Objectives: To distinguish genetic leukodystrophies from similar-appearing autoimmune and inflammatory leukoencephalopathies. 

Methods: This was a retrospective case series focused on immunologic, genetic, imaging, and histologic investigations of biopsy-proven inflammatory leukoencephalopathy. 

Results: Five patients had magnetic resonance imaging of the brain that demonstrated symmetric white-matter abnormalities like those of genetic leukodystrophies. However, in contrast to genetic disorders, all patients had subacute onset of symptoms within mean of 16 weeks and severe neurologic disability within 3 years in multiple domains: cognitive (80%), psychiatric (60%), pyramidal (100%), autonomic (100%), and cerebellar (100%). Cerebrospinal fluid, histopathology, or both were consistent with chronic inflammation. Only 1 patient had an antibody biomarker positive for glial fibrillary acidic protein. 

Conclusions: Inflammatory and autoimmune causes should be considered in the differential diagnosis of adult-onset leukoencephalopathy, particularly cases of subacute onset. Paraclinical clues include cerebrospinal fluid abnormalities or gadolinium enhancement.