Progressive Leukoencephalopathies

Pediatric Progressive Leukoencephalopathies

• Definition: Pediatric progressive leukoencephalopathies are characterized by ongoing degeneration of the brain’s white matter, causing neurological decline.
• They include genetic, infectious, metabolic, inflammatory, vascular, neoplastic, toxic, and iatrogenic causes.
• Classification is informed by etiology, modern molecular approaches, neuroimaging patterns, age of onset, and clinical relevance.

I. Etiological Classification

Genetic Causes (Hereditary Leukodystrophies and Leukoencephalopathies)

• Comprise over 90 known hereditary white matter disorders.
• Classified by primary cellular or molecular defects: oligodendrocytes, astrocytes, microglia, vasculature.
• Include lysosomal (e.g. MLD, Krabbe), peroxisomal (e.g. ALD), mitochondrial (e.g. Leigh), amino/organic acidopathies, astrocytopathies (e.g. Alexander disease), and eIF2B-related (VWM).
• Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1)

Infectious Causes

• Rare but potentially fatal if untreated.
• Examples: PML (JC virus), SSPE (post-measles), HIV encephalopathy, rubella panencephalitis.

Metabolic and Nutritional Causes

• Include PKU, B12 deficiency, hypothyroid encephalopathy, hepatic encephalopathy, porphyria, copper deficiency.
• Usually non-genetic, caused by toxic buildup or deficiencies.

Inflammatory and Autoimmune Causes

• Acquired demyelination: Pediatric MS, ADEM, NMOSD, MOGAD.
• Chronic CNS vasculitis and Susac syndrome are important differential diagnoses.

Vascular Causes

• Include CARASIL, Moyamoya disease, chronic hypoxic-ischemic injuries.

Neoplastic Causes

• Diffuse gliomas, PCNSL, paraneoplastic syndromes, neurodegenerative LCH can cause progressive white matter injury.

Toxic Causes

• Include inhaled toluene, CO poisoning, lead encephalopathy, drug-induced white matter injury.

Iatrogenic Causes

• Caused by chemotherapy (e.g. methotrexate), radiotherapy, post-transplant PRES, gene/enzyme therapies.

II. Modern Classification Approaches

Molecular-Genetic Classification

• Shift from traditional gene-based to cell/process-based classification.
• Subtypes: myelin disorders, astrocytopathies, leuko-axonopathies, microgliopathies, leuko-vasculopathies.

Neuroimaging-Based Phenotyping

• Symmetric T2 hyperintensities suggest genetic/metabolic causes.
• Distribution, myelination pattern, cystic degeneration help narrow differential.
• Advanced imaging (MRS, DTI) refines classification.

Pathological Classification

• Dysmyelination, demyelination, vacuolation.
• Correlates with genetics and helps prognosticate response to therapy.

III. Age-Specific Considerations

Infantile-Onset (0–2 years)

• Severe, rapidly progressive: Krabbe, Canavan, Alexander disease, connatal PMD, Leigh syndrome.

Early Childhood-Onset (2–6 years)

• ALD, Krabbe, MLC, VWM, MLD – with varying courses and triggers (e.g., fever).

Juvenile-Onset (7–15 years)

• Juvenile MLD, AMN, juvenile Alexander, classical PMD, pediatric MS.

Adolescent-Onset (15+ years)

• Includes milder leukodystrophies, CADASIL/CARASIL, chronic MS, Behçet disease.

IV. Clinical Relevance and Notable Disorders

Common Disorders

• ALD, MLD, Krabbe, PMD, VWM, Alexander disease – important for screening and emerging therapies.

Rare/High-Impact or Recently Recognized Disorders

• AGS, 4H syndrome, MLC, pediatric PML, SSPE, CTX.

Clinical Pearls

• Classification aids stepwise diagnosis based on etiology, age, MRI, and genetics.
• Heritable leukodystrophies are collectively common enough to be clinically relevant (~1:7,600).
• Accurate diagnosis enables access to emerging therapies.