlap in their clinical and neuroimaging presentations Large cohort descriptions of ADEM and MS in children since 2000

3 Acquired CNS inflammatory/demyelinating disorders: Background information In the abscense of specific biomarkers, operational criteria are needed. Distinction between transient syndromes (ADEM-CIS) and lifelong diseases (MS, NMO/NMOSD) was crucial Specific biomarkers were recently described: IgG-AQP4, MOG-abs, NMDR-ab, VGKC-autoabs, AMPA-antir-abs. MRI has proven to be pivotal in the diagnostic workup of children with acquired leukoencephalopathies. Recent neuroimmunology findings enable us to consider alternative diagnostic categories.

4 Acute disseminated encephalomyelitis (ADEM)

5 ADEM: Background information Immune-mediated inflammatory disorder of the CNS Preceded by an infection or vaccination Acute-subacute encephalopathy, Polyfocal neurological deficits, MRI evidence of widespread demyelination Usually monophasic Diagnosis is still based on clinical and radiologic features Tenembaum et al. Neurology 2002

6 International Pediatric MS Study Group

7 Proposed 2012 IPMSSG criteria

8 Proposed 2012 IPMSSG criteria for pediatric ADEM Pediatric ADEM (all are required) A first polyfocal CNS event with presumed inflammatory demyelinating cause Encephalopathy that cannot be explained by fever, systemic illness or postictal symptom No new clinical and MRI findings emerge three months or more after the onset Brain MRI is abnormal during the acute (three-month) phase. Typically on brain MRI: Diffuse, poorly demarcated, large (>1 2 cm) 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 Clarification of terminology: ADEM is a heterogeneous entity and is best viewed as a syndrome rather than a specific disorder

9 ADEM: MRI criteria WM multifocal lesions Gray matter frequently involved. Large (>1 cm in size) Hyperintense (T2/FLAIR) Bilateral, asymmetric Without radiologic evidence of previous involvement. Tenembaum, Neurology 2002; Inflammatory and autoimmune disorders of the NS in children

10 ADEM: MRI criteria Spinal cord MRI may show: confluent intramedullary lesions Variable enhancement In addition to brain lesions Krupp, Banwell, Tenembaum. Neurology 2007; 68(Suppl 2): S7-S12

11 Proposed 2012 IPMSSG criteria for pediatric ADEM ADEM followed by subsequent clinical event(s) Multiphasic ADEM: definition was revised and defined as: Two episodes consistent with ADEM separated by three months but not followed by any further events. The second ADEM event can involve either new or a re-emergence of prior neurologic symptoms, signs and MRI findings. Relapsing disease following ADEM that occurs beyond a second encephalopathic event is no longer consistent with multiphasic ADEM but rather indicates a chronic disorder, most often leading to the diagnosis of MS or NMOSD.

12 Pediatric Multiple Sclerosis

13 International Pediatric MS Study Group

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16 2010 Diagnostic criteria: Dissemination in space DIS: 1 asymptomatic T2 lesion in 2 topographies

17 2010 Diagnostic criteria: Dissemination in time New T2 lesion on follow-up MRI at any time March, 2011 June, 2011 Simultaneous presence of asymptomatic gad-enhancing and non-enhancing lesions, at any time

18 Proposed 2012 IPMSSG criteria for pediatric MS

19 Proposed 2012 IPMSSG criteria for pediatric MS Pediatric MS (can be satisfied by any of the following): 1. 2 non-encephalopathic inflammatory CNS clinical events, > 30 days apart, and involving more than 1 CNS area (DIS). OR 2. One non-encephalopathic episode typical of MS, and MRI findings: 2010 Revised McDonald Criteria for DIS, Follow-up MRI 1 new enhancing or non-enhancing lesion (DIT). OR 3. One ADEM attack plus one non-encephalopathic event > 3 months later, plus MRI lesions satisfying 2010 McDonald DIS criteria (EXCEPT <12 YEARS OLD). OR 4. Among children 12 years old, one non-adem event + MRI satisfying McDonald criteria for DIS/DIT. Krupp L et al. Mult Scler 2013

20 Neuromyelitis optica spectrum disorders

21 Neuromyelitis optica: Background information Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder of the CNS distinct from MS, that predominantly affects the optic nerves and spinal cord NMO is mediated by antibodies to the Aquaporin-4 (AQP4) water channel in most cases Pathological studies demonstrated that astrocytes are selectively targeted in NMO: AUTOIMMUNE ASTROCYTOPATHY

22 The evolving diagnostic criteria of NMO/NMOSD ON + TM Monophasic ON + Acute TM Recurrent IgG-AQP4 ON + TM Monophasic Recurrent NMOSD Paediatric NMO Internat. Panel for NMO Diagnosis Eugene Devic Dean Wingerchuk Vanda Lennon Sean Pittock Dean Wingerchuk No CNS involvement outside ON or spinal cord Negative brain MRI Brain MRI abnormalities

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25 Concordance, sensitivity and specificity comparing six AQP4-IgG assays Waters et al; Neurology 2012

26 International Consensus Diagnostic Criteria for NMOSD 2015 I. NMOSD with AQP4-antibodies Positive test for AQP4-IgG 1 core clinical characteristics No better explanation for the clinical syndrome Core clinical characteristics for seropositive patients 1. Optic neuritis 2. Acute myelitis 3. Area postrema syndrome: unexplained nausea, vomiting, or hiccups 4. Acute brain stem syndrome 5. Symptomatic narcolepsy or acute diencephalic clinical syndrome: with NMOSDtypical diencephalic MRI lesions 6. Symptomatic cerebral syndrome: with NMOSD-typical brain lesions Wingerchuk et al, Neurology 2015; 85:

27 International Panel for NMOSD diagnosis 2015 II. NMOSD without AQP4 antibodies or with unknown AQP4-IgG status 2 core clinical characteristics + all of the following: 1. 1 must be ON, LETM, or area postrema syndrome 2. Dissemination in space 3. Fulfillment of additional MRI requirements (as applicable) Negative test for AQP4-IgG using best available assay (CBA), or testing unavailable No better explanation for this clinical syndrome Wingerchuk et al, Neurology 2015; 85:

28 II. NMOSD without AQP4-Abs or unknown AQP4-IgG status MRI requirements for seronegative patients 1. ACUTE ON requires brain MRI : A- Normal findings or non-specific white matter lesions B- Optic nerve: Longitudinal optic neuropathy : T2 or T1-w gad-enhancing lesion extending over >1/2 optic nerve length or Involving optic chiasm 2. ACUTE MYELITIS requires spinal cord MRI with, >3 contiguous spinal cord segments (LETM) or >3 contiguous segments of spinal cord atrophy in patients with prior history compatible with acute myelitis 3. AREA POSTREMA SYNDROME requires associated dorsal medulla/area postrema lesion 4. ACUTE BRAINSTEM SYNDROME requires associated peri-ependymal brain stem lesion

29 Guidelines for differential diagnosis Hearing loss Atypical neurological and MRI findings Susac syndrome, NMOSD Considerations Severe or recurrent ON Longitudinal extensive myelopathy NMOSD, LHON, CRION NMOSD, HTLV-1 infection, B12 or copper deficiency, Alexander disease (juvenile) Hypothalamic symptoms-lesions Brain stem syndrome NMOSD, neurosarcoidosis, histiocytosis NMOSD, pontine glioma, brainstem stroke Snowball-like lesions centrally located in corpus callosum Leptomeningeal enhancement Large lesions with expansion Susac syndrome CNS infection, vasculitis, malignant processes Brain tumor, lymphoma, PML,

30 Key messages IPMSSG consensus diagnostic criteria are expected to facilitate earlier and more accurate diagnosis IPND consensus diagnostic criteria for NMOSD should also provide greater specificity for distinguishing both AQP4-IgG seropositive and seronegative NMOSD from MS Identifying the brain and spinal cord MRI features suggestive of ADEM, MS and NMOSD has diagnostic and prognostic implications Contributor to misdiagnosis: Inappropiate application of diagnostic criteria

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35 Hospital Nacional de Pediatría Dr. Juan P. Garrahan Buenos Aires, Argentina