Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations

Abstract

Pigmented orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34-50 years with adult onset leukodystrophy. Their disease course ranged from 1.5-8 years. Three patients had progressive cognitive and behavioral changes; however, one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense Magnetic Resonance Imaging signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provide clinical-pathologic support for association pathways linking distributed neural circuits sub-serving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.

Figure 1

Magnetic Resonance Imagine (MRI) images of patient 1 with adult onset leukodystrophy with neuroaxonal spheroids. A. and B. Axial and sagittal T1‐weighted MRI demonstrating hypointense signal in the white matter underlying the prefrontal cortex and mildly enlarged lateral ventricles and atrophy of the anterior corpus callosum. C. Fluid attenuated inversion recovery (FLAIR) image showing confluent high signal in the periventricular, deep and subcortical white matter of the frontal and parietal lobes extending through the posterior corpus callosum.

Figure 2

Magnetic Resonance Imagine imaging of patient 3. A. T2‐weighted fast spin echo images (TR/TE = 8200/108) demonstrate confluent high signal in the periventricular, deep and subcortical white matter with sparing of the U‐fibers and volume loss in both frontal lobes. B. Diffusion‐weighted image (DWI) demonstrates small foci of high signal within the area of high T2 signal abnormality. C. Apparent diffusion coefficient map confirming the DWI abnormality and showing isointense signal corresponding to the foci of DWI hyperintensity. D. T2 weighted image showing voxel placement location for MR spectroscopy. E. Multi‐voxel magnetic resonance (MR) spectroscopy demonstrates high choline‐to‐creatine ratio in the cortical/subcortical region of the abnormal left frontal lobe. F. Post‐contrast T1‐weighted image (TR/TE = 800/25) demonstrates lack of contrast enhancement in the abnormal white matter areas in the frontal lobes.

Figure 3

Postmortem findings in the brain. A. Mid‐sagittal section of case 1 demonstrating extensive thinning and brown discoloration of the corpus callosum with relative sparing of sector 3 and enlarged lateral ventricle. B. Coronal section of the parietal lobe from case 4 demonstrating gray discoloration of the white matter with U‐fiber preservation at the level of the hippocampus. The parietal is more severely affected than the temporal lobe white matter.

Figure 4

Paraffin section of the frontal lobe from case 4 stained with luxol fast blue Hematoxylin and Eosin demonstrates loss of white matter myelin and axons with only a rim of preserved U‐fibers (original magnification 4×).

Figure 5

A. Microscopic section of the frontal white matter in case 2 demonstrating several axonal spheroids (original magnification 20×) (Luxol fast blue Hematoxylin and Eosin stain). B. Neurofilament immunostain of the white matter; reveals a milder loss of axons compared with myelin and an axonal spheroid (original magnification 20×). C. Scattered macrophages containing luxol fast blue material in white matter (case 4) (Luxol fast blue Hematoxylin and Eosin stain; original magnification 40×). D. CD68 immunostain demonstrates scattered macrophages (brown) within the white matter (original magnification 40×).

Figure 6

Ultrastructure. A. The brain biopsy from case 3 revealed enlarged axons filled with neurofilaments characteristic of axonal spheroids. Epoxy embedded brain (original magnification 4500×.). B. Large aggregates of mitochondria, some with preservation artifact and large number of vesicles consistent with an axonal spheroid (original magnification 3400×). C. and D. Cell containing intracytoplasmic coiled filamentous inclusions, a myelin figure and dilated endoplasmic reticulum (original magnification 4500×). D. Enlarged area highlighted by rectangle in image (C) demonstrating coiled filamentous inclusions and a myelin figure.