Control# 591

Title: “It’s not a Rorschach test” Imaging pattern recognition of pediatric metabolic disorders of the brain

eEdE# eEdE-162

Nothing To Disclose

“It’s not a Rorschach test” Imaging pattern recognition of pediatric

metabolic disorders of the brain

Nucharin Supakul, MD1

Chang Y Ho, MD2

1 Ramathibodi Hospital, Mahidol UniversityBangkok, Thailand

2 Riley Hospital for ChildrenIndiana University School of MedicineIndianapolis, Indiana, USA

Purpose• To review the characteristic imaging

findings of inherited metabolic disorders involving the brain categorized primarily by location Gray matterWhite matterBoth Gray and White matter

• To recognize imaging patterns for the most common disorders in each group

Introduction • Metabolic brain disorder

Genetic condition enzyme deficiency and metabolism problem

• Overall incidence: 1: 1,000 – 2,500 newborns

• Higher incidence in certain ethnic population: Ashkenazi Jews• Imaging is typically bilateral and symmetric, with progressive functional

deterioration without treatment.

• Type Hypomyelination (Pelizaeus – Merzbacher disease, 18q deletion syndrome, 4H syndrome)

Lysosomal storage disorder (Hurler syndrome, Neimann-Pick disease, metachromatic leukodystrophy, Tay-Sachs disease, Gaucher disease, Fabry disease, Krabbe disease)

Mitochondrial disorders (Leigh syndrome, myoclonic epilepsy with Ragged red fiber (MERRF), MELAS)

Peroxisomal disorder (Zellweger syndrome, X-linked adrenoleukdystrophy)

Glycogen storage disease (von Gierke disease (type I), Pompe disease (type II), type III-VII)

Metal metabolism disorders (Wilson disease, hemochromatosis)

Others: Alexander disease, Canavan disease, Galactosemia, Maple syrup urine disease, Phenylketouria (PKU), Friedreich ataxia, Organic academia, Urea cycle disorder

http://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-types-and-treatments

Case list

Predominantly White Matter

• Pelizaeus - Merzbacher disease

• X-linked adrenoleukodystrophy (ALD)

• Metachromatic leukodystrophy

• Alexander disease

Predominantly Gray Matter

• Leigh syndrome• MELAS

Both Gray and White Matter

• Canavan disease• Krabbe disease• Tay-sachs disease

Predominantly White Matter

T1hyper/T2hypo

Demyelination(Loss of myelination)

Pelizaeus-Merzbacher disease

Subcortical WM(Early subcortical U-fiber involvement)

Look at thalami

- Krabbe disease- GM2 gangliosidosis (Tay Sachs) Look at brainstem/

corticospinal tract

X-linked ALD- Metachromatic leukodystrophy- Phenylketouria

Normocephaly

- Galactosemia- Salla disease

- Alexander disease- Megalencephalic leukoencephalopathy with subcortical cysts (MLC)

Hypomyelination(Myelination never matures)

Deep WM

Normal thalami

Involvement No involvement

Macrocephaly

Predominantly Gray Matter

Deep GM

- Leigh syndrome- MELAS- Organic acidurias- Wilson’s disease- Juvenile Huntington’s disease- Hypoglycemia

Normal T2/ T1 hyperintense

- Urea cycle disorder- Organic acidurias- Kernicterus- CO, cyanide toxicity

- Pantothenate kinase-associated degeneration

Cortical GM

Striatum (caudate + putamen)

T2 hyperintense T2 hypointense

- Chronic liver disease- Mineralizing angiopathy

Globus pallidus

Both Gray and White Matter

Deep GM

Globus pallidusThalami

Cerebral cortex

- Leigh syndrome- MELAS- Organic acidurias- Wilson’s disease

- Krabbe disease- GM1/ GM2 gangliosidoses

Normal Abnormal

+ Cortical migrational anomalies- Congenital CMV- Congenital muscular dystrophy (type II lissencephalies)

- Cortical migrational anomalies- Alpers disease- Menkes disease

- Lipid storage disorder- Peroxisomal disorders

- Canavan disease- Late phase Kearns-Sayre syndrome- Maple syrup urine- CO/ cyanide toxicity

Striatal (putamen + caudate)

Look at long bones and spinal column

PELIZAEUS-MERZBACHER DISEASE

Pelizaeus - Merzbacher disease • X-linked disorder

• Mutation of proteolipid protein 1 (PLP1) gene

• Chromosome X (Xq22)

• Defective central nervous system myelination

• 1: 500,000 in USA

• 1: 100,000 – 1,000,000 internationally

• Clinical presentation Nystagmus in 1st year of life Delayed motor and cognitive

milestones Ataxia

• Prototype of hypomyelination syndrome: Involving WM only

• Normal myelination pattern

Sequence to look for maturation < 1 year of life: ↑ T1 > 1 year of age: ↓ T2 for myelin

compaction, delays ↑ T1

Pattern of ↑ T1 At birth: Corticalspinal tract,

Rolandic gyri

4 months: Splenium, Anterior limb of the internal capsule, deep cerebellar white matter and brain stem

6 months: Genu of corpus callosum, paracentral WM of occipital and parietal lobes

8 months: Nearly adult configuration with lack of myelination of frontal subcortical WM in T1

Pelizaeus-Merzbacher disease

3-month-old male infant, with history of nystagmus, hypotonia and developmental delay

A: Axial T1 of the basal ganglia level shows lack of normal T1 hyperintensity of the posterior limb of the internal capsule (orange arrows) in this 3 month old, normally expected to be myelinated at birth.

B: Axial T2 of the basal ganglia level shows a lack of T2 hypointensity from normal myelin compaction with some expansion of the posterior limb of the internal capsule from edematous change (orange arrows).

C: Axial T2 through the cerebellum shows diffuse T2 hyperintensity of the cerebellar white matter (yellow arrows), normally expected to be myelinated with decrease in T2 signal. There is only mild myelin compaction in the dorsal brainstem (blue arrow).

A B C

Back to case list

X-LINKED ADRENOLEUKODYSTROPHY

X-linked Adrenoleukodystrophy • 1: 20,000 - 70,000

• Peroxisomal disorder

• Chromosome X

• Mutation of ABCD1 gene

• Impaired oxidation of very long chain fatty acids accumulation of very long chain fatty acids in tissues throughout body

• Affects myelin, spinal cord, peripheral nerves, adrenal cortex and Leydig cells of the testes

• Classic Radiographic Findings: Symmetrical, confluent T2

hyperintensity

Early: peritrigonal (parietooccipital white matter), splenium of corpus callosum

Late: corticospinal tract, fornix, visual and auditory pathway

Enhancement and restricted diffusion in peripheral zone of active disease

Spared subcortical U fiber

X-linked Adrenoleukodystrophy 9-year-old boy with history of developmental delayed

A: Axial FLAIR shows symmetric T2 prolongation involving the splenium (orange arrow), periatrial (blue arrows) and capsular white matter (pink arrows) is seen in this classic pattern of X-linked adrenoleukodystrophy.

B: DWI image shows peripheral areas of diffusion restriction (green arrows), indicative of acute demyelination

C: Coronal T1 post contrast shows enhancement (purple arrow) of the intermediate zone of demyelination which is typical of progressive X-

ALD.

D: MRI spectroscopy of the involved white matter demonstrates decrease

in NAA (yellow arrow), elevation of choline (red arrow) and myo-inositol (blue arrow) with significant presence of lactate (orange arrow) and lipid break down products including very long chain fatty acid molecules in the 0.9 to 2.4 ppm range (pink star).

A B

C D

Back to case list

METACHROMATIC LEUKODYSTROPHY

Metachromatic Leukodystrophy• 1: 100,000 in USA

• Autosomal recessive

• Lysosomal storage disorder

• Defect in arylsulfatase-A (ARSA) accumulation of sulfatides in both PNS and CNS demyelination with lack of perivascular inflammation and uptake within macrophages of metachromatic granules

• Risk: Habbanite Jews and Navajo Indians

• Clinical presentation: toddler with visual and oromotor impairment and abdominal pain

• Classic Radiographic Findings: Confluent butterfly-shaped T2 hyperintensity involving deep cerebral white matter

Early: spares subcortical U-fibers

Late: involves subcortical U-fibers and corpus callosum

No enhancement lack of inflammation

Tigoid appearance spared perivenular myelin

Metachromatic leukodystrophy6-year-old girl, progressive hypotoniaA: Axial T2 FLAIR shows diffuse white matter demyelination with symmetrical, confluent areas of T2 hyperintensity in a "butterfly" pattern within frontoparietal deep periventricular white matter (orange arrows) and corpus callosum (blue arrows).

B: Axial T2 image above the ventricles shows confluent symmetric involvement of the centrum semiovale with sparing of the subcortical U fibers (yellow arrows) as well as the perivenular myelin (pink arrows) giving the appearance of a "tigroid" pattern.

C: Post contrast imaging shows no enhancement, due to the lack of parenchymal inflammation seen with this disease.

D: There is decreased diffusion seen in the areas of active demyelination (green arrows).

A B

C D

Back to case list

ALEXANDER DISEASE

Alexander Disease• Fibrinoid leukodystrophy

• Rare

• Autosomal dominant

• Mutation of glial fibrillary acidic protein (GFAP)

• Chromosome 17 (17q21)

• Rosenthal fiber intracytoplasmic astrocytic inclusion leading to oligocytic dysfunction

• 3 forms Infantile (most common): birth –

2 years Juvenile: 2-12 years Adult : > 12 years old

• Clinical presentation Macrocephaly

Seizure

Developmental delay

Symmetrical T2 hyperintense bifrontal WM

• Classic Radiographic Findings: Confluent T2 hyperintensity

involving periventricular white matter with frontal to occipital gradient

Basal ganglia involvement in infantile form

Nodular areas of enhancement

Extension to subcortical white matter in late stage

Alexander Disease3-year-old girl with developmental delay

A-D: Axial FLAIR images show confluent areas of FLAIR hyperintensity involving subcortical U-fiber and periventricular white matter predominantly in bifrontal lobes with some parietal and occipital lobes as well as periaqueductal gray matter and cerebellum (orange arrows). Involvement of the caudate head and putamen is also noted (blue arrow).

A B

C D

Back to case list

LEIGH SYNDROME

Leigh syndrome• Synonym: subacute necrotizing

encephalomyelopathy

• A group of heterogenous diseases involving mitochondrial metabolism

• Autosomal recessive, X-linked

• Progressive neurodegeneration leading to respiratory failure and death

• 1:32,000

• Clinical presentations: usually by age of 2 years Psychomotor delay/regression Hypotonia Progressive BS & BG dysfunction:

ataxia, ophthalmoplegia, ptosis, swallowing & respiratory difficulties, dystonia

• Diagnostic clue Bilateral, symmetrical ↑ T2/FLAIR hyperintensity Locations:

Basal ganglia (BG): putamen > caudate heads > globi pallidi

Brainstem (BS): periaqueductal gray matter, substantia nigra/subthalamic nuclei, pons, medulla

Thalami and dentate nuclei Restricted diffusion in acute

phase MRS: ↑ choline, ↓ NAA, ↑ lactate

peak

Remark: lower BS (pons, medulla) with minimal BG involvement = SURF1 mutation

Leigh syndrome

Differential diagnosis:• Profound perinatal asphyxia appropriate

clinical history, low APGAR• MELAS asymmetric/unilateral• Glutaric aciduria type 1 opercular

widening• Wilson disease T1 shortening GP from

hepatic failure

Leigh syndrome (non-SURF1)7-year-old girl with history of spasticity and developmental delays

A-B: Axial T2 (A) and FLAIR (B) image shows T2 hyperintensity of the bilateral caudate and putamen (orange arrows) as well as the corpus callosum and periventricular white matter (blue arrows). The bilateral caudate heads appear swollen, while the putamina appear atrophic. Note the cavitation of the splenium and periatrial white matter (pink arrows).

C: Axial b=1000 DWI image shows decreased diffusion corresponding to bright signal of the bilateral

caudate heads and some spots in the putamina (yellow arrows). This correlates with more acute injury.

D: MR spectroscopy of the basal ganglia shows a prominent lactate doublet peak at 1.4ppm (green arrow).

A B

C D

Leigh syndrome (SURF1 mutation)8-month-old with history of seizure

A: Axial T2 image at the level of the lower medulla shows abnormal T2 hyperintensity of the central gray structures (blue arrow).

B-D: Axial DWI b=1000 shows focal symmetric bilateral diffusion restriction of the pontine tegmentum, midbrain tegmentum the subthalamic nuclei, and cerebral peduncles (orange arrows).

A B

C DBack to case list

MELAS(MITOCHONDRIAL MYOPATHY ENCEPHALOPATHY LACTIC ACIDOSIS AND STROKE-LIKE EPISODE)

MELAS• Synonym: Mitochondrial

myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes

• Mitochondrial disorder

• Multiple mutations of mitochondrial DNA

• Defect in oxidative phosphorylation of the brain parenchyma and vessels

• Clinical presentation Weakness and exercise intolerance Neuropsychiatric changes Migraines Cardiomyopathy Diabetes Hearing loss

• Classic Radiographic Findings: Stroke-like lesions

indistinguishable from vascular infarction, but typically does not follow a vascular distribution

Usually involve posterior cerebral hemispheres and basal ganglia

Multiple stroke-like lesions of varying age

Consider MELAS in unexplained strokes in pediatric patients and young adults

MELAS20-year-old female with history of new onset left facial droop, and visual loss. Additional history of prior stroke

A-B: Axial FLAIR images shows FLAIR hyperintensity and swelling of the right temporal lobe, occipital, and insular cortex (orange arrows). In addition, the pulvinar region of the thalamus is also involved (yellow arrow) in the these stroke-like lesions. This involves both the PCA and MCA arterial distributions.

Note the atrophy of the left occipital lobe and left temporal lobe tip from prior stroke-like involvement (blue arrow).

C: Axial ADC image shows decreased signal of the right posterior parietal lobe consistent with an acute stroke-like lesion (pink arrows).

D: Coronal T2 image shows right temporal and occipital hyperintensity and swelling from acute stroke-like lesion (orange arrow). Note the focal hyperintensity and swelling in the inferior left cerebellar hemisphere (green arrow) which showed no diffusion restriction consistent with a subacute lesion.

A B

C D

Back to case list

CANAVAN DISEASE

Canavan disease• Synonym: spongiform

leukodystrophy

• 1: 6,000 – 14,000 among Ashkenazi Jews

• 1: 40 carrier risk

• Autosomal recessive

• Chromosome 17

• Defect of aspartoacylase accumulation of N-acetyl aspartic acid in brain and urine

• Clinical presentation Macrocephaly Seizure Hypotonia

• Classic Radiographic Findings: Symmetrical confluent T2

hyperintensity

Location: Peripheral WM: subcortical U-

fiber involved early Deep gray matter: thalami, globi

pallidi, dentate nuclei

Early sparing internal capsule, corpus callosum,

Restricted diffusion in acute phase

No enhancement

Highly suggestive : ↑NAA on MRS

Canavan disease4-month-old boy with history of macrocephaly and seizure

A-B: Axial DWI (b=1000) images show restricted diffusion in the subcortical U-fibers of the frontal and occipital lobes and corpus striatum (orange arrows).

C: Axial T2 on a followup imaging in 3 months of the same patient shows increased T2 signal of the bilateral caudate and putamen

(blue arrows).

D: MRI spectroscopy of the affected left parietal white matter demonstrates significant elevation of NAA (pink arrow) and relative decrease in choline (green arrow).

A B

C D

Back to case list

KRABBE DISEASE

Krabbe disease• Synonym: Globoid cell

leukodystrophy

• 1:100,000 in USA and Europe

• 6:1,000 in Israel

• Autosomal recessive

• Deficiency of lysosomal galactocerebroside b-galactosidase

• Accumulation of galactosylceramide and psychosine within oligodendroglia and Schwann cells in early period of myelin turnover

• Formation of globoid cell (hematogeneous often-mulinuclearted macrophages): Hallmark of Krabbe disease

• 4 forms Infantile: 3 - 6 months Late infantile: 6 months – 3 years Juvenile: 3 - 8years Adult : > 8 years

• Classic presentation of Infantile form Early: Irritability, hypertonia,

hyperesthesia, psychomotor arrest

Late: Rapid deterioration, elevated protein in CSF, neurological evidence of WM disease, optic atrophy and death

• Classic Radiographic Findings: Confluent areas of T2 hyperintensity Involving bilateral central WM,

corticospinal tract, basal ganglia and thalami

Cranial nerve and peripheral nerve enlargement and enhancement

Krabbe disease20-month-old girl with history of seizure, and developmental delay

A-B: Axial T2 images shows diffuse confluent white matter T2 hyperintensity and atrophy with some sparing of subcortical U-fibers (orange arrows). Note the atrophy of the involved bilateral thalami, brain stem and corticospinal tract in cerebral peduncle (blue arrows).

C: Axial FLAIR image shows symmetric, confluent T2 hyperintensity of the central white matter with involvement of the corticospinal tract (posterior limb of the internal capsule) (pink arrows) and sparing of the subcortical white matter (red arrows).

D: Axial T1 postcontrast shows enlarged bilateral cranial nerve V (green arrows), a hallmark of metabolite deposition in Krabbe disease.

A B

C D

Back to case list

TAY-SACHS DISEASE

Tay-Sachs disease• Tay-Sachs and Sandhoff diseases

are both GM2 gangliosidoses, and are clinically indistinguishable

• Autosomal recessive

• Lysosomal storage disorder

• b-hexosaminodase A deficiency (Sandhoff disease is deficiencies in both A and B subunits)

• Accumulation of glycosphingolipids (GM2 gangliosides) in brain

• 1:30 carrier frequency in Ashkenazi Jewish and French Canadians

• 3 Forms: Infantile: symptom onset in 1st year Juvenile: 2-6 years Adult: 1st-3rd decades

• Clinical presentation Infant: psychomotor retardation Juvenile/Adult: atypical spinocerebellar

ataxia

• Classic Radiographic Findings: Infantile

T1 hyper/T2 hypo thalami (CT hyperdense)

Mild T2 hyper striatum Location: thalami, striatum, cerebral >>

cerebellar WM Deep white matter delayed myelination

with callosal sparing

Juvenile/adult Cerebellar atrophy Location: rare striatal and mass-like

brainstem involvement

No contrast enhancement

No corpus callosum involvement

Tay-Sachs disease

2-year-old boy with history of seizure and feeding dysfunctionA: Axial CT shows bilateral diffuse symmetric hyperintensity of the thalami (orange arrows).

B: Axial T1 image shows diffuse T1 hyperintensity of the thalami (orange arrows), and lack of normal T1 bright myelination of the posterior periventricular white matter (pink arrows). There is sparing of the corpus callosum.

C: Axial T2 image shows heterogeneous signal of the thalami (orange arrows) (more specific to Tay-Sachs) and increased T2 signal of the basal ganglia (red arrows). There is loss of normal T2 hypointense myelin compaction of the periventricular white matter (blue arrow) with sparing of the corpus callosum

A B C

Back to case list

Summary: Predominantly White MatterCauses Classic Radiographic findings Remarks

Pelizaeus - Merzbacher disease

Hypomyelination Location: Isolated WM involvement

Description: Hypomyelination compared to patient’s age

• Prototype of hypomyelination

• Lack of normal myelin maturation

Metachromatic Leukodystrophy

Lysosomal storage disorder

Location: Anterior and posterior deep white matter

Description: Confluent butterfly-shaped T2 hyperintensity involving deep cerebral white matter

• Anterior and posterior• Central WM• Sparing subcortical U fiber

in early course• No enhancement• Tigroid appearance

X-linked adrenoleukodystrophy

Peroxisomal disorder

Location: Posterior/peritrigonal white matter

Description: Confluent T2hyperintensity involving predominantly parietooccipital white matter (posterior) and splenium of corpus callosum

• Posterior location • Central WM• Restricted diffusion and

enhancement in the edge of the lesions

• Can be frontal (anterior) in atypical cases (10%)

Alexander disease Other Leukodystrophy(Mutation of glia fibrillary acidic protein (GFAP))

Location: Anterior periventricular > subcortical white matter± BG, thalami, brain stem, cerebellum, fornix, optic chiasm, spinal cord

Description: Confluent T2hyperintensity involving predominantly frontal white matter (anterior)

• Anterior predominantly• Central WM• Enhancement in the edge

of the lesions• Macrocephaly

Summary: Predominantly Gray matter Causes Classic Radiographic findings Remarks

Leigh syndrome- Non- SURF1 mutation

Mitochondrial disease

Location: BG: putamen > caudate heads > globi pallidiBS: periaquedutal gray matter, substanita nigra/subthalamic nucleiThalami and dentate nuclei

Description: Symmetrical areas of T2/FLAIR hyperintensity with restricted diffusion in acute phase

• Restricted diffusion in acute phase

• No contrast enhancement

Leigh syndrome- SURF1 mutation

Mitochondrial disease

Location: Lower BS (pons, medulla) with mild BG involvement

Description: Symmetrical areas of T2/FLAIR hyperintensity with restricted diffusion in acute phase

• Lower BS (pons, medulla) with mild BG involvement

MELAS Mitochondrial disorder

Location: Posterior cerebral hemisphere and basal ganglia

Description: Stroke-like lesions, varying age. Do not follow vascular territory.

• Consider MELAS for unexplained strokes in pediatric patients

Summary: Both Gray and White matter Causes Classic Radiographic findings Remarks

Canavan disease

Other Leukodystrophy:Autosomal recessive(Deficiency of enzyme aspartoacylase)

Location: Peripheral WM: subcortical U-fiberDeep Gray matter: Globi pallidi, thalami

Description: Conflent T2 hyperintenisty involving subcortical U-fiber, globi pallidi, thalami with early sparing of the internal capsule and corpus callosum

• ↑ NAA• No enhancement• Restricted diffusion in

acute phase

Tay-Sachs disease

Lysosomal storage disorder

Location: Thalami, striatum, cerebral >> cerebellar WM

Description: - Areas of T1 hyper/T2 hypointensity involving thalami- Hyperdensity on CT - Deep white matter delayed myelination

• No contrast enhancement

• No corpus callosum involvement

Krabbe disease Lysosomal storage disorder

Location: Central WM, corticospinal tract basal ganglia, and thalami

Description: Symmetrical confluent areas of T2/FLAIR hyperintensity involving central WM, cortical spinal tract, BG and thalamiCranial nerve and peripheral nerve enlargement and enhancement

• Cranial nerve and peripheral nerve enlargement and enhancement

Conclusion • Inherited metabolic disorders affecting the brain are

complex, heterogeneous and have varied clinical symptoms, but primarily present with progressive functional deterioration without treatment

• Cross-sectional imaging can be helpful, especially MRI, which can be tailored to narrow the differential diagnosis and guide further evaluation and treatment. Bilateral symmetric findings are typical.

• Characteristic imaging findings and patterns suggesting metabolic brain disease should prompt further genetic/ metabolic evaluation, particularly when the clinical history is nonspecific.

References1. Barkovich, A. James, and Charles Raybaud. Pediatric neuroimaging.

Lippincott Williams & Wilkins, 2012.

2. Barkovich AJ. An approach to MRI of metabolic disorders in children. J Neuroradiol. 2007 May;34(2):75-88.

3. Grodd, W., et al. "Metabolic and destructive brain disorders in children: findings with localized proton MR spectroscopy." Radiology 181.1 (1991): 173-181.

4. Cecil, Kim M., and Blaise V. Jones. "Magnetic resonance spectroscopy of the pediatric brain." Topics in Magnetic Resonance Imaging 12.6 (2001): 435-452.

5. Bianchi, M. Cristina, et al. "Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance." American journal of neuroradiology 24.10 (2003): 1958-1966.

6. http://www.webmd.com/a-to-z-guides/inherited-metabolic-disorder-types-and-treatments