Which histologic findings are characteristic of amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)?

Updated: Apr 28, 2014
  • Author: Hidehiro Takei, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Answer

The cardinal histologic change seen in amyotrophic lateral sclerosis (ALS) is loss of both upper motor neurons (UMNs) and lower motor neurons (LMNs) with associated astrogliosis. In the LMN system, there is loss or degeneration of the anterior horn cells (especially the large neurons) with anterior nerve root atrophy, as well as of the brainstem motor nuclei (eg, cranial nerve [CN] XII, motor VII, and motor V) (see the images below).

Amyotrophic lateral sclerosis. Histologic features Amyotrophic lateral sclerosis. Histologic features of markedly degenerated anterior spinal nerve root (cross section) with extensive demyelination. (Luxol fast blue-periodic acid-Schiff stain, ×40)
Amyotrophic lateral sclerosis. Histologic features Amyotrophic lateral sclerosis. Histologic features of unremarkable posterior nerve root. Compare with previous image showing markedly degenerated anterior spinal nerve root (cross-section) with extensive demyelination. (Luxol fast blue-periodic acid-Schiff stain, ×40)
Amyotrophic lateral sclerosis. Neurofilament prote Amyotrophic lateral sclerosis. Neurofilament protein (NFP) immunohistochemistry shows diffuse loss of both small- and large-diameter axons in this atrophic anterior nerve root. (NFP immunohistochemical stain, ×40)
Amyotrophic lateral sclerosis. Immunohistochemical Amyotrophic lateral sclerosis. Immunohistochemically, both small- and large-diameter axons are well-preserved in posterior nerve root, in contrast to previous image, where diffuse loss of both small- and large-diameter axons is seen in atrophic anterior nerve root. (Neurofilament protein immunohistochemical stain, ×40)

However, the brainstem nuclei controlling eye movements (CNs III, IV, and VI), the Clarke column (see the first image below), and the Onufrowicz nucleus (see the second image below) in the sacral spinal cord (involved in maintenance of micturition and fecal continence) are largely spared until late in ALS.

Amyotrophic lateral sclerosis. Histologic features Amyotrophic lateral sclerosis. Histologic features of spinal (lumbar) anterior horn, with loss of neurons and associated severe gliosis and well-preserved Clarke column (circle).
Amyotrophic lateral sclerosis. Neurons of Onufrowi Amyotrophic lateral sclerosis. Neurons of Onufrowicz nucleus in sacral cord are relatively well preserved. (Hematoxylin and eosin stain, ×40)

The anterior horns show varying degrees of astrogliosis, depending on the stage of the disease, and the surviving motor neurons usually show chromatolysis and cytoplasmic shrinkage with abundant lipofuscin granules in the soma (see the first image below). Axonal spheroids are frequently observed (see the second image below).

Amyotrophic lateral sclerosis. Histology shows res Amyotrophic lateral sclerosis. Histology shows residual anterior horn cells filled with abundant lipofuscin pigments (arrowhead) and of axonal spheroids (arrow) in very gliotic lumbar anterior horn. (Hematoxylin and eosin stain, ×200)
Amyotrophic lateral sclerosis. Neurofilament prote Amyotrophic lateral sclerosis. Neurofilament protein (NFP) immunohistochemistry labels rare residual neurons and scattered axonal spheroids (arrows) in lumbar anterior horn. (NFP immunohistochemical stain, ×400)

Neuronophagia and perivascular lymphocytic cuffing is occasionally seen in ALS. In the UMN system, the motor cortex is affected and shows loss or degeneration of neurons with astrogliosis mainly in the third and fifth layers (cell bodies of Betz cells), a feature that is more apparent in cases of longer duration (see the first image below). Superficial cortical spongiosis may also be seen (see the second image below).

Amyotrophic lateral sclerosis. Precentral gyrus (p Amyotrophic lateral sclerosis. Precentral gyrus (primary motor cortex) shows diffuse cortical gliosis highlighted with glial fibrillary acidic protein (GFAP) immunostain. (GFAP, ×40)
Amyotrophic lateral sclerosis. Precentral gyrus (p Amyotrophic lateral sclerosis. Precentral gyrus (primary motor cortex) shows diffuse superficial cortical spongiosis (arrowheads) and residual Betz cells (arrow). (Hematoxylin and eosin stain, ×20)

Other histologic findings reported in the precentral gyrus in ALS patients include clusters of astrocytes in the upper cortical layers (layers II and III), an increase in the size and number of subcortical white matter astrocytes, and astrocytosis in the gray-white matter junction (see the image below). [34]

Amyotrophic lateral sclerosis. Precentral gyrus (p Amyotrophic lateral sclerosis. Precentral gyrus (primary motor cortex) shows loss of neurons, associated astrogliosis, shrunken neuron (arrowhead), and features suggestive of neuronophagia (arrow). (Hematoxylin and eosin stain, ×400)

The cytopathology of the affected motor neurons in ALS is characterized by the following:

  • Bunina bodies (BBs)

  • Skeinlike inclusions (SLIs)

  • Round hyaline inclusions (RHIs), including Lewy body–like hyaline inclusions (LBHIs)

  • Basophilic inclusions (BIs)

BBs are currently considered to be a specific histologic hallmark of ALS and can be observed in frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) and Guam ALS. In contrast, these findings have not been reported in patients with SOD1 -mutated familial ALS.

BBs are small, eosinophilic (on hematoxylin and eosin [H&E] stain), and blue (on Luxol fast blue stain) granular perikaryal inclusions in the remaining LMNs, appearing either singly or in a group and sometimes arranged in small beaded chains (see the image below). They average 2-5 µm in diameter, and the number varies in each neuron.

Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Bunina bodies are small eosinophilic inclusions arranged in group or in small beaded chains that are present in residual neurons (arrows). (Hematoxylin and eosin stain, ×400)

BBs are seen predominantly in the somata and occasionally in the dendrites; however, they have not been found within the axoplasm. [35] BBs are seen more frequently in the lumbar cord than in the cervical and thoracic cords, are primarily distributed in the motor nuclei of the spinal cord and brainstem, but are rarely found in Betz cells, neurons of the oculomotor nuclei, and the Onufrowicz nuclei. [36]

Ultrastructurally, BBs are composed of electron-dense amorphous material containing tubules or vesicular structures, with a few central clear areas containing cytoplasmic components. [36] Although their morphologic structure is well known, their origin and nature remain unknown.

SLIs are intracytoplasmic filamentous structures that are found as aggregates of threadlike structures (see the images below). They are usually detected with immunohistochemical stains (see Immunohistochemistry); on H&E staining, they are barely visible or, sometimes, are detected as faintly eosinophilic linear or curvilinear structures. [35] SLIs are made of bundles of filaments 15-20 nm thick. They have been reported to be significantly related to neuronal loss, especially in the spinal cord. [37]

Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Skeinlike inclusions are intracytoplasmic filamentous structures found as threadlike aggregations in residual neurons. (Ubiquitin immunostain, ×200)
Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Skeinlike inclusions are intracytoplasmic filamentous structures found as threadlike aggregations in residual neurons. (Transactivation response DNA-binding protein 43 [TDP-43] immunostain, ×400)

RHIs are round, eosinophilic, hyaline structures in the remaining anterior horn neurons; some of them consist of cores and halos and are referred to as LBHIs. LBHIs are indistinguishable from the Lewy bodies seen in Parkinson disease on H&E staining. They range in size from quite small to as large as 20 µm in diameter or larger. [38] The somata usually contain a single inclusion. It should be kept in mind that there is confusion surrounding the definitions of these 2 very similar inclusions, and the 2 terms (RHI and LBHI) are often used interchangeably.

BIs are irregularly-shaped neuronal, cytoplasmic, light basophilic inclusions, initially described in patients with sporadic juvenile ALS. They are stained light red by methyl green-pyronin, which suggests that they have an RNA component. BIs are seen not only in the residual large anterior horn cells but also in the small anterior horn cells and neurons in the intermediolateral nuclei. [39] Generally, BBs and SLIs are not found in cases with BIs.

Widespread neuronal loss and degeneration can be seen with BIs in areas including the cerebral cortex, basal ganglia, and thalamus; thus, cases of ALS with BIs are considered to be within the spectrum of the most recently recognized entity, basophilic inclusion body disease (BIBD). [40]

In ALS, there is characteristic degeneration of the descending motor tracts (ie, anterior and lateral corticospinal tracts). This degeneration is most evident in the lower spinal segments, supporting the so-called dying back hypothesis. The posterior columns and spinocerebellar tracts are usually spared in the spinal cord. Some forms of familial ALS are known to show posterior column involvement. [34]

In the degenerated tracts, there is loss of large myelinated fibers, which can be highlighted with myelin stains (eg, Luxol fast blue), in association with infiltration of foamy macrophages and variable astrogliosis.

In FTLD-MND/ALS, spongiosis (microvacuolation) is observed in the frontal and temporal cortices, in addition to ALS features.

The striated muscles show neurogenic atrophy, characterized by clumps of pyknotic nuclei, small and large group atrophy, scattered angulated atrophic fibers, and fiber type grouping (see the images below).

Amyotrophic lateral sclerosis. This muscle biopsy Amyotrophic lateral sclerosis. This muscle biopsy shows neurogenic atrophic changes, with clumps of pyknotic nuclei, large group (fascicular) atrophy, hypertrophic fibers, and scattered angulated atrophic fibers. (Hematoxylin and eosin stain, ×100)
Amyotrophic lateral sclerosis. This muscle biopsy Amyotrophic lateral sclerosis. This muscle biopsy shows neurogenic atrophic changes with fiber type grouping. (Fast myosin heavy chain immunostain, ×100)

In the late stage of ALS disease, especially at autopsy, the muscles usually show marked atrophy with interstitial fibrosis and fatty infiltration (see the image below).

Amyotrophic lateral sclerosis. Markedly atrophic q Amyotrophic lateral sclerosis. Markedly atrophic quadriceps muscle obtained at autopsy shows end-stage myopathic changes with diffuse fatty infiltration. (Hematoxylin and eosin stain, ×200)

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