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.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

There is bilateral symmetric involvement of the thalamic nuclei, with neuronal loss and astrocytic gliosis in the absence of inflammation or vascular disease. Atrophy of the inferior olives has been described in some cases.

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.

Table 33.2

Pallidal degenerations

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

These include the neuroaxonal dystrophies (see below), multiple system atrophy, DRPLA, and ALS.

A diagnosis of pallidal degeneration should not be made if there are dystrophic axonal swellings, inclusions of multiple system atrophy, or extramotor inclusions of ALS.

NEUROAXONAL DYSTROPHY

CLASSIFICATION

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

Table 33.4

Known gene defects and related neuroaxonal dystrophies

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.

33.2 Immunoreactivity of dystrophic axonal swellings.
(a) Axonal swellings can be detected by immunohistochemistry for ubiquitin. (b) They can also be detected by immunohistochemistry for neurofilament protein. Strong immunoreactivity is generally seen only in small spheroids.

33.3 Pigment accumulation in spheroids.
Spheroids may contain brown-colored pigment, which is a mixture of lipofuscin-like material and iron. The iron is demonstrated in this section stained by Perls’ method and appears blue in color.

PHYSIOLOGIC NEUROAXONAL DYSTROPHY

Dystrophic axons are a relatively common normal finding in certain parts of the CNS, particularly in the elderly. The main sites are:

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.

Zona reticulata of the substantia nigra (Fig. 33.4b).

Inner segment of the globus pallidus.

In most instances, there is little associated pigment. Dystrophic axons also accumulate with age in the peripheral sympathetic ganglia.

PRIMARY NEUROAXONAL DYSTROPHY

In the following diseases, dystrophic axonal swellings are the principal pathologic abnormality in the nervous system:

Diseases with PLA2G6 mutations: infantile, late infantile, juvenile, and adult neuroaxonal dystrophy.

Neuroaxonal leukodystrophy (hereditary diffuse leukoencephalopathy with spheroids (HDLS)) and pigmented orthochromatic leukodystrophy (POLD).

Diseases with pantothenate kinase (PANK2) defects (PKAN): classical PKAN, atypical PKAN, HARP syndrome.

Nasu–Hakola disease.

Giant axonal neuropathy.

NEUROAXONAL DYSTROPHY WITH PLA2G6 Mutations

Infantile neuroaxonal dystrophy (INAD)

A neurodegenerative disease characterized by axonal swellings and spheroid bodies in the brain. The onset is within the first 2 years of life, and the disease results in death by 10 years. Also known as: classical INAD with brain iron (INAD-2); NBIA type 2; Seitelberger disease.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The cerebrum and cerebellum usually appear atrophic and the ventricles dilated. Other features can include a rusty discoloration of the globus pallidus.

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.