Our four patients with adult onset leukodystrophy with neuroaxonal spheroids, illustrate the clinical, neuroradiologic, and neuropathologic similarities as well as the differences that characterize this disorder. The illness commenced with changes in personality, disorganization and forgetfulness and progressed to devastation across multiple domains of cognition, with elementary neurological functions impaired only late in the course. These clinical features were matched by early destruction in the deep white matter of the prefrontal cortex, followed by the white matter deep to the association areas of the parietal and temporal lobes and secondary degeneration in the thalamus as demonstrated by neuroimaging and post-mortem examination.
The differential diagnosis for subacute confluent white matter disorders in adults is wide, including metabolic disorders (metachromatic leukodystrophy, adrenoleukodystrophy, adult-onset Krabbe’s disease) infectious causes including (HIV, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis), vascular disease (vasculitis, lupus cerebritis, Behçet’s disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and small vessel ischemia) and neoplastic (primary cerebral lymphoma) (7
). Adult onset leukodystrophy with neuroaxonal spheroids can be an autosomal dominant disease with variable age of onset (4
), or a sporadic disease (14
). The diagnosis depends on the presence of degeneration of white matter including loss of myelin and axons, neuroaxonal spheroids, gliosis, and macrophages (18
). Presenting symptoms have included early psychiatric changes (16
) or motor symptoms that progress to memory loss and a more generalized cognitive decline.
In our cases the duration of disease ranged from 1.5 to 8 years and correlated well with the extent and degree of cerebral damage seen on imaging and pathologic examination. The subject with the shortest duration, 1.5 years, showed predominantly frontal lobe involvement while the patient with the longest course, 8-years, had more widespread involvement of white matter, as well as cerebellar white matter, and corticospinal tracts, together with neuronal loss in cerebellum and medulla. As the clinical disease progressed there seemed to be a temporal pattern of involvement beginning in the frontal lobe white matter and extending to the corpus callosum and white matter of the somatosensory and eventually visual cortices. The white matter of the primary motor, sensory, and visual cortices were preserved until late in the course of the disease. Our patients reflect the published accounts of this condition, in that the heralding symptoms are generally neuropsychiatric (16
), progressing later to dementia and motor impairment, although case 2 initially presented with motor symptoms as has been previously reported (1
). Three of our patients had at least one other family member with similar symptoms and the fourth had a parent with early cognitive decline, but none of these family members had come to autopsy.
The distribution of white matter disease in our patients corresponds to that described previously (1
). The more recent white matter lesions had more abundant macrophages and more frequent axonal spheroids. Older lesions showed near total loss of all axons, with only U-fiber preservation, and fewer spheroids and macrophages. As the disease progressed there was secondary involvement of other structures such as the thalamic nuclei. This pattern of disease progression is illustrated by case 3. At the time of the biopsy 8 months into the disease course, the white matter had ill-defined regions of myelin sheath and axon loss with frequent axonal spheroids. Ten months later the autopsy revealed, well defined, more severe white matter loss and gliosis with fewer axonal spheroids. Neuroaxonal spheroids indicate axonal damage (23
) and can be seen in many conditions including trauma, neurodegenerative diseases, metabolic diseases, and tumors. The presence of neuroaxonal spheroids in the cortex in cases of short duration supports the speculation that this may be a primary axonal process with early axonal degeneration and resulting myelin loss (17
). The finding of rare ballooned neurons in two cases, located near areas of more acute white matter damage, perhaps represent ‘axonal reaction’ (5
) also supports the notion of a primary axonal injury.
The etiology of POLD and HDLS is uncertain. As pigmented cells were a minimal to absent component in all but one case, POLD is not the best category in which to consider our cases. Since not all of our cases show a definite family history of this disease, the term HDLS is similarly not ideal. The evolution of the neuropathology correlates with the clinical and radiological severity, pointing perhaps toward an underlying metabolic derangement. In cases 1 and 4, we detected changes in mitochondrial function lending support to the possibility of a mitochondrial derangement resulting in oxidative injury seen in both POLD and HDLS (2
). Elevated pre-mortem ANA levels found in cases 1 and 3 raised the possibility of an autoimmune process, but lack of an inflammatory component on neuropathologic examination makes this mechanism seem less likely.
The clinical manifestations of the white matter disease in these patients may be understood in the light of the organization of the fiber tracts that course through the white matter of the cerebral hemispheres. Every cerebral cortical area gives rise to short, neighborhood and long association pathways, as well as striatal fibers, and a cord system of fibers with two distinct fiber populations - one destined for the opposite hemisphere in the corpus callosum or anterior commissure and the other to thalamus and pons in the subcortical bundle (21
Disconnection syndromes were originally described as neurobehavioral impairments following focal white matter lesions of the cerebral hemisphere (11
). More recently, dementia resulting from microvascular ischemia (e.g., (6
)) and the cognitive effects of white matter lesions on MRI in otherwise healthy aged individuals and monkeys have been increasingly recognized (e.g., (15
Our cases support the concept of white matter dementia (3
), as the cognitive and behavioral changes occurred early in the course of the illness generally in the absence of weakness, sensory loss or blindness. The areas containing the long association tracts interconnecting the parietal, temporal and occipital lobes with the frontal lobe were the most severely affected in our cases. In contrast, projection pathways such as the corticospinal projections from peri-Rolandic cortices were spared until later in the illness. This is exemplified by case 1 in whom cortical blindness corresponded to the late pathological changes in the sagittal stratum that contains the optic radiations. This dichotomy of early dementia with preservation of gait, strength, dexterity and sensation until later in the illness provides an interesting glimpse into the clinicopathological distinction between association and projection fiber tract involvement, and the functional contributions of these different white matter tracts.
The location of the damage in the corpus callosum fibers also reflects the association-projection dichotomy seen in these cases. Case 1 had minimal sensorimotor deficits, and sector 3 of the corpus callosum that conveys sensorimotor fibers between the hemispheres (21
) was spared whereas sectors 1, 2, and 4 of the corpus callosum that convey association fibers between the hemispheres were devastated. In case 4 with progressive motor impairment as the disease evolved, almost the entire corpus callosum was degenerated, except for sector 5 that conveys fibers between the caudal parts of the temporal lobes which were relatively less devastated.
Whereas cerebral cortical neurons were spared in our cases, there was marked neuronal dropout in thalamus which could reflect the loss of sustaining cortical/subcortical projections (30
). In patient 3, damage was concentrated in the white matter of the prefrontal cortex and this patient had the characteristic frontal lobe syndrome. Thalamic degeneration was confined to the anterior thalamic nuclear complex which has reciprocal interconnections with medial prefrontal and cingulate cortices (13
), and the medial dorsal thalamic nucleus projections to cortex essentially define the frontal lobe with strict reciprocal thalamocortical topography (13
). Similarly, in patient 1, neuronal loss in the medial dorsal thalamic nucleus likely reflects destruction of projection fibers between prefrontal cortex and thalamus; the neuronal loss in the lateral dorsal thalamic nucleus likely reflects paralimbic association cortical interaction with thalamus, particularly cingulate gyrus and posterior parietal cortex (20
); and the lateral posterior thalamic neuronal drop-out reflects the white matter devastation in parietal association areas (20
We have described the clinical, neuroimaging and neuropathological features that characterize adult onset leukodystrophies with neuroaxonal spheroids and related the functional impairments in our patients to the pattern of morphologic damage identified in their cerebral hemispheres. Our cases of white matter disruption in adult onset leukodystrophy with neuroaxonal spheroids underscore the critical importance of cerebral white matter for cognition and emotion, as the fiber pathways they contain link cerebral cortex with other cortical and subcortical regions and are a key element in the anatomic underpinning of the distributed neural circuits that subserve higher order behavior.