Roadmap to Demyelination: Clinical Features€¦ · Defining ADEM • ADEM may follow a prodromal illness • ADEM patients may have fever and meningismus • ADEM patients are younger

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Roadmap to Pediatric Demyelination:Clinical FeaturesTeri Schreiner, MD MPH

June 1, 2014

Sunday, June 08, 2014CMSC

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Disclosures

I participate in clinical research funded by Biogen, Teva, Novartis, NIH/NINDS, MSDx, Questcor

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Acute central nervous system demyelination in children

• Monophasic Diseases– Acute disseminated encephalomyelitis (ADEM)

– Clinically Isolated Syndrome (CIS)• Optic neuritis

• Transverse myelitis

• Chronic Diseases– Multiple sclerosis (MS)

– Neuromyelitis optica (NMO)

• Mimickers of demyelination

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Acquired Demyelinating Syndrome (ADS) Incidence

• Canadian cohort

– 0.9 per 100,000 Canadian children

• Californian cohort

– 1.63 per 100,000 person‐years

• Washington DC cohort

– 11.79 cases per million children

• Banwell, et al. Incidence of acquired demyelination of the CNS in Canadian Children. Neurology, 2009; 72:232‐239.• Langer‐Gould, et al. Incidence of acquired CNS demyelinaing syndromes in a multiethnic cohort of children. Neurology, 2011; 77:1143‐1148.• Vanderver, et al. Relative Incidence of Inherited White Matter Disorders in Childhood to Acquired Pediatric Demyelinating Disorders. Seminars in Pediatric Neurology;19:219‐223.

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Roadmap to Pediatric ADS

First, the basics

Consider the differential diagnosis

Look for red flags

Acknowledge the differences between adults and children

Location, location, location!

Consider genetic & environmental factors

Provide anticipatory guidance

Maintain a holistic approach

Roadmap

First, the basics


Look for red flags






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Heterogenous Mechanisms

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Clinically Isolated Syndromes (CIS)

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Paradigm for evaluation: CIS

• Chitnis, Tanuja. Pediatric Demyelinating Diseases. Continuum. 2013; 19(4):1023‐1045.

CIS: Optic Neuritis

• May be a presenting feature of MS, ADEM, NMO

• Clinical presentation:

– Younger children may be more likely to have bilateral involvement

– Clinically, only 40% report pain with eye movement

– Mean age of onset 9‐12 years, slightly increased Female: Male

• Wilejto, et al. The clinical features, MRI findings and outcome of optic neuritis in children. Neurology, 2006; 67:258‐262..

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CIS: Optic Neuritis

• Evaluation– Formal visual fields, low contrast sensitivity

– VEP or OCT

• Differential Diagnosis– B12 deficiency, optic nerve glioma, Leber’sHereditary Optic Neuropathy

• Outcome– Demyelination outside the optic nerve portends progression to multiple sclerosis

Wilejto, et al. The clinical features, MRI findings and outcome of optic neuritis in children. Neurology, 2006; 67:258‐262.Banwell, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neuro 2011; 10 (5): 436‐445.

CIS: Transverse Myelitis

• May be an isolated occurrence (idiopathic or ADEM) or a manifestation of a relapsing disease, MS or NMO

• Clinically– Most cases are idiopathic, resulting from autoimmune process

• 47% preceded by a febrile illness• 25% preceded by vaccination

– Weakness, paresthesias and urinary dysfunction are common presenting features

– Up to 58% with longitudinally extensive TM in one cohort

• Pidcock, et al. Acute transverse myelitis in childhood: center‐based analysis of 47 cases. Neurology 2007.

• Thomas, et al. The demographic, clinical and magnetic resonance imaging (MRI) features of transverse myelitis in children. J Child Neurol 2012.27(1):11‐21.

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• Evaluation

– MRI brain and spinal cord with contrast

– Lumbar puncture

• Differential diagnosis

– Compressive lesions, intramedullary tumors, spinal cord infarction, vascular malformations, infection, lupus

– Guillain Barre Syndrome

• Pidcock, et al. Acute transverse myelitis in childhood: center‐based analysis of 47 cases. Neurology 2007.

• Thomas, et al. The demographic, clinical and magnetic resonance imaging (MRI) fatures of transverse myelitis in children. J Child Neurol 2012.27(1):11‐21.

T2: Longitudinally extensive transverse myelitis extending from pons to conus


• Outcome

– Cervical lesions, length of lesion predict worse outcome

– Focal acute TM carries greater risk of progression to MS

– Among one cohort of children with complete TM (n=24), none progressed within 7 years

Banwell, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neuro 2011; 10 (5): 436‐445.Defresne, et al. Efficacy of high dose steroid therapy in children with severe acute transverse myelitis. J Neuro Neurosurg Psychiatry. 2001;18 (6): 401‐406.

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CIS: Polyfocal presentation

• More than one area of the CNS involved

• Without encephalopathy: polyfocal CIS

• With encephalopathy: ADEM

Acute Disseminated Encephalomyelitis

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Krupp, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune‐mediated central nervous system demyelinating disorders: revision to the 2007 definitions. Mult Scler 2013; 19:1261.

Axial FLAIR

Axial T2

ADEM

• Clinically– Most children present before age 10

– Acute or subacute onset• Viral infection or vaccination within one month

– Multifocal neurologic deficits with encephalopathy

– Additional clinical features: headache, fever, meningismus, seizures

– Monophasic, with duration up to 3 months

• Multiphasic: 2 episodes consistent with ADEM separated by 3 months

Axial FLAIR

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ADEM

• Evaluation

– MRI brain and spinal cord

– Lumbar puncture

• Pleocytosis, elevated protein, normal glucose, transient oligoclonal bands

– Viral studies: HSV, enterovirus, cytomegalovirus, EBV, VZV and West Nile virus

ADEM

• Outcomes

– >50% patients experience full recovery over several weeks

– Rubella and varicella infections are associated with a worse outcome

– Neurobehavioral and cognitive sequelae common

– A minority of patients will progress to MS (<20%)

Tenembaum et al. Acute disseminated encephalopmyelitis. Neurology 2007; 68 (16 suppl 2): s23‐s36.Banwell, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neuro 2007;6:2063.

Axial FLAIR Axial FLAIR

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Defining ADEM

• ADEM may follow a prodromal illness

• ADEM patients may have fever and meningismus

• ADEM patients are younger (mean age 7.4 years) than CIS patients (11.2 years for multifocal presentation)

• Myelopathy of ADEM is often complete

• Ataxia is a common presenting feature

Banwell, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neuro 2007;6:2063.

Role of MRI in the differentiation of ADEM from MS in children

• Callen, DJA, Shroff, MM et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology 2009; 72:968‐973.

1. Absence of a diffuse, bilateral lesion pattern2. Presence of black holes3. Presence of two or more periventricular

lesions

Retrospective analysis of MRI scans obtained at first attack:

28 children subsequently diagnosed with MS20 children diagnosed with ADEM

Total number of lesions did not vary between groups.>=2 of the following (sensitivity 85%, specificity 98%):

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MRI in Peds MS

Pediatric Multiple Sclerosis

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Pediatric Multiple Sclerosis

• ~5% of all patients with MS

• ~1% patients have onset before age of 10 years

• Acute and chronic inflammation in the brain, optic nerves or spinal cord

• >95% relapsing and remitting

• Female: Male of 2.8:1 in post‐puberty

• Renoux, et al. Natural History of multiple sclerosis with childhood onset. N Engl Journal Med 2007;356:2603.

Clinical phenotype in children

• Little/ no progressive form from onset

• Higher relapse rate

• More frequent involvement of brainstem or cerebellum at disease onset

• Presence of “encephalopathy” at disease onset in children < 11 years: up to 20%

• Better recovery from early relapses than adults, yet disability is achieved at a younger age

Duquette 1997, Trojano 2005, Gorman 2009, Waubant 2009, Fay 2010

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Dissemination in Time (DIT) and Space (DIS)

• Polman, et al. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Annals of Neurology 2011; 69: 292‐302.

2010 McDonald Criteria for Diagnosis of Pediatric MS

2010 McDonald Criteria for Diagnosis of Pediatric MS

• DIT and DIS require serial clinical & MRI observations if patient presents with encephalopathy

• For children presenting with non‐ADEM demyelinating event:– Sensitivity 100%

– Specificity 86%

– Positive Predictive Value 76%

– Negative Predictive Value 100%

Sedaka, et al. 2010 McDonald Criteria for Diagnosing Pediatric Multiple Sclerosis; 2012.

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IPMSSG criteria for pediatric MS

Neuromyelitis Optica

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Neuromyelitis Optica

• Classically characterized by optic neuritis and longitudinally extensive transverse myelitis

• Core characteristics:– Optic neuritis, – Acute myelitis, – Area postrema syndrome (nausea, vomiting, hiccups),– other brainstem syndromes, – Symptomatic narcolepsy or acute diencephalic syndrome with MR

findings and – Symptomatic cerebral syndrome with MRI findings

• If antibody positive, only one core characteristic required• If antibody negative, must have 2 or more core characteristics• Clinical course may be fulminant and monophasic or relapsing and

remitting

NMO IgG

• Selectively binds to aquaporin 4 water channel

• 93% seropositive patients had recurrent attacks

• Overlap with other autoimmune disorders, including systemic lupus erythematosis, anti‐NMDAR encephalitis and Sjogren’s syndrome

1: McKeon, A . Et al. CNS Aquaporin-4 autoimmunity in children. Neurology (2008;) 71; 93-100.2. Collongues, N et al. Long-term follow-up of neuromyelitis optic with a pediatric onset. Neurology (2010) 75: 1084-1088.

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NMO Images

Axial FLAIR: biliateralmedial thalamic and hypothalamic involvement

Roadmap

First, the basics


Look for red flags






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728 Patient Evaluations407 USA1

321 Canada2

12% Other DiagnosesUSA = 69 Canada = 20

88% Acquired Demyelinating Syndromes

338 USA301 Canada

70% (226) Monophasic ADS19% (63) RRMS4% (12) NMO spectrum

30 Inflammatory/vascular14 Migraine11 CNS vasculitis1 Other1 SLE1 Neurosarcoid1 Coagulopathy1 Stroke

Infectious

Inflammatory

Genetic

11 Genetic/Metabolic5 Mitochondrial3 Leukodystrophy1 Acute Necrotiz Encephalopathy1 Cerebral folate deficiency

7 Infectious3 Chronic infection2 Cerebellitis1 Lyme1 Congenital CMV

18 Transient symptoms, other12 Paresthesias5 Tumor4 PVL/Static encephalopy4 Cortical dysplasia3 Peripheral neuropathy

Other

1Belman, A. et al. Ann Neurol. (62) Suppl. 11, 20072O’Mahony J et al, J Child Neurology, epub May 2012

Incidence in children

• Pediatric MS: 0.51 per 100,000 person‐years

• Other ADS (ADEM, ON, TM, CIS): 1.56 per 100,000 person‐years

• NMO (adult and child): 0.05‐0.4 per 100,000 patient‐years

• Primary vasculitis (adults): 0.24 per 100,000 person‐years

• Neurosarcoidosis (adult and child): 0.2 per 100,000 persons

• Langerhans Cell Histiocytosis (CNS): 0.2 per 100,000 persons

• CNS Sjogren syndrome (adult and child): unreported

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Gardner-Medwin, et al. Incidence of Henoch-Schonlein purpura, kawasaki disease and rare vasculitides in children of different ethnic origins. Lancet 2002; 360:1197-202.Hahn, et al.IPMSSG Differential Diagnosis and Evaluation in pediatric multiple sclerosis. Neurology 2007; 68 (suppl2) S18-20.Langer-Gould, et al. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology 2011; 77: 1173-1148.Lower, et al. Neurosarcoidosis. Clin Chest Med 29 (2008) 475-492.

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Laboratory studies

Suspected autoimmune or inflammatory workup:– CBC, LFTs, CRP/ESR, ACE if considering neurosarcoidosis

– NMO IgG (serum) if severe optic neuritis, longitudinally extensive transverse myelitis, atypical periventricular brain lesions

– ANA panel, dsDNA, anticardiolipin and antiphospholipidantibodies, ferritin, C3, C4

– TSH, T4, anti‐TPO antibodies if Hashimoto encephalopathy is a consideration

– CSF: cell count, protein, glucose, cytology (if indicated), oligoclonal bands with IgG index; NMO IgG only if serum NMO IgG negative with a high index of suspicion

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Roadmap

First, the basics


Look for red flags






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Clinical History: Red Flags

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IF: CONSIDER:Hyperacute onset Cerebral sinus venous thrombosis (CSVT), infarction

Presence of headache Primary angiits of the CNS (PACNS), CSVT, Susac syndrome

Recurrent or Severe Optic

Neuropathy

Neuromyelitis optica (NMO), Leber’s Hereditary Optic Neuropathy

(LHON), chronic relapsing optic neuropathy (CRION),

neurosarcoidosis, Sjogren Syndrome

Seizures Autoimmune encephalitis (anti‐NMDA Receptor), PACNS, Neuro

Behcet, CNS Lupus

Psychosis PACNS, autoimmune encephalitis, CNS Lupus, Susac syndrome

Systemic disease Neurosarcoidosis, vasculitis, CNS lupus, Susac syndrome,

Langerhans cell histiocytosis, Sjogren syndrome

Family history of

autoimmune disease

Neuro Behçet, CNS Lupus, NMO

Phelan, Jonathan A., Lowe, Lisa H. and Glasier, Charles M. Pediatric neurodegenerative white matter processes: leukodystrophies and beyond. PediatrRadiol (2008) 38: 729-749.Chitnis, et al. Pediatric Multiple Sclerosis. Neurol Clin 29 (2011) 481-505.O’Mahony et al. 2012

Exam: Red Flags

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IF: CONSIDER:

Cranial nerve

involvement

Neurosarcoidosis (50‐75%), Neuro Behçet’s,

infection

Joint involvement CNS Lupus

Focal neurologic

change with

headache

Vasculitis

Fever,

constitutional

symptoms

Infection, lymphoma

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Red Flags: Laboratory EvaluationCSF white blood cells greater than 50

– Think: Infection, HLH, AHLE, NMO

Elevated opening pressure

– Think: neurosarcoidosis, PACNS, lymphoma, CSVT

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Awad, et al. Analyses of cerebrospinal fluid in the diagnosis and monitoring of multiple sclerosis. Journal of Neuroimmunology2010; 219: 1-7.O’Mahony, J. et al. Masquerades of Acquired Demyelination in Children: Experiences of a National Demyelinating Disease Program.Journal of Child Neurology 2012; 00:1-15.

Conditions associated with oligoclonal bands:Paraneoplastic disordersSLENeurosarcoidosisNeuro‐Behçet’sSjogren’s syndromeAnti‐Glutamic acid decarboxylase antibody syndromeSteroid‐responsive encephalopathy (Hashimoto encephalopathy)

Vogt‐Koyanagi‐Harada (uveomeningoencephalitis)

Roadmap

First, the basics


Look for red flags






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Clinical features specific to children

• Optic neuritis– Clinically, only 40% of children report pain with eye movement

– Younger children may be more likely to have bilateral involvement

• Transverse Myelitis– May have hyperacute presentation, sometimes confused with Guillain‐Barre Syndrome

• Neuromyelitis Optica– Time to severe residual vision loss is shorter– Brain lesions are common

Clinical features specific to children

• Pediatric MS– Children commonly present with isolated optic neuritis, isolated brainstem syndrome or encephalopathy

– Relapsing and remitting course

– Annual relapse rate 2‐3 times that of adults

– Pediatric MS patients are more racially & ethnically diverse

– Boys and girls are more evenly affected prior to puberty

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Laboratory features specific to children with MS

MRI features specific to pre‐pubertal children with MS

Chabas 2008

3 months later

At onset

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Chabas 2008

3 months later

At onset

MRI features specific to post‐pubertal children with MS

Roadmap

First, the basics


Look for red flags






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Location, Location, Location

• Lesions that occur within a vascular territory should raise concern for infarction

• Symmetric, confluent lesions should raise concern for inherited and metabolic disorders

NMO lesions occur at the sites of greatest AQP4 concentration

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Roadmap

First, the basics


Look for red flags






Risk Factors for Pediatric MS

• Genetic susceptibility

– 5% lifetime risk of developing MS in first degree relatives

– Monozygotic twins have 25% risk

– Haplotypes DRB1*1501, DQA1*1501, DQB1*0602

– Up to twice as common in African Americans

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• Among patients with European ancestry, risk of MS was greater with + DRB1 status: 37% v.15%, p=0.001

• Risk of MS in non‐European children was not influenced by DRB status, 36% v. 22%, p=0.15

• Logistic regression: When accounting for age and sex, DRB1*15 status remained an independent predictor of MS diagnosis – OR=3.2, CI 1.7‐6.1

Disanto, et al., 2011

Disanto, et al., 2011

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Interactions between HLA‐DRB1 and viral status in predicting MS

• Interaction for HSV‐1 and HLA‐DRB1 (p<0.001)

• using neurological controls p=0.024,

• using healthy controls p<0.001.

• In HLA‐DRB1 ‐ :

– OR=4.11, 95%CI 1.17, 14.37; p=0.03

• In HLA‐DRB1 +:

– OR=0.07, 95%CI 0.02, 0.32; p=0.001

Waubant, 2011.

Environmental Factors

• Exposure to viruses

– EBV seropositivity: 3‐5 fold increased likelihood of MS

• Parental smoking

– Risk 2 fold higher if parents smoke

• Vitamin D status

• Obesity

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Roadmap

First, the basics


Look for red flags






Anticipatory Guidance

• In the case of uncertain diagnosis, present a plan for surveillance

• Involve school personnel and establish an Individualized Education Plan or 504 plan

• Establish neuropsychologic “baseline“

• Recognize that anticipatory guidance will change as the patient matures in his/her disease

• Stay connected!

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Anticipatory Guidance for Peds MS

• Natural history of disease

– Number of relapses within the first 2 years portends worse prognosis

• Each additional relapse increases rate of disability by 31‐41%

• Cognitive sequelae

Natural History of Disease

EDSS 4

EDSS 6

EDSS 7

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Natural History of Disease

EDSS 4

EDSS 6

EDSS 7

Cognitive Outcomes

• N=37 patients with pediatric MS

• Within 19 months of diagnosis, 30% with deficits seen in:– Attention

– Memory

– Confrontational naming

• Correlations with EDSS, number of relapses and disease duration

• 50% with depressive symptoms

MacAllister, et al. Neurology, 2005.

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Roadmap

First, the basics


Look for red flags






Pediatric patients exist within a system

• Diagnosis of a chronic disease affects:

–Parents

– Siblings

–Patient, self identity

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Summary Points

• Acquired demyelinating syndromes of childhood have distinct diagnostic criteria yet overlap commonly at onset

• Differential diagnosis of ADS is broad, and includes genetic, metabolic, neoplastic and infectious causes

• Clinical presentation of ADS in pre‐pubertal children often includes encephalopathy

• Recovery from attacks is robust in early MS disease, yet these children reach disability at younger ages

Summary points

• Environmental and genetic triggers are similar to those of adults

– Epidemiologic studies of children with pediatric onset disease may provide clues

• Psychosocial impact of a chronic disease is huge, and impacts the entire family

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Thank you for your attention

Radiographic evaluation

• Gray and white matter?

• Venous sinus thrombosis?

• Persistent contrast enhancement?

• Distribution of disease?

– Diffuse?

– Hypothalamic?

– Periventricular?

– Brainstem, thalamic or basal ganglia involvement?

– Meningeal involvement?

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Phelan, Jonathan A., Lowe, Lisa H. and Glasier, Charles M. Pediatric neurodegenerative white matter processes: leukodystrophies and beyond. Pediatr Radiol (2008) 38: 729-749.Schiffmann, R and van der Knapp, MS. Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology(2009) 72:750-759.

Consider: Neurosarcoidosis, NMO, Langerhans Cell Histiocytosis

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Case #2

• 11 yo F presented with bilateral, painless vision loss, vomiting

• Past medical history: ADHD, Mood d/o, HTN

• Family history: MGM with rheumatoid arthritis

• Neurologic exam:

– No light perception left eye, + APD

– Nystagmus

– Dysmetria

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Laboratory Confirmation• CSF: unremarkable, no oligoclonal bands

• MRI brain and orbits, spinal cord: optic nerve atrophy (L), bilateral enhancement, periventricular lesions adjacent to middle cerebellar peduncle

• NMO antibody: POSITIVE

70FLAIR

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Case #2 Red Flags

• 11 yo F presented with bilateral, painless vision loss,vomiting

• Past medical history: ADHD, Mood d/o, HTN

• Family history: MGM with rheumatoid arthritis

• Neurologic exam:

– No light perception left eye, + APD

– Nystagmus

– Dysmetria

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Laboratory Confirmation

• CSF: unremarkable, no oligoclonal bands

• MRI brain and orbits, spinal cord: optic nerve atrophy (L), bilateral enhancement, periventricular lesions adjacent to middle cerebellar peduncle

• NMO antibody: POSITIVE

72FLAIR

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Antibody mediated Disorders

• Encephalopathies:

– Anti‐NMDAR encephalitis

– Voltage gated potassium channel‐complex

– Glutamic acid decarboxylase

• Neuromyelitis optica

Location, Location, Location

• Pediatric MS

– More frequent involvement of brainstem or cerebellum at disease onset

• Transverse myelitis

– Short, peripheral, circumscribed lesions are morecommon in CIS/MS

Documents

Roadmap to Demyelination: Clinical Features€¦ · Defining ADEM • ADEM may follow a prodromal illness • ADEM patients may have fever and meningismus • ADEM patients are younger