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Neuroimaging in Childhood

• Neuroimaging issues are distinct from Pediatric Neuroimaging in adults Neurometabolic-degenerative disorder • Sedation/anesthesia and Epilepsy • Motion artifacts Bhagwan Moorjani, MD, FAAP, FAAN • Requires knowledge of normal CNS developmental (i.e. myelin maturation) • Contrast media • Parental anxiety

Diagnostic Approach Neuroimaging in Epilepsy

• Age of onset • Peak incidence in childhood • Static vs Progressive • Occurs as a co-morbid condition in many – Look for treatable causes pediatric disorders (birth injury, – Do not overlook abuse, Manchausen if all is negative dysmorphism, chromosomal anomalies, • Phenotype presence (syndromic, HC, NCS, developmental delays/regression) systemic involvement) • Predominant symptom (epilepsy, DD, • Many neurologic disorders in children weakness/motor, psychomotor regression, have the same chief complaint cognitive/dementia)

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Congenital Malformation

• Characterized by their anatomic features • Broad categories: based on embryogenesis – Stage 1: Dorsal Induction: Formation and closure of the neural tube. (Weeks 3-4) – Stage 2: Ventral Induction: Formation of the segments and face. (Weeks 5-10) – Stage 3: Migration and Histogenesis: (Months 2-5) – Stage 4: Myelination: (5-15 months; matures by 3 years)

Dandy Walker Malformation Dandy walker

• Criteria: – high position of tentorium – dysgenesis/agenesis of vermis – cystic dilatation of fourth ventricle • commonly associated features: – hypoplasia of cerebellum – scalloping of inner table of occipital bone • associated abnormalities: – 75% – dysgenesis of corpus callosum 25% – heterotropia 10%

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Etiology of Epilepsy: Developmental and Genetic Classification of Gray Matter Heterotropia Cortical Dysplasia 1. Secondary to abnormal neuronal and • displaced masses of nerve cells • Subependymal glial proliferation/apoptosis (gray matter) heterotropia (most • most common: small nest common) 2. Secondary to abnormal neuronal adjacent to lateral ventricles • Band heterotropia (double migration • Range from nodular to band cortex) 3. Secondary to abnormal cortical heterotropia to , • lissencephaly and • Cobblestone cortex (lis 2) organization or late migration 4. Not otherwise classified • clinical: • Subcortical heterotropia •IEM • MRI: isointense with gray • Other unclassified dysplasia matter in all sequence

Subependymal heterotropia Subcortical heterotropia

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Double cortex Double cortex

Double cortex Double cortex

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Polymicrogyria polymicrogyria

• multiple abnormal tiny indentation along brain surface (5-7mm) • abnormal cortical histology • can be unilateral • MRI: decreased number of broad, thick, smooth gyri

Polymicrogyria

• thick and more completely developed gyri • commonly diffused with relative sparing of temporal lobes • associated with: agenesis of CC and heterotopias • clinical: , seizures, MR, developmental delay • MRI: circumferential band of high signal on T2 within the cortex

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Lissencephaly Lissencephaly Imaging

• Severe form of neuronal migration Disorder • Hourglass or figure of 8 • Can be seen in: – Shallow sylvian fissure – Isolation • LIS 1: parietal-occipital – Miller Dieker Syndrome • X-LIS: Subfrontal/temporal – TORCH infection (CMV) • 3 layers ay be seen in neonates on T2W • Clinical S/S: – Outer layer – thin, smooth – Mental Retardation – Intervening cell sparse layer – Intractable Epilepsy – Microcephaly – Deeper thick layer – mimicking band heterotropia • Posterior > Anterior involvement in LIS 1

lissencephaly Lissencephaly Variants

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Miller dieker Lissencephaly syndromes

Agyria Lis 1

• Complete lissencephaly • Smooth brain

Identified by figure eight due to shallow sylvian fissures.

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Schizencephaly Schizencephaly Imaging

• Gray matter- lined • Transmantle gray matter lining clefts cleft that extends from – Dimple in wall of ventricle if closed or narrow the ventricular ependyma to the pia. • Frontal and Parietal lobes near central • Unilateral or bilateral sulcus • Two types: • Distinction of GM lining cleft can be – Closed lip (type I) difficult prior to myelination – Open lip (type II) • DVA overlie cleft seen on MRV

Schizencephaly Schizencephaly Differential Diagnosis • – Lined by gliotic white matter – No dysplastic gray matter

• Semilobar Holoprocencephaly – Can mimic bilateral open lip schizencephaly

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Schizencephaly Schizencephaly

Hemimegalencephaly

• Primary hamartomatous malformation • No differences between Isolated or Syndromic type. • Onset usually in neonatal period • Plain Skull Films: look for macrocrania & • Catastrophic asymmetry. • One type of onset is Tonic (Ohtahara • May see intracranial calcifications & bony Syndrome) dysplasia • US: prenatal may suggest HME, may see • Can be asymmetric and often precede or , ventricular asymmetry with overlap with West Syndrome (IS) enlargement of lateral ventricle – Postnatal: may see unilateral ventricular dilation with • IS= 50% hemispheric enlargement

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Hemimegalencephaly Imaging Hemimegalencephaly

•CT & MRI: – Gross asymmetry – 1 hemisphere enlarged • Posterior falx and occipital pole displaced to contralateral side – Dysplastic Cortex – Asymmetry of Ventricular System -

• 4 points of abnormal ventricle. – 1. Straightened frontal horns (pointed) – 2. mild-extreme dilation of lateral ventricle – 3. reverse of contralateral horn (mass effect appearance) –4. (disproportionate developmental dilation of occipital horn of lateral ventricle) in all grades of HME

Hemimegalencephaly

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FCD with Balloon Cells FCD, Balloon Cell

• Abnormal gyral pattern when large • Blurring of gray-white junction • Abnormal tissue: cortex to border of lateral ventricle • Typically associated with TS • Solitary – no other TS features • T2 hyperintense “comet tail” from cortex to ventricle – Best seen on flair

FCD with balloon cell FCD with balloon cell

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DNET DNET

• Intractable epilepsy • Focal deficits • More common 2nd and 3rd decade • Considered part of abnormal neuronal/glial proliferation - neoplastic • MRI Findings: – T1 hypointense – T2 hyperintense – Modest to no enhancement – Scalloping – Lack of mass effect, edema

DNET DNET

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Neurometabolic-Degenerative Disorders Neurometabolic-Degenerative Disorders • Type of myelination involvement • Knowledge of normal myelination pattern – Delayed myelination is essential – Demyelination – Dysmyelination • General rules: – Caudal to cranial • involvement – Brainstem involvement – Posterior to anterior – Cerebellar involvement • MRI provides the best imaging modality – involvement – T1 matures at 12-14 months • Tissue Involvement – T2 matures at 24-26 months – Gray matter involvement – White matter involvement

1 month Factors to Consider

• Age of Onset • Degree of derangement 9 months • Abnormal metabolite – Deficiency or excess • Stage of the disease process 36 months • Phenotype

From Alberico

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Symptoms of Progressive CNS Disease Symptoms of Progressive CNS Disease Early Onset (Newborn or young infant) Later Onset ( older infant or child)

• Intermittent lethargy, decreased responsiveness • Change in temperament, behavior or activity associated with emesis level • Irritability, excessive or absent startle response • Disturbance in gait (progressive ataxia), • Decreasing interest in surroundings, excessive clumsiness sleepiness, decreased smiling • Unusual movements, dystonia, chorea • Poor or absent eye fixation, nystagmus • Progressive muscle weakness, change in tone • Poor head control, weak suck • Feeding difficulties, FTT • Progressive loss of speech, vision or hearing • Excessive tongue trusting, asymmetric • Headaches movements • Change in bowel/bladder function • Floppy or spastic •Seizures •Seizures

White Matter versus Gray Matter White Matter versus Gray Matter Early Disease Advanced Disease White Matter Gray Matter White Matter Gray Matter • Gait disturbance • Progressive cognitive • Progressive cognitive •Ataxia •Ataxia impairment impairment • Hyperreflexia • Brisk reflexes •Seizures • Blindness • • Spasticity • Blindness • Deafness • Babinski sign • Babinski sign •Seizures

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Leukodystrophies Leukodystrophies Differential Diagnosis • Abnormal signal in white matter • Radiation and Chemotherapy injury • Symetric usually • Periventricular, deep or subcortical in location • Viral encephalitis • Failure to achieve myelination milestones •ADEM • MRS abnormalities reflect neuronal loss and •MS increased cellular turnover • In neonates: HIE • Some have contrast enhancement – Periventricular pattern – ALD: zone of active inflammation – Alexander: ventricular lining, periventricular rim, frontal WM, optic chiasm, fornix, BG, thalamus, dentate nucleus

Head Circumference Alexander Disease

Macrocephalic Microcephalic/Normal • Clinical S/S: macrocephaly, seizures • Canavan •ALD • Mutation: GFAP, Chromosome 17q21 • Alexander •MLD • Imaging • Tay Sachs (GM2 • Cockayne Disease – Extensive WM changes with frontal predominance gangliosidosis) • Pelizaeus Merzbacher – Abnormal signal in BG and thalami • Vanishing White Matter disease – Enhancement: ventricular lining, periventricular rim, • Van der Knaap Disease • Zellweger Disease frontal WM, optic chiasm, fornix, BG, thalamus, dentate nucleus • L-2-hydroxyglutaric • Krabbe aciduria • Give contrast to all unknown cases of hydrocephalus and abnormal WM

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Alexander Disease Alexander Disease

Alexander Disease Alexander Disease

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Alexander Disease Alexander Disease - late

Canavan Disease Canavan Disease

• Clinical S/S: Macrocephaly, • Imaging: – Diffuse T2 hyperintensity preferentially involves subcortical U fibers – Spares internal capsule and corpus callosum – Involves thalamus, globus pallidus + dentate – Spares caudate and putamen – MRS shows marked elevation of NAA peak

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Canavan Disease Canavan Disease

Canavan Disease Hypomyelination Disorder Differential Diagnosis • Maple Syrup Urine Disease • Areas to assess: internal capsule, – Elevated branch chain AA pyramidal tracts, peripheral frontal lobe • Pelizaeus-Merzbacher Disease WM – Spares GP and thalami • T1 signal reflects presence of myelin • Alexander Disease – Children < 10 months – Enhances – Myelinated WM - hyperintense – Predoinantly frontal WM • T2 reflects displacement of water – Children > 10 months – Mature WM - hypointense

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Pelizaeus-Merzbacher Disease Pelizaeus-Merzbacher Disease

• Clinical S/S: microcephaly, hypertonia, stridor • Deficiency of proteolipid protein (PLP) • Hypomyelination disorder • Imaging – Variable – Nonspecific and symmetrical abnormality of WM – Lack of myelin

Vanishing white matter disease Hypomyelination

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Metachromatic Leukodystrophy MLD

• Decreased arylsulfatase A – Central and peripheral demyelination • Imaging – Confluent butterfly-shaped increased T2 signal deep cerebral WM • Spares U fibers in early disease • Involves U fibers in late disease – Sparing of perivenular myelin producing the tigroid appearance – No enhancement of WM – May have enhancement of cranial nerves and cauda equina

MLD Krabbe Disease

• aka Globoid cell leukodystrophy • Clinical S/S: irritability • CT: hyperdensity in thalamus, BG • MRI Imaging: – Faint hyperintensities in thalamus and BG (T1W) – Ring like appearance around dentate nucleus (T2W) – PV WM hyperintensities (T2W) • Initially spares U fibers – Enlarged optic nerves and cranial nerves (T1W) • MRS: increased choline,myoinositol, decreased NAA, lactate accumulation

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Krabbe Disease Krabbe Disease CT Scan

Krabbe Disease Krabbe Disease

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Adrenoleukodystrophy (ALD) Adrenoleukodystrophy

• Rare, characterized by the • slow mentation, lack of interest or hyperactivity breakdown or loss of the myelin sheath • dysphagia, dysarthria, surrounding nerve cells in the brain • occasional psychotic behavior • Progressive dysfunction of the adrenal gland • visual loss and hearing loss • X linked recessive • progressive hemiplegia may appear • seizures in 1/3 of patients • vegetative in 1 to 2 years Chromosome Xq28

ALD ALD

• Always abnormal in neurologically symptomatic males • Often provides first lead • Predominately posterior white matter – 80% • Splenium of corpus callosum usually involved

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SSPE SSPE

• Nonspecific leukoencephalopathy •MRS: – decreased NAA/Cr – Increased Cho/Cr; Ins/Cr and Lac-Lip

Gray Matter Metabolic Disorder Leigh Syndrome

• Wilson Disease • Progressive neurodegenration • Leigh Disease • Respiratory chain disorder • PKAN • Clinical S/S: psychomotor delay/regression • 3-methylglutaconic aciduria • Imaging: – Bilateral symmetric increased T2/FLAIR signal • Biotin dependent encephalopathy • Putamen>caudate>GP, periaqueductal gray, • Methylmalonic acidemia SN/STN, dorsal pons, cerebellar nuclei – Restrictive diffusion in areas of acute disease • MRS: increased lactate; decrease NAA, increase choline

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Leigh Syndrome Leigh Syndrome

Pantothenate kinase-associated Leigh Syndrome neurodegeneration (PKAN)

• Neurodegeneration with brain iron accumulation (NBIA) • Clinical S/S: progressive dystonia, dysarthria, rigidity, and pigmentary retinopathy • Approximately half of the individuals have identifiable mutations in the PANK2 gene • 'eye-of-the-tiger' sign found to have at least one mutation in PANK2 • Differential Diagnosis: signal changes in GP

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PKAN PKAN

Differential diagnosis Wilson Disease

• Abnormalities of plasma ceruloplasmin • Clinical S/S: hepatic abnormality; psychiatric concentration or copper metabolism (Wilson • Imaging: Disease) – T1 shortening of GP – Symmetrical T2 hyperintensity or mixed signal intensity in • Evidence of neuronal ceroid lipofuscinosis putamen, GP, CN, thalami • Family history of Huntington disease or other – BG: initially enlarged due to edema than atrophy – ‘face of the giant panda’ – midbrain level (axial) dominantly inherited movement disorder • Hyperintensity tegmentum except RN • Caudate atrophy • Hypointensity superior colliculi • Normal signal lateral portion of pars reticularis of SN • ß-hexosaminidase A deficiency or GM1- – Increased signal intensity in cerebral and cerebellar WM galactosidase deficiency (T2W) – DWI + - acute/active

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Wilson disease Wilson Disease

Summary

• Neuroimaging has a role in the determining the etiology of pediatric neurologic conditions • Serial MRI may provide for prognostication and progression of disease • Knowledge of normal myelination pattern will decrease the chances of misinterpretation • To obtain the most complete data set for pattern recognition, a systematic and comprehensive evaluation of brain structures is mandatory

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