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INTRODUCTION

Amyotrophic lateral sclerosis (ALS)—one type of motor neuron disease and more commonly known as Lou Gehrig’s disease—is a rare, rapidly progressive, degenerative neuromuscular disease that primarily targets upper and lower motor neurons causing widespread muscle wasting (“amyotrophy”) and, eventually, the paralysis of all skeletal muscles.¹ At least 16,000 people are estimated to be living with ALS in the United States (U.S.).² Men have a slightly higher risk than women of developing ALS over the majority of the lifespan, but the risks for men and women are approximately equal after roughly 65 to 70 years of age.

To date, there is no cure for ALS. On average, the disease is fatal within 2 to 5 years after diagnosis, although this is not consistent among all variants of ALS, as some types of the disease have prolonged survivals of 20 years or more.^3,4 Death is usually not caused directly by neurodegeneration but by disease-related complications such as aspiration pneumonia and respiratory insufficiency.⁵

While the direct cause of ALS is largely unknown, there are risk factors implicated in the development of the disease. Established risk factors include age and family history, and genetic variability, military service, cigarette smoking, and numerous other risk factors have been linked to the disease.^1,6,7

There are 2 “types” of ALS: sporadic and familial. The overwhelming majority of patients (90%) are classified as sporadic cases and few (10%) are classified as familial.^1,6 Familial ALS is diagnosed on the basis of the presence of a family history of ALS and it is believed to be acquired via a dominant trait with more than 50 different genes implicated in the development of the disease.¹ Genetic involvement is very complex, and it is thought that there is also a significant genetic component involved in the sporadic form. 

ALS has many variants, each with its own clinical characteristics and prognosis. The vast majority of ALS falls within 3 classic presentation categories: bulbar onset, limb onset, and pure lower motor neuron disease. Bulbar onset progresses faster than limb onset, and limb onset progresses faster than pure lower motor neuron disease.⁸ Several less common variations in presentation have also been described, including flail arm or flail leg, respiratory or bulbar only, and pure upper motor neuron presentations.⁸

The development of ALS, whether sporadic or familial, is particularly complicated and is likely the result of a multistep process transpiring in a significant order that allows for the disease to be expressed. In addition to selective upper and lower motor neuron loss, ALS can be characterized in a similar manner to other neurodegenerative diseases by intracellular protein aggregates, neuroinflammation, and oxidative stress.⁹

CLINICAL PRESENTATION AND DIAGNOSIS OF ALS

As is the case for many neurodegenerative conditions, there is no single diagnostic test for ALS. It is a clinical diagnosis, which can be very difficult, since the presenting symptoms of ALS can be fairly subtle and nonspecific; these challenges can lead to delays in diagnosis. Many tools can aid in the diagnosis and help distinguish ALS from other neuromuscular conditions, and it is important that the diagnosis is made or verified by a practitioner who regularly participates in the care of patients with established ALS.¹⁰

Several diagnostic criteria have been proposed for ALS. The El Escorial criteria have been widely accepted for the diagnosis of ALS since their publication in 1990, and they have been subsequently revised over the last 3 decades to increase diagnostic specificity. The El Escorial revised diagnostic criteria state that, for a diagnosis of ALS, patients much demonstrate, by history or examination, upper and lower motor neuron degeneration within 1 region or between multiple regions (i.e., cranial, cervical, thoracic, or lumbosacral spinal cord regions). Additionally, there must be a lack of electrophysical or pathological evidence and neuroimaging evidence that could indicate other disease processes that mimic ALS. Without pathological confirmation, the El Escorial revised criteria allow for categorization of ALS with levels of certainty. Terms used to describe these levels of certainty include clinically definite ALS, clinically probable ALS, clinically probable ALS – laboratory-supported, and clinically possible ALS.⁴

In 2008, The Awaji criteria were proposed as an adjunctive diagnostic criteria that allowed for earlier diagnosis of ALS and, ultimately, allowed for earlier entry of patients into clinical trials.¹¹ The Awaji criteria use the revised El Escorial criteria as a backbone and add fasciculation potentials associated with signs of reinnervation as evidence of lower motor neuron damage.