2021 NPA-08

This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 64-year-old man first noticed weakness in the left hand, which subsequently progressed to involve the rest of his left arm, left leg, and right arm over the course of about six months. He also experienced multiple falls due to sudden giving way of the left leg. The patient denied any history of difficulty in chewing and swallowing. His family history was significant for dementia in his mother. Physical examination revealed signs of upper motor neuron and lower motor neuron dysfunction in the affected limbs. MRIs of the brain and upper limb showed no significant abnormalities. Electromyography of the upper limb demonstrated widespread acute and chronic denervation. As the disease progressed, the patient developed difficulty breathing, which eventually led to his death two years later.

Tissue Site
Skeletal muscle, spinal cord, and brain

The whole slide image provided is an LFB/H&E-stained slide of the spinal cord.

The diagnosis in this case is amyotrophic lateral sclerosis (ALS). First described in the 19th century, ALS is a progressive neurodegenerative disorder affecting both upper and lower motor neurons that produces muscle weakness, paralysis, and eventually death. It has several alternate names, including motor neuron disease, Charcot disease, and Lou Gehrig disease (named after the famous New York Yankee baseball player of the 20th century who succumbed to the disease in 1941). ALS has an annual incidence of one to three cases per 100,000 people. The only recognized risk factors for ALS are age and family history.

ALS is most commonly sporadic, with genetic or familial ALS (fALS) representing only 10% of cases. Although most fALS cases follow an autosomal dominant inheritance pattern, recessive and X-linked forms have also been described. Superoxide dismutase 1 (SOD1) was the first gene linked to fALS and represents about 20% of familial cases. A hexanucleotide repeat expansion in the C9orf72 gene is the most frequent genetic cause of ALS, accounting for about 30% to 40% of fALS. TARDBP (TAR DNA binding protein 43; TDP-43) and FUS (fused in sarcoma) are other commonly implicated genes. It is now recognized that there is significant genetic, pathologic, and clinical overlap between ALS and frontotemporal lobar degeneration (FTLD) with TARDBP, FUS, and C9orf72 also involved in various forms of FTLD, of which C9orf72 is the most common.

The clinical diagnosis of ALS is based on the revised El Escorial criteria which include: 1) evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathological examination; 2) evidence of upper motor neuron degeneration by clinical examination; 3) progression of signs or symptoms within a region or to other regions, as determined by history or examination; and 4) the absence of electrophysiologic, neuroimaging, or pathologic evidence of another disease process that could explain the patient’s signs and symptoms. Up to 40% of patients with ALS may also develop cognitive dysfunction, thought to be related to the ALS and FTLD neurodegenerative spectrum. Frontotemporal executive dysfunction may either precede or follow the onset of motor symptoms in a subset of patients.

Postmortem examination of ALS patients reveals spinal cord atrophy with the ventral nerve roots appearing thinner than the uninvolved dorsal roots. There may be variable atrophy of the primary motor cortex, and frontotemporal atrophy may be present in cases associated with FTLD. The histopathological hallmark of ALS is degeneration of both upper and lower motor neurons with associated reactive astrogliosis and microglial proliferation. Examination of the primary motor cortex reveals patchy loss of the large upper motor neurons (UMNs/corticospinal neurons or Betz cells) in layer five of the cortex. Remaining UMNs and lower motor neurons (LMNs) often show abnormal cytoplasmic accumulations of proteins such as ubiquitin, TDP-43 (Image E), and FUS (rare). TDP-43 shows a nuclear staining pattern in normal cells but highlights abnormal cytoplasmic inclusions with loss of nuclear staining in affected cells. TDP-43 aggregates can also be found in surrounding glial cells, including oligodendroglia and astrocytes. Loss of large motor neurons in the hypoglossal nucleus and the anterior horn of the spinal cord is also seen (Image D). In addition to degeneration of lower motor neurons, there is also loss of axons and myelin with associated gliosis in the corticospinal tracts, thus the term “lateral sclerosis.” Luxol fast blue staining highlights this loss of myelin in the lateral columns (Image C). Residual LMNs may harbor Bunina bodies, eosinophilic neuronal cytoplasmic inclusions comprised of cystatin C that are considered specific for ALS. Neurofilament and SOD1 immunoreactive inclusions may also be seen.

Skeletal muscle is occasionally biopsied when the clinical differential diagnosis includes chronic inflammatory myopathies such as inclusion body myositis and adult-onset muscular dystrophies. Muscle biopsy changes in ALS are not unique and include the characteristic features of denervation and reinnervation seen in many neurogenic disorders, including adult-onset spinal muscular atrophy. Histopathological findings depend on the timing of loss of innervation to the muscle and the degree of reinnervation and may range from scattered acutely angulated atrophic fibers to large group atrophy (Image A). Fiber type grouping may be demonstrated with immunostains for fast and slow myosin or histochemical stains for ATPase at low and high pH. Acutely angulated atrophic fibers often stain darkly with NADH and esterase (Image B). Target fibers and moth-eaten fibers may also be observed.

A multidisciplinary approach to treating ALS has increased both the quality of life and survival of patients with respiratory management through early noninvasive ventilation being one of the most important determinations of survival. There is, however, still no curative treatment for ALS patients. Riluzole (glutamate inhibitor) and edaravone (antioxidant) are the only Food and Drug Administration-approved disease-modifying drugs shown to have any impact on survival in ALS, though the survival benefit was only a few months in the several controlled clinical trials performed. Gene therapy, including antisense oligonucleotides and viral-directed gene delivery, potentially offers great promise as an ALS treatment and is currently being actively investigated.

• ALS is a progressive neurodegenerative disease characterized by muscle weakness with eventual paralysis and death.
• While the majority of cases are sporadic, up to 10% are familial, with alterations commonly identified in C9orf72, SOD1, TARDBP, or FUS.
• Prevailing evidence suggests that ALS and FTLD represent a neurodegenerative continuum with significant genetic, clinical, and pathologic overlap. C9orf72 is the most commonly altered gene in ALS/FTLD.
• Characteristic pathologic features include degeneration of both upper and lower motor neurons and the presence of Bunina bodies and TDP-43 aggregates. Muscle biopsy shows evidence of denervation and/or reinnervation.

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