Diagnosis of ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons, the nerve cells that control muscle movements, become progressively damaged and die.

Because it shares common symptoms with other neurological diseases, ALS is not diagnosed with one test. Instead, the diagnosis is based on a period of observation to track the progression of symptoms, combined with a series of clinical tests to rule out other conditions. The time from symptom onset to diagnosis can range from eight to 15 months.

According to the El Escorial criteria, revised by the World Federation of Neurology in 2015, a diagnosis of ALS requires three conditions: signs of degeneration of lower motor neurons in the spinal cord and brainstem, and of the upper motor neurons in the brain; the progression of symptoms from one body region to other regions; and no evidence of other diseases that could explain the symptoms.

For a full ALS diagnosis, a doctor will perform a complete neurological exam and require clinical tests to rule out other neurological diseases, based on the symptoms shown by the patient. These include:

Nerve conduction study

A nerve conduction study — also called a nerve conduction velocity test — measures the speed at which nerve cells transmit electrical impulses to muscles in different areas of the body. This test can help exclude disorders that affect the peripheral nerves (the nerves outside the brain and spinal cord).

To diagnose ALS, at least two sites are tested during the exam, including one upper limb and one lower limb and starting with the site that shows the most severe symptoms. During the test, one metal disc electrode stimulates the nerve by delivering a small electrical shock, while another is placed over the muscle directly supplied by that nerve to record the electrical signal.

Patients with ALS tend to show mostly normal results, especially for sensory nerves. However, ALS patients commonly show abnormally low compound muscle action potential amplitudes, meaning the signal produced by the muscle fibers after nerve stimulation is low.

Electromyography

An electromyography (EMG) consists of inserting a small needle electrode into various muscles and recording the electrical activity at rest and during muscle contractions.

As the lower motor neurons controlling muscle function are damaged in ALS, patients typically exhibit spontaneous electrical activity when the muscle is at rest. This abnormal result can be observed even before signs of motor neuron degeneration are evident.

A normal EMG result will often lead to a diagnosis of primary lateral sclerosis, but does not rule out the possibility of ALS developing later.

Magnetic resonance imaging

MRI is a noninvasive method that uses a magnetic field along with radio waves to produce detailed images of the brain and spinal cord.

Many different MRI techniques and sequences — including voxel-based morphometry, diffusion tensor imaging, magnetic resonance spectroscopy, iron-sensitive sequences, and functional MRI — are available to study ALS-related changes in the brain or spinal cord.

People with ALS generally have normal MRI scans, but the test is used to rule out other conditions that may be causing the symptoms. Some changes in brain structures observed in MRI scans can also serve as potential biomarkers that aid in early ALS diagnosis and tracking disease progression over time.

Muscle and nerve biopsies

In rare cases, a muscle biopsy — which involves removing a section of muscle under local anesthesia — will be performed to rule out other muscle conditions.

This procedure can also help monitor the progression of the disease over time. The loss of motor neurons in ALS leads to muscle atrophy (shrinkage), and clinicians may also observe changes in muscle morphology (the appearance and shape of the muscle cells), loss of nerve supply, or abnormalities in mitochondria, which supply energy to cells.

A nerve biopsy, which is usually collected via a two-inch long incision to access a nerve below the skin, can also help rule out other conditions that affect peripheral nerves.

However, there are specific markers of ALS that can be found in a nerve biopsy. One of them is the presence of Bunina bodies, small aggregates of immune cells in the lower motor neurons that are present in 70%–100% of ALS patients, and rarely seen in other conditions. Ubiquitinated inclusions, or aggregates of proteins marked for degradation, are also specific for ALS and occur in up to 95% of patients.

Spinal tap

A spinal tap, also called a lumbar puncture, can be used to collect a sample of cerebrospinal fluid (the liquid that surrounds the brain and spinal cord) to be examined for abnormal cells and proteins.

This approach is usually performed to exclude inflammatory nerve conditions when the patient has unusual symptoms of ALS, such as spinal nerve abnormalities, or no sign of abnormal reflexes or spasticity.

It can also detect certain biomarkers of nerve damage, such as levels of structural nerve proteins called neurofilaments, that help track disease progression.

Other tests

If an individual has a known family history of ALS, even if they show no symptoms of the disease, a genetic test can identify disease-causing mutations. But because the genetics of ALS are complex, and new disease-causing mutations are continually being discovered, it is difficult to diagnose ALS definitively with a genetic test.

People with ALS symptoms may test negative if their disease-causing mutation has not yet been identified and linked to ALS, and those who have no symptoms and test positive may never develop the condition.

Several other tests are used to look for evidence of other diseases whose symptoms are similar to those of ALS. These include blood tests, which can exclude conditions such as hepatitis, cancer, infections, thyroid diseases, and autoimmune diseases. These conditions must be ruled out before an ALS diagnosis is confirmed. An accurate diagnosis is important as all these diseases are managed in different ways.

 

Last updated: Aug. 5, 2021

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