1	Pediatric Leukoencephalopathies: A Neuroimaging Review of Common Myelin Disorders
2	Pediatric Leukoencephalopathies: A Neuroimaging Review of Common Myelin Disorders
3	Introduction The term leukoencephalopathy is broad and encompasses a heterogeneous group of diseases that primarily affect the white matter of the CNS. The disease entities include both primary myelin disorders, axonal/neuronal degeneration and inflammatory disorders.
4	Introduction Leukoencephalopathies are commonly divided into two categories: Dysmyelinating Diseases Also known as leukodystrophies, these disorders result from an inherited defect usually in an enzyme pathway or organelle function, which leads to abnormal formation, destruction, or turnover of myelin. Demyelinating Diseases A group of acquired disorders which result in abnormal destruction of intrinsically normal myelin and/or axons.
5	Learning Objectives MR imaging has emerged as the primary modality for detecting and characterizing white matter disorders. MR findings are often nonspecific. We present a systematic review of the most common features of leukoencephalopathies to help the reader better organize and evaluate these complicated disorders. Diagnosis is ultimately made from a combination of physical, biochemical, and imaging findings. We will begin with a review of the current classification of the leukoencephalopathies.
6	Classification of Leukoencephalopathies Disorders of white matter are divided into heritable enzyme/organelle defects and acquired processes which destroy normal myelin. These categories are further subdivided into:
7	Heritable Leukodystrophies Lysosomal Metachromatic Leukodystophy (MLD) Krabbe Disease Mucopolysaccharidosis Gangliosidoses GM2 Peroxisomal X-linked Adrenoleukodystrophy Zellweger syndrome Mitochondrial MELAS Leigh Disease Kearns-Sayre Syndrome Glutaric Aciduria Alpers Disease Non-Specific Mitochondrial encephalopathy
8	Acquired Demyelinating Diseases Non-infectious/ Non-inflammatory Multiple Sclerosis Neuromyelitis Optica (Devic disease) Infectious/Inflammatory Acute Disseminated encephalomyelitis (ADEM) Subacute Sclerosing Panencephalitis (SSPE) Progressive Multifocal Leukoencephalopathy (PML) Subacute HIV infection Viral Encephalitides
9	The Heritable Leukodystrophies
10	Lysosomal Disorders
11	Metachromatic Leukodystrophy (MLD) Inheritance pattern: Autosomal recessive Enzyme defect: Lysosomal Arylsulfatase A This enzyme is necessary for the normal metabolism of sulfatides, a normal constituent of myelin MLD is diagnosed biochemically on the basis of an abnormally low level of arylsulfatase A in peripheral blood leukocytes.
12	Metachromatic Leukodystrophy (MLD) Clinical: 3 forms: late infantile – most common; manifests between 12 and 18 months juvenile adult Characterized by motor signs of peripheral neuropathy including muscle hypotonia, deterioration in intellect, speech and coordination. Vision is impaired due to optic nerve atrophy. Eventually the child becomes blind and completely tetraplegic in a decerebrate state without purposeful movements. Death occurs 6 months to 4 years after symptom onset.
13	Metachromatic Leukodystrophy (MLD) MR imaging features: ↑ T2 signal reported earliest in the corpus callosum, the internal capsules and corticospinal tracts are frequently involved (see figs c & d) T2 high signal is seen more or less symmetrically in the periventricular white matter, in a highly confluent pattern (see figs a & b) with characteristic sparing of the subcortical U-fibers A striped or tigroid appearance of the periventricular white matter is seen (fig b) with central low signal indicating sparing of the perivascular white matter Cerebellar white matter may also be involved Typically no enhancement
14	Krabbe Disease (Globoid Cell Leukodystrophy) Inheritance pattern: Autosomal Recessive Enzyme defect: Lysosomal Galactocerebroside ß-galactosidase This enzyme is necessary in the first step of metabolism of cerebroside, a normal constituent of myelin – cerebrosides accumulate in the lysosomes within white matter, creating the characteristic globoid cells.
15	Krabbe Disease (Globoid Cell Leukodystrophy) Clinical: 4 recognized forms: Infantile – most common; manifests between 1 and 6 months Late infantile Juvenile Adult Initially presents with hyperirritability and periods of fever without other signs of infection. Muscle tone increases with subsequent rapid and severe motor and mental deterioration with constant opisthotonus and hypertonic flexion of the arms and extension of the legs. The disease rapidly progresses with death ensuing between 5 months and 3 years of age.
16	Krabbe Disease (Globoid Cell Leukodystrophy) MR Imaging features ↑T2 seen in the periventricular white matter with sparing of the subcortical U-fibers A radiating striped or tigroid appearance is often observed in the white matter, correlating pathologically with perivascular deposits of globoid cells (fig b) Posterior limb internal capsule, cerebellar white matter and pyramidal tracts in the brainstem are involved (arrow fig a) With progression of disease, the subcortical white matter becomes involved with generalized atrophy Subtle enhancement is variably seen, usually at the junction between normal and abnormal white matter
17	Mucopolysacchridoses Mucopolysaccharidoses constitute a group of disorders caused by deficiencies of lysosomal enzymes responsible for metabolism of mucopolysaccharides (glycosaminoglycans). Demonstrates ↑ concentration of glycosaminoglycans in the brain and leptomeniges. There are a total of six subdivisions to date which share several clinical features and are subdivided by genetic and biochemical differences.
18	Hurler - Scheie Syndrome (Mucopolysaccharidosis I) Inheritance pattern: Autosomal recessive Enzyme defect Autosomal recessive Deficiency in α-L-ironidase Clinical: 3 subtypes: Hurler, Hurler–Scheie, Scheie (mild) There is considerable clinical variability Normal intelligence to progressive mental retardation, macrocephaly, skeletal abnormalities, hepatosplenomegaly, cardiovascular involvement Patients with Hurler’s demonstrate progressive physical and neurologic deterioration, rarely surviving beyond 16 years of age, while patients with Scheie syndrome may be nearly normal
19	Hurler - Scheie Syndrome (Mucopolysaccharidosis I) MR imaging features: Cystic foci in corpus callosum, basal ganglia and cerebral WM representing enlarged perivascular CSF spaces filled with CSF or mucopolysacchride (arrow fig a) Multifocal ↑ T2 signal in the cerebral WM representing gliosis Ventricular enlargement 2° to hydrocephalus
20	Hunter Syndrome (Mucopolysaccharidosis II) Inheritance pattern: X-linked Enzyme defect: Deficiency in L-sulfoiduronate sulfatase Clinical: Visual disturbances, progressive deafness, hepatosplenomegaly, cutaneous manifestations
21	Hunter Syndrome (Mucopolysaccharidosis II) MR imaging Scattered ↑ T2 & flair signal predominantly through out the white matter representing gliosis Small punched out cystic lesions in subcortical WM representing enlarged perivascular spaces filled with CSF or mucopolysacchride. (figs a & b) Ventricular enlargement 2° to hydrocephalus
22	Gangliosidoses GM2 Inherited disorder of GM2 ganglioside metabolism resulting in neuronal loss and WM degeneration 3 Major subtypes Type AB – Infantile form Type B – Tay-Sachs disease Type O – Sandhoff disease Inheritance pattern: Autosomal recessive Enzyme defect Deficiency in hexosaminidase with abnormal accumulation of GM2 ganglioside in cytoplasm of neurons resulting in neuronal loss WM degenration Dx: assaying hexosaminidase A & B in serum, leukocyte or cultured skin fibroblasts.
23	Gangliosidoses GM2 Clinical Similar clinical presentation for Tay-Sachs and Sandhoff Psychomotor retardation and hypotonia, neurologic deterioration in the 1^st year of life Progressive motor weakness, spasticity, dystonia, choreaform movements, ataxia, blindness, macrocephaly and seizures Patient becomes bedridden and demented 3 – 10 years
24	Gangliosidoses GM2 Tay-Sachs disease MR imaging ↑ T2 thalami, caudate nucleus, globus pallidus and putamen ↑ T1 in globus pallidus, putamen and thalami Diffuse progression of ↑ T2 in the WM Sandhoff disease MR imaging Similar findings to Tay-Sachs with less severity
25	Peroxisomal Disorders
26	X-linked Adrenoleukodystrophy Inheritance pattern: X - linked Enzyme defect: Genetic defect terminal segment of long arm of X chromosome Deficiency of acyl-CoA synthetase Dx by chromosomal assay of plasma, RBC’s or cultured fibroblasts
27	X-linked Adrenoleukodystrophy Clinical: Effects white matter in CNS, adrenal cortex and testes Two major forms Childhood cerebral form Between 5 and 12 yrs Initial presentation of learning difficulties, impaired visual acuity, hearing difficulties, gait disturbance Abnormal skin pigmentation (bronzing), typically predates neurologic abnormalities 2° to adrenal insufficiency Adrenomyeloneuropathy Presents in young adults Incontinence, progressive paraparesis, progressive cerebellar dysfunction
28	X-linked Adrenoleukodystrophy MR features Marked ↑ T2 and ↓ T1 white matter signal abnormalities Posterior predominance, splenium of corpus callosum (80%) Frontal white matter, genu of corpus callosum (15%) Typically spares the U-fibers Enhancement of inflammatory leading edge of demyelination (correlates with worsening clinical status)
29	Mitochondrial Disorders
30	MELAS (Mitochondrial Encephalopathy with Lactic acidosis and Stroke-Like Episodes) Etiology: Possible deletions of mitochondrial DNA Theory – mitochondrial vasculopathy of small arteries resulting in areas of infarct Clinical: Episodes of throbbing headache, nausea, vomiting, permanent or reversible stroke-like events Presentation most commonly 2^nd decade, however may present at any age ↑ serum and CSF lactate
31	MELAS MR features: Variable distribution of ↑T2 and flair signal abnormalities that do not follow vascular distribution. Cortex is more severely affected than the underlying WM Cortex enhances after contrast ADC values controversial, studies showing ↑, normal or ↓ values.
32	Glutaric Aciduria Type I Inheritance pattern: Autosomal recessive Enzyme defect: Deficiency of glutaryl-CoA dehydrogenase Clinical: Age of presentation by 12 months Excessive excretion of glutaric acid, glutaconic acid and 3-hydroxy-glutaric acid in the urine Macrocephaly, acute encephalopathy, gradual hypotonia, progressive dystonia, choreoathetosis, tetraplegia
33	Glutaric Aciduria Type I MR features Large CSF spaces over convexities in frontoparietal and frontotemporal regions Prone to developing subdural hemorrhage from stretched bridging veins (ddx. nonaccidental trauma) (fig c) Wide sylvian fissures (fig a) due to lack of operculeriztion of the frontal and temporal lobes ↑ T2 in putamen, globus pallidus, caudate head, dentate nucleus, substantia nigra Delayed myelination affecting the frontal and occipital PVWM
34	Leigh Syndrome Subacute necrotizing encephalopathy Neurodegenerative disorder Inheritance pattern: Autosomal recessive (most cases) and X-linked Etiology Inborn error of energy metabolism Defective terminal oxidative metabolism divided into 4 main groups Pyruvate dehydrogenase deficiency complex Complex I deficiency Complex II deficiency Complex IV - Cytochrome oxidase deficiency Complex V – defects in subunit 6 of ATP synthetase
35	Leigh Syndrome Clinical: Variable clinical and pathologic manifestations Multisystem disorder dominated by signs of CNS dysfunction Pathologic abnormalities – microcystic cavitation, vascular proliferation, neuronal loss, demyelination in midbrain, basal ganglia and dentate nuclei and occasional white matter involvement Present typically toward the end of 1^st yr of life in infants Hypotonia, psychomotor deterioration, ataxia, ophthalmoplegia, ptosis, dystonia, cranial nerve palsies Causes of death – neurogenic disturbances of respiration, convulsions, coma, hyperpyrexia, cardiac
36	Disorders of Amino Acid & Organic Acid Metabolism
37	Canavan Disease (Spongiform leukodystropy) Inheritance pattern: Autosomal recessive Enzyme defect: Biochemical studies are diagnostic Deficiency in aspartoacylase resulting in ↑ N-acetyl aspartic acid in urine and plasma Accumulation of N-acetylaspartate in oligodendrocytes Clinical: Marked hypotonia with poor head control 1^st few wks of life Macrocephaly 2° to ↑ skull growth, psychomotor delay, spasitcity, intellectual failure, cortical blindness and seizures with death by 3 years.
38	Canavan Disease (Spongiform leukodystropy) MR Imaging features: Subcortical WM affected early and is most severe in the cerebral and cerebellar hemispheres Central WM structures (internl capsule, corpus callosum, periventricular rim WM are preseved) Progressive ↑ T2 and ↓ T1 in the cerebral WM centripetal and confluent in distribution
39	Disorders of Unknown Metabolic Defects
40	Alexander Disease (FIbrinoid Leukodystrophy) Inheritance pattern: Gene mutation for glial fibrillary acidic protiens (GFAP) with accumulation in the cytoplasm resulting in cellular dysfunction Diagnosis strongly suggested with combination of macrocephaly, with clinical and imaging findings along with GFAP gene confirmation 3 forms: Adult Juvenile Neonatal
41	Alexander Disease (FIbrinoid Leukodystrophy) Clinical: Macrocephaly, early onset clinical findings and imaging studies strongly suggest diagnosis, however, biopsy remains the definitive diagnostic tool Accumulation of Rosenthal fibers – hallmark Neonatal form is most severe, rapidly progressive, onset within 1^st month of life, death within 2 yrs of life Juvenile type, symptoms occur between 7 and 14 yrs, progressive bulbar signs and spasticity Adult form, similar clinical presentation to multiple sclerosis
42	Alexander Disease (Fibrinoid Leukodystrophy) MR Features: ↑ T1 & ↓ T2 periventricular and subcortical WM in frontal lobes, external and extreme capsules ↓ T1 & ↑T2 in caudate head, basal ganglia and hypothalamus Marked T1 hyperintensity periatrial ependymal lining Occipital lobes are spared
43	Pelizaeus-Merzbacher Disease Inheritance pattern: Classic form : X-linked recessive Connatal form : X-linked or autosomal recessive Enzyme defect: Accumulation of proteolipid protein 1 in the endoplasmic reticulum resulting in partly formed myelin molecules Clinical: Abnormal eye movements, nystagmus, extrapyramidal hyperkinesia, spasticity, seizures Death occurs in adolescence to early adulthood in the classic variety and in early childhood for connatal form
44	Pelizaeus-Merzbacher Disease MR imaging features ↑ T2 signal of all unmyelinated white matter extending to the subcortical U fibers, with corresponding ↓ T1 signal changes Some sparing of myelin in parts of the brainstem Progressive white matter atrophy
45	The Acquired Leukoencephalopathies
46	Non-infectious / Non-inflammatory
47	Multiple Sclerosis (MS) Etiology: Presumed autoimmune Idiopathic Facts: First described by Charcot in 1868, MS is the most common demyelinating disease encountered in clinical practice as well as in imaging. Peak age : 30 years with a female predominance (Can also occur in children and adolescents and those over 50 years)
48	Multiple Sclerosis (MS) Clinical: MS is a multiphasic disease with clinical symptoms presenting in 2 or more episodes spaced at least 1 month apart, according to the Schumacher criteria. Clinical presentation in childhood can present subtly as school-related problems and paresthesias, to diffuse encephalopathy with cerebral edema, meningismus and impaired consciousness. MR imaging can supplement the diagnosis by documenting the dissemination of lesions in space and time.
49	Multiple Sclerosis (MS) MR Imaging Imaging findings in children are not significantly different from those in adults. Sharply marginated lesions showing ↓ T1 and ↑ T2 signal in the periventricular white matter, including the corpus callosum. Variable enhancement depending on acuity of the lesion – new lesions enhance for an average of 3 weeks. Spinal cord lesions with associated cord swelling Plaques can show restricted diffusion (fig d, e & f) Tumefactive lesions are more common in children (fig c)
50	Multiple Sclerosis (MS) MR Imaging: Recommended diagnostic criteria for MS in children: (at least 3 of the following) One enhancing lesion or nine T2 bright lesions At least one infratentorial lesion (fig c) At least one juxtacortical lesion At least 3 periventricular lesions (fig b) One spinal cord lesion may be substituted for one brain lesion Enhancement is characteristically limited to one side of the lesion, along the demyelinating edge (fig d)
51	Neuromyelitis Optica (NMO) (Devic disease) A variant of MS, NMO is a syndrome consisting of optic neuritis, often with bilateral total blindness, in combination with transverse myelitis, usually thoracic in location. The optic neuritis and transverse myelitis can occur simultaneously or separated by a brief interval of several days to several weeks. Age range: 5 to 65 years (but rare over 50 years) No gender predilection More common in the Asian population, where the overall incidence of MS is low Prognosis is poor Until recently 15-20% of patients died in the acute stage due to ascending disease with respiratory arrest Now complete or near complete recovery occurs in roughly 35%
52	Neuromyelitis Optica (NMO) (Devic disease)
53	Infectious - Inflammatory
54	Acute Demyelinating Encephalomyelitis (ADEM) Etiology: Thought to be an autoimmune response to a CNS antigen triggered by viral infections Facts: An inflammatory/demyelinating process seen more frequently in children, but affects all age groups Typically a monophasic self-limited illness within weeks after: Non-specific respiratory illness Specific viral illness (measles, mumps, rubella, chickenpox, tetanus, flu) Vaccinations (rabies, diptheria, smallpox, tetanus, typhoid) Clinical: fever/headache/mental status changes/meningeal signs/ focal deficits (usually resolve ~ 1 month).
55	Acute Demyelinating Encephalomyelitis (ADEM) MR Features: Virtually identical to MS (mass-like with no mass effect) T2 bright lesions: Supratentorial white matter (fig a) Brainstem (fig b) Cerebellum Deep white matter (fig c) Optic Neuritis Spinal cord involvement Lesions can enhance and show restricted diffusion (fig d arrow)
56	Subacute Sclerosing Panencephalitis (SSPE) Etiology: A chronic measles virus infection which causes apoptosis of neurons, oligodendrocytes & lymphocytes. Although a rare disorder, it is the commonest of the chronic viral infections to affect children. Facts: Age range: 4 – 25 years; peak at 9 years; rare in adults Children who acquire measles under 1 year of age are more likely to develop SSPE. Clinical: Can be quite variable and range from 3 months to 7 years, usually with 4 discernable stages: Stage 1: insidious intellectual & behavioral deterioration, slurred speech, vision changes Stage 2: Myoclonia of all somatic muscles, convulsions, choreoathetosis, tremor & spasticity Stage 3: Severe dementia, frequent extrapyramidal dysfunction, myoclonia diminishes Stage 4: Child is in a vegetative state characterized by mutism and decerebrate or decorticate posture
57	Subacute Sclerosing Panencephalitis (SSPE) MR Features: Abnormal signal can be seen: Focal: Basal Ganglia Lateral geniculate bodies Diffuse: Subcortical white matter (WM) Deep & periventricular WM The overlying cortex is often affected (fig a) Bilateral striatal lesions, brain stem lesion, and cerebellar peduncle lesions are also seen. End-stage disease shows diffuse atrophy
58	Progressive Multifocal Leukoencephalopathy (PML) Etiology: PML is a rare demyelinating infection of the CNS by the JC polyomavirus virus -- a papovavirus Facts: Predominantly occurs in immunodeficient patients, and in recent years has been seen most commonly in the context of AIDS. Also seen in association with: Lymphoma/ SLE/ renal transplantation/ Multiple Myeloma/ Sarcoid/ TB/ Whipple disease Predominantly seen in adults, but has been described in children with similar imaging findings.
59	Progressive Multifocal Leukoencephalopathy (PML) Clinical: Typical early presentation includes cognitive impairment, sometimes with personality changes. Monoparesis, hemparesis, dysarthria, ataxia, sensory impairments and visual loss ensue. Quadriparesis, severe dementia and coma are seen in advanced stages of the disease. Once the disease appears it typically progresses until the patient dies.
60	Progressive Multifocal Leukoencephalopathy (PML) MR Features: Lesion with ↑ T2 signal can be found anywhere in the cerebral or cerebellar WM and the brainstem Most commonly involves the frontal and parieto-occipital subcortical WM; but can involve basal ganglia and thalami (fig a) Subcortical lesions form a scalloped appearance where they border the overlying gray matter. Confluence of multiple lesions give rise to the appearance of wide spread white matter disease Enhancement is seen in a minority of cases
61	Acute Necrotizing Encephalitis An acute encephalopathy with thalamotegmental involvement Most likely immune-mediated or metabolic Influenza A and B viruses and human herpes virus have been implicated Clinical: Infants between 6 to 18 months History of mild antecendent illness (90%) ~ 3 days followed by acute onset of convulsions, impaired conscoiousness, vomiting, coma in 24 hrs Biochemical analysis shows ↑ aspartate amino-transferase (82%) ↑ alanine aminotransferase (70%) ↑ lactate dehydrogenase (77%)
62	Acute Necrotizing Encephalitis MR imaging features Bilateral thalamic involvement with ↑ T2 and ↓ T1 signal Confluent lesions involving lateral putamina and external and extreme capsules These lesions become hemorrhagic and cavitate centrally Calcifications can be seen in the basal ganglia
63	Toxic - Metabolic
64	Posterior Reversible Encephalopathy Syndrome (PRES) Hypertensive episodes lead to transient clinical symptoms such as headache, nausea, vomiting, altered mentation and seizures. The MR findings can be associated with the following disease entities: Pre-eclampsia/ Eclampsia Renal insufficiency Hemolytic-uremic syndrome Thrombotic thrombocytopenic purpura Patients undergoing chemotherapy/ immunosuppressive therapy and bone marrow or solid organ transplantation Presumed etiologies: Immunological maternal reaction (in eclampsia) Dietary factors Genetic factors
65	Posterior Reversible Encephalopathy Syndrome (PRES) MR Features: ↑ T2 and ↓ T1 signal predominantly affecting the parieto-occipital regions symmetrically Involves white matter as well as cortex May solely affect the thalami, frontal border zones, midbrain, pons or cerebellum Initial period may have associated mass effect and hydrocephalus Some lesions may progress to infarction and DWI must be utilized With treatment lesions disappear completely or nearly completely
66	Post-chemotherapy Leukoencephalopathy Abnormalities in the white matter 2° chemotherapy agents Most common offending agents Methotrexate, Cisplatin, Arabinosylcytosine, Carmustine, Thiopeta WM abnormalities may be transient or permanent, with or without associated clinical abnormalities Clinical: Neurologic symptoms occur with acute injury
67	Post – Chemotherapy Leukoencephalopathy MR imaging features Symmetric ↑ T2, ↓ T1 abnormalities Central and periventricular WM, can be wide spread and diffuse Relative sparing of U-fibers Diffusion imaging shows reduced diffusion in affected areas (figs c & d)
68	In Summary Pediatric leukoencephalopathies comprise a broad group of disease entities many of which may have non-specific MR imaging characteristics which overlap one another Certain imaging findings, however, are characteristic and were highlighted in this presentation We’ve found that a systematic approach, using a well-described classification system, along with imaging, clinical and biochemical data, helps to narrow the differential
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