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Amyotrophic Lateral Sclerosis: Disease State Overview
Darrell Hulisz, PharmD, RPh
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Briana Santaniello, PharmD, MBA
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Amyotrophic Lateral Sclerosis: Disease State Overview

Darrell Hulisz, PharmD, RPh
Amyotrophic lateral sclerosis (ALS) is a disease that results in the progressive deterioration and loss of function of the motor neurons in the brain and spinal cord, leading to paralysis. ALS affects approximately 16,000 individuals, with a prognosis for survival of 2 to 5 years. There are 2 types of ALS differentiated by genetics: familial and sporadic (idiopathic). Diagnosis is determined by excluding other conditions and utilizing clinical examinations, laboratory tests, and nerve conduction/electromyography studies. Due to the collection of information from the participation of patients with ALS in registries, biomarkers and genes associated with ALS have been discovered. The best practices for the management of ALS include an interdisciplinary approach aimed at addressing the physical and psychological needs and desires of patients and their families and caregivers.
Am J Manag Care. 2018;24:-S0
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease and motor neuron disease (MND), is a progressive condition caused by the deterioration of the motor neurons in the spinal cord and brain, resulting in paralysis.1,2 A-myo-trophic means “no muscle nourishment” in Greek.3 The lack of nourishment leads to atrophy, or muscle wasting.3 “Lateral” denotes the areas where the nerves that signal muscles are located in the spinal cord.3 “Sclerosis” indicates the scarring or hardening of this region.3

The father of neurology, French physician Dr Jean-Martin Charcot, is credited with discovering ALS by correlating a series of case studies occurring from 1865 to 1869.4,5 Several pioneers in neurology, such as Sir Charles Bell, François-Amilcar Aran, and Charcot’s colleague Jean Cruveilhier, described the symptoms of ALS, but did not give it a name.6 In 1874, Charcot named this disease, “amyotrophic lateral sclerosis,” which is still known today as Charcot disease in many parts of the world.4,5,7 He stated, “The diagnosis as well as the anatomy and physiology of the condition amyotrophic lateral sclerosis is one of the most completely understood conditions in the realm of clinical neurology.”6 Unfortunately, this was an underestimation of the complex nature of ALS.6

Pathogenesis

The motor neurons are grouped into lower and upper populations.1 The lower population is located in the spinal cord and brain stem and the upper population is located in the motor cortex.1 Failure of the upper motor neurons (UMNs) results in brisk reflexes and slowed coordination of the limbs with spasticity and stiffness of the muscles.1 Disruption of the lower motor neurons (LMNs) is first exhibited by spontaneous muscle twitching, or fasciculations, and then progressively atrophies when the synapses connecting the muscles are lost.1 This tends to begin in the limbs and progresses to the eye and sphincter muscle neurons in the late stages.1 When the motor neurons of the spinal cord and brain stem perish, the ventral roots thin and the limb, tongue, and oropharynx muscles become amyotrophic.1 However, one-third of patients experience bulbar disease, manifesting as challenges with speaking, chewing, or swallowing.1 Signs of bulbar disease include dysarthria, facial weakness, weakness pushing the tongue outward (pulsion), poor palate elevation, difficulty chewing, impaired swallowing, and more typically noted, tongue fasciculations and atrophy.8

In the spinal processes, the degeneration of the corticospinal neurons causes the spinal cord’s lateral tracts to scar.9,10 Inclusions, or aggregated proteins consisting of round or threadlike shrunken spinal motor neurons, deposit as ALS progresses.9,10 These cytoplasmic inclusions become ubiquitinated in ALS.9,10 Cytoplasmic proteins are commonly present in the motor neurons of sporadic and patients with familial ALS.1 Because ALS has many variants, certain aggregates are only present in particular ALS subtypes.1

ALS Quality-of-Life Impact

The prognosis for survival in patients with ALS is 2 to 5 years.1,11,12 Despite this grim prognosis, 20% of patients live for 5 years, 10% for 10 years, and 5% for 20 years or longer.13 Patients with an older age at symptom onset, bulbar-onset ALS, lower Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS or ALSFRS-R) score, and early dysfunction of the respiratory muscles have a lower survival risk. However, patients with a younger age at ALS onset, limb-onset ALS, and longer time to diagnosis have independent factors associated with longer survival.14-16

Etiology

Prevalence

Age increases the prevalence and incidence of ALS.1 In the United States, 6000 new patients are diagnosed with ALS each year.13 The prevalence of ALS is 5.0 per 100,000 of the US population, with approximately 16,000 to 20,000 individuals being identified with definite ALS.13,17 The highest prevalence of ALS is in whites, males, and people 60 years or older.17 Globally, the mean age of ALS onset is 62 years.18 In the United States, the Midwest and Northeast have the highest prevalence of ALS, possibly due to higher proportion of whites compared with the South and West.17,19 Potential risk factors for the development of ALS include family history, occupations associated with heavy manual labor, agricultural work, military service (particularly in the Gulf War), football, pesticides, chemicals, smoking, heavy metals, geography, and electric shock.20-26 Studies suggest an association with ALS and the following: cyanotoxins, football, geography, smoking, heavy metals, electric shock, pesticides and chemicals, and military service, but there is no clear evidence to prove causation.24-26

Roberts et al examined the association between socioeconomic status (SES) and race/ethnicity in patients with ALS by using the National Longitudinal Mortality Study (NMLS) records.22 Because ALS is not a reportable condition in the United States, the incidence of ALS was determined by using mortality as a surrogate marker. Mortality information was obtained by correlating the National Death Index (1979-2011) to NMLS records. The study includes information from more than 2 million people: 1,011,172 men and 1,145,368 women. Of these, 1299 deaths were attributed to ALS. The data were collected prospectively. Race was self-reported as black, white, or other races, and ethnicity was reported as non-Hispanic or Hispanic. Non-Hispanic whites had a substantially higher risk of ALS mortality despite adjusting models for SES, health insurance type, or birthplace. Additionally, ALS rates did not differ by gender. Thus, the authors concluded that this finding might be attributed to varying genetic risk factors.22

Types

There are 2 primary classifications of ALS: sporadic (idiopathic) and familial. Familial ALS occurs in about 5% to 10% of patients with ALS, usually due to a dominant trait.1,27 Sporadic ALS encompasses all other patients with ALS.1 The affected population of sporadic ALS comprises approximately 67% males.1 In familial ALS, an almost 1:1 ratio of males to females is noted.1 Sporadic ALS usually occurs in patients in their mid-to-late fifties.1 On the other hand, familial ALS occurs in patients in their late teens or early adulthood.1 Sporadic ALS has no known cause, but it may possibly be caused by immune system abnormalities, toxic exposure, mitochondrial dysfunction, or glutamate toxicity.28

ALS has 4 main presentations: (1) Primary lateral sclerosis (PLS) with pure UMN involvement, (2) limb-onset ALS with a combination of UMN and LMN involvement, (3) progressive muscular atrophy with pure LMN involvement, and (4) bulbar-onset ALS with swallowing and speech difficulties initially and limb features later in the disease course.14,29 PLS involves the corticopontine and corticospinal motor neurons with slight dysfunction of the LMN.1,29 It is characterized by the gradual progression of severe muscle spasticity and stiffness, and modest muscle atrophy.1 PLS cannot be diagnosed as ALS until there is evidence of LMN dysfunction of at least 1 limb or region and it progresses to ALS in most patients.30 Limb-onset ALS is also known as flail leg or flail arm (Vulpian Bernhardt) variants and cannot be diagnosed as ALS until a minimum of 2 body regions are involved.30 Similar to limb-onset syndrome, progressive muscular atrophy (PMA) cannot be diagnosed as ALS until a minimum of 2 body regions are affected, but relevant genetic testing to rule out other motor neuron diseases should also be completed.30 PMA is considered a subform of ALS, based on postmortem findings of UMN dysfunction in a majority of patients, and several having an ALS-causing genetic mutation.30 Bulbar-onset ALS or progressive bulbar palsy (PBP) can be diagnosed as ALS when both UMN and LMN dysfunction is determined.30

Diagnosis

Symptoms

Most patients develop ALS from age 40 to 70 years, with 55 years being the average in the United States.13 There are patients who have developed the disease as early as their twenties.13 Diagnosis is primarily determined by clinical examination coupled with nerve conduction studies (NCSs), electromyography (EMG), and laboratory testing.1,8,31,32 NCSs tend to be normal or slightly abnormal with an absence of motor conduction block in patients with ALS.8 The presence of motor conduction block excludes an ALS diagnosis.8 Moreover, sensory nerve action potentials (SNAPs) tend to be normal in patients with ALS.8 Significantly abnormal SNAPs would not suggest ALS and would require further investigation into other potential causes.8 The use of needle EMG tests for acute and chronic denervation may lead to a diagnosis even before evident clinical onset.8 Needle EMG is not specific for ALS and must be coupled with extensive denervation in multiple muscle segments of distal and proximal muscles.8 Furthermore, EMG is used to determine the presence of muscle denervation to differentiae ALS from other conditions.1,31,32

The primary initial symptom of ALS is progressive, unilateral weakness in the distal legs and arms without remission or relapse.8 Atypical presentation includes emotional lability, frontal lobe-type cognitive dysfunction, weight loss, and fasciculations and cramps without muscle weakness.8,14 Signs of UMN disease include muscle tone increase, slow movement, and hyperreflexia.8 The presence of the Babinski sign, or upward response of the plantar reflex, is also evidence of UMN dysfunction and is discovered in 30% to 50% of patients.8 Symptoms may be described as “limb onset” and “bulbar onset.” With limb onset, patients may experience difficulty with simple actions, such as holding a cup or buttoning a shirt, stumbling more easily, and experiencing changes in their running or walking gaits.33 Patients with bulbar onset may experience challenges with chewing, swallowing, and speaking, such as nasal or slurred speech.33 Patients may also experience other symptoms, such as muscle cramps or twitches.33 Unfortunately, patients with ALS are aware of their gradually declining ability to function.33 They usually retain higher mental functions, such as problem solving, reasoning, understanding, and remembering.33 Additionally, patients do not always progress on a linear path.13 Weeks to months may pass where there is little to no function loss.13 A rare patient will have considerable improvements, such as recovering lost function.13 These ALS “reversals” and “arrests” are regrettably fleeting with fewer than 1% of patients maintaining marked improvement for at least 12 months.13

 
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