Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: report on a case with morphometric studies

Two previously distinct leukodystrophies, pigmentary orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids, have recently been interpreted as variants of the same disease, adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP). We report a sporadic case of a 56-year-old male with ALSP presenting as frontotemporal dementia behavioral variant (FTD-bv). He had a history of depression and developed socially inappropriate behaviors consistent with FTD-bv. His first neurological exam was normal, but he developed new symptoms in the next 1.5 years: executive functional difficulties, anosognosia, urinary incontinence, epilepsy, extrapyramidal syndrome, severe gait disturbance, dysarthria, dysphagia and mutism. He died of pneumonia 20 months after initial presentation. MRI revealed increased T2-FLAIR signal in periventricular white matter and corpus callosum atrophy. Histology showed extensive demyelination of the centrum semiovale, most severe in frontal and temporal lobes, sparing U-fibers. There was no cortical neuronal loss, but selective loss of thalamic neurons. Histopathological hallmarks were cortical neuronal ballooning, white matter orthochromasia, pigmented macrophages, oligodendroglial loss, and axonal spheroids, some myelinated and some vacuolated. Morphometric studies for myelin, spheroids, oligodendrocytes and astrocytes showed that: 1) spheroids were most abundant in areas of partial demyelination rather than areas of extensive demyelination, being absent in normal appearing areas, 2) oligodendrocyte loss only occurred in regions of extensive demyelination and not in partial demyelination, and 3) there was no statistically significant change in number of astrocytes. There were also many more spheroids than physiologically expected in the gracile and cuneate nuclei. These findings suggest that the formation of spheroids is an early-stage event in disease progression. *These authors contributed equally to this work.