Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by the gradual deterioration and death of motor neurons. These nerve cells transmit signals from the brain and spinal cord to the muscles, enabling voluntary movement. As motor neurons degenerate, the brain’s ability to initiate and control muscle function is lost, leading to increasing paralysis and damage within the spinal cord.
The Neuropathology of ALS in the Spinal Cord
In Amyotrophic Lateral Sclerosis, a “lesion” is not a physical injury but an area of profound cellular damage and death. The primary event is the degeneration of motor neuron cells, which involves the abnormal accumulation and clumping of proteins like TDP-43. These protein aggregates disrupt the motor neurons’ normal function, ultimately leading to cell death and are a molecular signature in nearly all cases of sporadic ALS.
The term “sclerosis” in ALS literally means hardening. After the motor neurons die, the surrounding tissue undergoes a scarring process known as astrogliosis. In this process, specialized glial cells, particularly astrocytes and microglia, become activated to clear away the debris from the dead neurons. Their sustained activity leads to the formation of a dense, fibrous scar in the affected area of the spinal cord.
This cellular cleanup and subsequent scarring give the spinal cord lesions their characteristic hardened or “sclerotic” nature. Pathological examination of spinal cord tissue from individuals with ALS reveals this loss of motor neurons and the corresponding increase in glial cells. It also shows the presence of specific intracellular inclusions, like Bunina bodies, which are considered a hallmark of the disease.
Locating the Damage Within the Spinal Cord
The damage in ALS is highly specific, targeting the nerve cells and pathways responsible for movement. The disease affects both upper motor neurons (UMNs) and lower motor neurons (LMNs), which have distinct locations. UMNs originate in the motor cortex of the brain and send their long fibers, called axons, down through the spinal cord to connect with the LMNs.
Within the spinal cord, the UMN pathways primarily affected are the corticospinal tracts. These are large bundles of nerve fibers located in the lateral and anterior white matter of the spinal cord. Post-mortem examination of this tissue shows a loss of both the axons and the myelin sheaths that insulate them.
Lower motor neurons reside in a specific part of the spinal cord’s gray matter called the anterior horns. These neurons send their axons directly out of the spinal cord to connect with and control muscles throughout the body. In ALS, these anterior horn cells degenerate and die, leading to visible atrophy of this region. The combination of damage to both the corticospinal tracts and the anterior horn cells is the defining pathological feature of ALS.
How Spinal Cord Lesions Translate to Symptoms
The symptoms of ALS are a direct result of the location of the neuronal damage within the spinal cord. The degeneration of lower motor neurons (LMNs) in the anterior horns leads to a specific set of clinical signs because the final link between the nervous system and the muscles is broken. This results in muscle weakness, visible muscle shrinking (atrophy), and spontaneous, involuntary muscle twitches known as fasciculations.
Damage to the upper motor neurons (UMNs) as their corticospinal tracts pass through the spinal cord produces a different cluster of symptoms. Because UMNs regulate signals to LMNs, their loss leads to overactivity in reflex pathways. This manifests as muscle stiffness and tightness (spasticity), slowness of movement, and exaggerated reflexes (hyperreflexia).
The combination of both upper and lower motor neuron signs is a classic presentation of ALS. A person might experience weakness and atrophy in their hands (LMN signs) alongside stiffness in their legs (UMN signs). This mixture of symptoms, reflecting widespread damage to motor pathways, is characteristic of the disease.
Identifying Lesions in Clinical Practice
Diagnosing ALS involves a comprehensive process aimed at identifying the functional consequences of these lesions. Magnetic Resonance Imaging (MRI) of the brain and spinal cord is a standard part of the workup, mainly to rule out other conditions that can mimic ALS, such as spinal cord tumors or multiple sclerosis. Conventional MRI scans are often normal in ALS, especially in the early stages.
The most direct functional assessment of motor neuron health comes from electrodiagnostic tests. Electromyography (EMG) involves inserting a fine needle electrode into muscles to record their electrical activity, which can reveal nerve damage even before clinical weakness is apparent. A nerve conduction study (NCS) measures how well nerves send electrical signals and can help confirm the issue lies with the motor neurons.
These electrical tests provide evidence of lower motor neuron degeneration. Combined with a clinical examination that finds evidence of both upper and lower motor neuron dysfunction, a diagnosis can be made. However, the absolute confirmation of the specific cellular lesions—the loss of motor neurons and sclerosis in the corticospinal tracts and anterior horns—can only be achieved through a post-mortem examination.