Increased Diffusion: Abnormal Water Homeostasis with Myelin Vacuolation
Inherited: Megalencephalic Leukoencephalopathy with Subcortical Cysts
In addition to regulating myelin formation and neurogenesis, and supplying neurons with metabolic substrates, astrocytes play a key role in water and ion homeostasis in the CNS, including at the BBB via astrocyte endfeet. In the classic, most common form of megalencephalic leukoencephalop- athy with subcortical cysts, autosomal-recessive mutations in the astrocyte-specific MLC1 gene product disrupt brain ion and water homeostasis, leading to vacuolating myelin degeneration. Vacuoles form in the outer lamellae of the myelin sheath, and in the intracellular structures and end- feet of astrocytes.32 Early diffuse cerebral white matter swelling, with increased ADC (? Fig. 10.9b, c) and decreased anisotropy, ultimately leads to atrophy by the adult years. Bilateral anterior temporal lobe (? Fig. 10.9a), and sometimes parietal and frontal lobes, subcortical cysts follow white matter rarefaction in infancy.33
In Canavan disease, autosomal recessive defects in oligodendrocyte aspartoacylase causes accumulation of N-acetyl aspartate (NAA) in the extracellular space and unavailability of acetate for myelin lipid synthesis. Altered osmotic-hydrostatic pressures due to accumulation of NAA in the
Fig. 10.9 Megalencephalic leukoencephalopathy with subcortical cysts. Generalized hyperintensity of white matter on (a) T2-weighted imaging is due to rarefaction and cystic degeneration of white matter and myelin vacuolation, resulting in increased water diffusion as evidenced by decreased signal on (b) diffusion weighted imaging and increased on (c) the apparent diffusion coefficient map.
Fig. 10.10 Canavan disease. (a) Axial T2-weighted imaging, (b) diffusion weighted imaging, and (c) apparent diffusion coefficient (ADC) map. ADC differentiates T2 hyperintensity due to restricted water diffusion in the subcortical white matter (dark on ADC, arrows) from T2 hyperintensity due to white matter rarefaction and increased size of water spaces (asterisks). (Courtesy of Dr. Ata Siddiqui, Kings College Hospital, London, UK.)
extracellular space are the proposed cause for the extracellular and astrocytic edema and myelin vacuolation observed at pathological section.34 Progression is centripetal, with early changes in the subcortical white matter accompanied by restricted diffusion (? Fig. 10.10), which persists over an extended period of time. This is likely due to restriction of the extracellular spaces due to early cellular swelling and myelin vacuolation. Ultimately, diffusion is increased in demyelinated white matter due to increased size of the extracellular spaces later in the disease.5