Thalamic and pallidal degenerations, neuroaxonal dystrophy, and autonomic failure
THALAMIC DEGENERATIONS
Thalamic degeneration is a feature of several multisystem neurodegenerative disorders (Table 33.1), but can also rarely occur in a ‘pure’ form.
Table 33.1
Diseases in which thalamic degeneration may be prominent
Multiple system atrophy (glial cytoplasmic inclusions)
Spinocerebellar degenerations
Wernicke’s encephalopathy
Huntington’s disease
Creutzfeldt–Jakob disease
Menkes syndrome
Membranous lipodystrophy
Neuroaxonal dystrophy
Fatal familial insomnia
PURE THALAMIC ATROPHY
PURE THALAMIC ATROPHY
DIFFERENTIAL DIAGNOSIS OF PURE THALAMIC ATROPHY
The conditions listed in Table 33.1 should be excluded. These include fatal familial insomnia, which has a primary thalamic pattern of involvement and is a form of prion disease (see Chapter 32).
Neuronal loss from the thalamus has been described in patients that have undergone leukotomy.
PALLIDAL DEGENERATIONS
The grouping together of pallidal degenerations is based on the morphologic finding of degeneration centered on the globus pallidus, either alone or in combination with degeneration of the subthalamic nucleus or substantia nigra. These disorders have been subdivided according to the regions of the brain showing pathologic changes (Table 33.2). Clinically, pallidal degenerations are associated with a variety of movement disorders, with or without dementia. Some are familial and others sporadic.
It is difficult to evaluate the nosologic status of many of the cases described in the literature as their relationship to disorders that can now be better defined by molecular genetic and immunohistochemical techniques is uncertain. In particular, cases of dentatorubropallidoluysian atrophy (DRPLA) (see Chapter 29), spinocerebellar atrophies (see Chapter 29), multiple system atrophy (see Chapter 28), and diseases characterized by the ubiquitinated inclusions seen in ALS (see Chapter 27) are probably included in most of the historic series. Once these entities are excluded, a group of pallidal degenerations remains that can be classified on a purely descriptive basis, although it is not clear to what extent they represent distinct diseases.
DIFFERENTIAL DIAGNOSIS OF PALLIDAL DEGENERATIONS
NEUROAXONAL DYSTROPHY
Several conditions, grouped as neuroaxonal dystrophies, are characterized pathologically by the presence of axonal swellings, which are thought to develop as a result of neuronal dysfunction that produces distal axonal degeneration. In most cases, the nature of the neuronal dysfunction and the pathogenesis of the axonal swelling are poorly understood. Neuroaxonal dystrophy occurs in three contexts (Tables 33.3, 33.4)).
Table 33.3
Classification of neuroaxonal dystrophic processes
Physiologic neuroaxonal dystrophy: normal brain aging
Gracile and cuneate nuclei
Globus pallidus
Substantia nigra
Spinal anterior horns
Primary neuroaxonal dystrophy: diseases in which the main pathology is neuroaxonal dystrophy
Neuroaxonal dystrophies with PLA2G6 mutations (phospholipase A2 group VI)
Infantile neuroaxonal dystrophy (INAD)
Late infantile neuroaxonal dystrophy
Juvenile neuroaxonal dystrophy
Adult neuroaxonal dystrophy
Childhood onset phospholipase A2 group 6-associated neurodegeneration (PLAN; atypical neuroaxonal dystrophy)
Schindler disease (PLA2G6 mutation and co-occurrence of α-N-acetylgalactosaminidase (α-NAGA) deficiency)
Neuroaxonal leukodystrophy
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)
Familial pigmentary orthochromatic leukodystrophy (POLD)
Pantothenate kinase-associated neurodegeneration (PKAN; formerly Hallervorden–Spatz disease)
Classical PKAN
Atypical PKAN
Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome)
Nasu–Hakola disease
Giant axonal neuropathy (caused by mutation of GAN, the gigaxonin gene)
Secondary neuroaxonal dystrophy: accentuation of neuroaxonal dystrophy in other disease processes
Neurodegenerative disease
Metabolic disease
Infective disease
MICROSCOPIC APPEARANCES
Dystrophic axonal swellings can be identified in sections stained with hematoxylin and eosin as rounded or elongated eosinophilic structures varying from 20 μm to 120 μm in diameter (Fig. 33.1a,b). Some dystrophic axons contain an intensely stained eosinophilic core surrounded by a paler zone (Fig. 33.1c). The swollen axons can be demonstrated by silver impregnation techniques (Fig. 33.1d). In toluidine-blue-stained resin sections, the swellings are seen to contain granular material (Fig. 33.1e). Electron microscopy shows this to consist of mitochondria, electron-dense lysosome-related bodies, tubulomembranous structures, and amorphous matrix material (Fig. 33.1f). Generally, relatively few neurofilaments are present and those that are may be displaced towards the periphery of the axon. Immunoreactivities for neurofilament protein and ubiquitin are largely confined to axonal swellings smaller than 30 μm in diameter (Fig. 33.2). Iron-containing and lipofuscin-like pigment may accumulate in axonal spheroids (Fig. 33.3), leading to the descriptive term pigment-spheroidal dystrophy.
33.1 Microscopic features of neuroaxonal dystrophy.
(a) Axonal spheroids appear as pale eosinophilic rounded structures. (b) Many have a granular appearance in sections stained with hematoxylin and eosin. (c) Some spheroids show slight central pallor. Others, particularly the large spheroids, may contain a densely eosinophilic central region and a paler surrounding zone, as shown here. (d) The axonal swellings can be demonstrated by silver impregnation (arrows). (e) In resin sections, spheroids (arrow) appear pale and granular. (f) Electron microscopy shows that the spheroids contain abundant electron dense granules, mostly membrane-bound, and derived from lysosomes and degenerating mitochondria.
PHYSIOLOGIC NEUROAXONAL DYSTROPHY
Gracile and cuneate nuclei in the medulla (Fig. 33.4a).
33.4 Physiologic neuroaxonal dystrophy.
(a) Pale eosinophilic axonal swellings (arrows) in the gracile nucleus of an elderly person. (b) In the substantia nigra, axonal swellings (arrow) are typically more eosinophilic.
PRIMARY NEUROAXONAL DYSTROPHY
Diseases with PLA2G6 mutations: infantile, late infantile, juvenile, and adult neuroaxonal dystrophy.
NEUROAXONAL DYSTROPHY WITH PLA2G6 Mutations
MACROSCOPIC AND MICROSCOPIC APPEARANCES
Axonal spheroids and reactive astrocytic gliosis are widely distributed in the central and peripheral nervous system (Fig. 33.5). Degeneration of the corticospinal and spinobulbar tracts is usually prominent. There is often a moderate to severe diffuse cortical Lewy body pathology as well as tau pathology with neurofibrillary tangles and neuropil threads.
33.5 Infantile neuroaxonal dystrophy.
(a) Axonal spheroids are widely distributed in both white and gray matter in the CNS, as shown here in the hemispheric white matter. (b) Axonal spheroids in the basal ganglia. (c) Axonal spheroids are especially prominent in long tracts in the spinal cord. (d) Dystrophic axonal swellings (arrows) composed of granular eosinophilic material are also seen in peripheral nerves. (e) Dystrophic axonal swellings (arrowheads) and a degenerating neuron (arrow) in sympathetic ganglia. (f)
