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Supplements A Managed Care Perspective on Scientific Advances in Amyotrophic Lateral Sclerosis
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Amyotrophic Lateral Sclerosis: Disease State Overview
Darrell Hulisz, PharmD, RPh
ALS Managed Care Considerations
Briana Santaniello, PharmD, MBA
Participating Faculty

Amyotrophic Lateral Sclerosis: Disease State Overview

Darrell Hulisz, PharmD, RPh
The ALSFRS was developed in 1996 to assess activities of daily living (ADLs) in patients with ALS in an easily administered format.34 In 1999, the ALSFRS was revised and named the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).35 The ALSFRS-R is a 12-item scale with each item scored from 0 (unable) to 4 (normal ability) with a possible total score range of 0 to 48. The higher the score, the better the patient is physically functioning. The items evaluate speech, salivation, swallowing, handwriting, cutting food and handling utensils (with or without gastrostomy), dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. The major difference between the ALSFRS and ALSFRS-R is that the ALSFRS-R weighs respiratory function similarly to bulbar and limb function, possibly increasing the scale’s sensitivity.35

Laboratory tests are done in patients with ALS to exclude other conditions.8 These tests include complete blood count, electrolytes, liver and thyroid function tests, creatine kinase, erythrocyte sedimentation rate, antinuclear antibody, rheumatoid factor, vitamin B12, anti-GM1 ganglioside antibody, serum protein electrophoresis with immunofixation, and 24-hour urine protein electrophoresis with immunofixation.8 Differential diagnoses include Lyme disease, metal toxicity, peripheral neuropathy, thyroid disease, multifocal motor neuropathy, myasthenia gravis, Guillain-Barré syndrome, and vitamin B12 deficiency.1,36,37 Additionally, a clinical similarity exists between PLS and hereditary spastic paraplegias, with the exception of the pronounced bulbar association found with PLS.1 In patients experiencing dementia with Pick disease, 15% to 20% have progressive cognitive abnormalities.1,38

Other tests are available, some for research purposes, to aid in the diagnosis of ALS. Examples of testing used for research include magnetic resonance imaging of all regions rostral to symptoms, magnetic resonance spectroscopy, diffusion tensor imaging, and transcranial magnetic stimulation. Cerebrospinal fluid (CSF) analysis should be considered in patients with malignancy, Lyme disease, chronic inflammatory demyelinating polyneuropathy, and HIV, and possibly to obtain a CSF protein profile for future use. Additionally, muscle biopsies may be performed in patients with possible myopathy.8

The El Escorial criteria were developed to create a consistent diagnostic process for ALS, guarantee its certainty, and clarify that the varying clinical qualities are complex. These criteria also assisted with determining clinical trial inclusion and exclusion indicators. Despite its original purpose, the staging system of possible, probable, and definite ALS, as determined by the number of affected body areas, has given rise to the ability of researchers to determine if the initial diagnosis has any effect on a patient’s prognosis. Conditions such as PMA, PBP, limb-onset ALS, and PLS have similar pathologic processes to ALS and should therefore be considered for neuroprotective therapies as well.39

The Lambert criteria used to diagnose ALS by using EMG was incorporated into both the original and revised El Escorial criteria.39 The Lambert criteria has since been deemed incomplete and insensitive.39 Additionally, the studied muscle had to have exhibited both ongoing denervation and motor unit remodeling, decreasing the chances of early ALS diagnosis.39 In an effort to increase the potential of earlier diagnoses, the Awaji Island criteria were created.39,40 The Awaji consensus criteria reformulated the EMG measures to allow for diagnosis based on the presence of either fasciculations in the presence of chronic neuropathic muscle potentials or fibrillation muscle potentials alone to be markers of acute denervation in patients with clinically suspected ALS.14,41 

After all other diagnoses have been excluded, the revised El Escorial criteria–2015 requires at least one of the following: the progression of UMN and LMN dysfunction in at least 1 limb or body region or LMN dysfunction in 1 region identified by clinical examination and/or by EMG in 2 regions (ie, lumbosacral, bulbar, thoracic, cervical). The EMG findings consist of sharp waves and/or fibrillation and neurogenic potentials.30

Genetic testing is recommended if the patient has a family history suggestive of ALS.8 This should be contemplated if a minimum of 1 first- or second-degree relative has ALS and/or frontotemporal dementia (FTD).30 If ALS or FTD is present within 3 generations, the association should be termed familial ALS (FALS).30 According to Ludolph et al, “If a pathogenic mutation in a disease-causing gene is found in the patient and segregates with the disease, the term hereditary or primary genetic ALS (HALS/GALS) should be used.” 30 If GALS/HALS is present, ALS diagnosis can be made based on LMN or UMN in 1 region of the body.30

Relevant Biomarkers

Biomarkers are laboratory tests used to measure the alteration of biological pathways associated with a disease.42 T cells have been linked to immune modulation and disease progression in patients with ALS, particularly by promoting microglia to generate a neuroprotective environment.42,43 The excitotoxicity of glutamate occurs when synaptic glutamate is not quickly removed, resulting in the excessive firing of motor neurons.10 Astrocytes, a type of glial cell, are responsible for regulating glutamate with assistance from the excitatory amino acid transporter 2.10 Glutamate causes the repetitive firing of action potentials, leading to mitochondrial and endoplasmic reticulum stress due to increases in calcium overwhelming the storage capacity of these structures.10 Moreover, poly(GP)peptide from the CSF is an emerging biomarker.44 Outside of the genetic mutations, other relevant biomarkers include inflammatory expression, TDP-43, and urinary p75.42,45

Impact of Novel Genetic Mutations

In 1993, SOD1 was the first gene linked to ALS.1,46 Since then, more than 120 genetic variants, linked with ALS risk, have been identified.1,10,47 Of these, roughly 25 genes have been associated with sporadic ALS, familial ALS, or both.1,10,48,49 In patients with sporadic ALS, ubiquitinated inclusions resulting from gene mutations are found in the spinal cord.15 Ubiquitin marks proteins for degradation by covalently binding to them by the ubiquitin/ATP-dependent pathway.50 This pathway has a large role in the degradation of abnormal proteins caused by mutations, oxidative stress, and neurotoxicity.50 When ubiquitinated proteins are not properly removed, cellular homeostasis may be disrupted, leading to deterioration and loss of functional activity.50 Chromosome 9 open reading frame 72 (C9orf72), FUS, SOD1, and TARDBP are the most common genes associated with ALS.26 NEK-1 is the most recent gene discovered.51 The ALS On-line Database (ALSoD) is a central genetic repository of various gene mutations linked to ALS.47 It also gives information about patients’ family history, gender, phenotype, geographical data, and age of onset, divided into phenotypic group, gene, or mutation.52

The genes are loosely categorized by function: disturbance of distal terminal and motor neuron axon cytoskeletal dynamics, alteration of protein quality control and proteostasis, and disruption of RNA metabolism, stability, and function. Most mutations are missense substitutions, but C9orf72 is caused by a 6-nucleotide repeat.1,10 The intraneural protein aggregates, such as SOD1, TDP-43, and FUS, associated with ALS, are speculated to cause cellular stress and disrupt protein homeostasis by commandeering RNA and other critical cellular proteins.26


C9orf72 is the most common genetic variant detected in patients with ALS. Approximately 25% to 40% of patients with familial ALS and a few with sporadic ALS have a defect in this gene, most especially in patients with FTD.26,33 Patients with behavioral variant FTD experience disinhibition, inappropriate social behavior, perseveration, abnormal eating patterns, apathy, loss of empathy, and obsessive-compulsive behaviors.26


Fused in sarcoma (FUS) is a nucleoprotein responsible for the regulation of gene expression, DNA and RNA binding, and mRNA gene splicing.26 It is found in approximately 5% of patients with familial ALS.26,53 FUS shares mechanisms of pathogenesis with TDP-43 and co-localizes with it, resulting in motor neuron granules.26 FUS mutations are correlated with a rapid progression, young onset, and prominent bulbar manifestations.25


SOD1, or copper zinc superoxide dismutase, is found in roughly 1% of sporadic ALS and 12% to 20% of familial ALS.26,33 The mutations are believed to be caused by autosomal dominant inheritance.26 SOD1 is responsible for the conversion of the superoxide anion to a less-damaging hydrogen peroxide.8 However, loss of this function due to mutation does not result in significant motor neuron loss.8 It is believed that neuron loss is caused by the damage to mitochondrial function and axonal transport.8,54 Depending on the variant, SOD1 mutations are linked with rapidly progressing or slow course by mutation of Ala4Val and Asp90Ala, respectively.25,55


Transactive response (TAR) DNA-binding protein 43 (TARDBP/TDP-43) is usually found in the alpha- and tau-synuclein-negative, ubiquitinated, cytoplasmic aggregates or inclusions seen in ALS and a subgroup of FTD.15,26 These mutations are found in about 5% of patients with familial ALS and are autosomal dominant.26 TDP-43, a DNA- and RNA-binding protein, is responsible for the regulation of transport, transcription, stability, and mRNA splicing.26 It is relocated from its usual position in the nucleus, causing it to accumulate in the cytoplasm of affected spinal cord motor neurons.1,9

Benefits of Early Diagnosis

Clinical Outcomes and Progression

The time of symptom onset to ALS diagnosis is reportedly about 9 to 12 months.1,12 This delay in diagnosis is a challenge to providing patients with early treatment. It is estimated that by the time patients experience ALS signs and symptoms, approximately 50% to 70% of the motor neurons are nonfunctional.12,31

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