Early Diagnosis of ALS Benefits Patients


Amyotrophic lateral sclerosis is difficult to diagnose early because it can mimic other neurological diseases.

On average, individuals with the neurodegenerative condition amyotrophic lateral sclerosis (ALS) are diagnosed approximately 12 months after their first symptom and survive for approximately 3 to 5 years following diagnosis.

ALS is relentlessly progressive; the loss of motor neurons in individuals with ALS can cause weakness and impaired function of axial, bulbar, limb, and respiratory muscles, eventually leading to disability and death. There are factors associated with more favorable survival, such as younger age at symptom onset and body site of first symptoms, such as limb rather than bulbar onset, but longer survival is in part dependent upon the ability to make informed management decisions based upon a definitive ALS diagnosis.

Impact of Diagnostic Delay

A variety of factors contribute to the delay in diagnosis of ALS. First, there are only about 17,000 individuals in the United States who have ALS, and the presentation of symptoms and course of disease is highly variable among them. The early signs and symptoms of ALS are easy to dismiss as signs of aging or mistake for another neuromuscular condition. There is also no test that can provide a rapid or definitive diagnosis for ALS. An estimated 10% to 15% of individuals with ALS have a family history of the disease, and approximately 70% of these cases may be diagnosed by genetic testing. In the remaining cases, however, clinicians must evaluate clinical history, electromyography, neuroimaging, and physical examinations to diagnose ALS. As a result, ALS can be difficult to identify, and the diagnostic journey of an individual with the disease may involve many health care professionals and testing before the correct diagnosis is established.

Delayed diagnosis is a problem, because it prevents individuals with ALS from seeking multidisciplinary care that may improve their quality of life and defers the initiation of disease-modifying treatment. Although treatment for ALS was previously limited to the glutamate blocker riluzole (Rilutek), which moderately increases life expectancy by 3 to 6 months, the availability of new therapeutic options and the promise of investigational therapies, makes early diagnosis more critical for individuals living with ALS. In 2017, the FDA approved intravenous (IV) administration of the antioxidant drug edavarone (Radicava) for treatment of ALS.1 Participants receiving edaravone in clinical trials experienced a significantly reduced decline in a measure of daily function (ALSFRS-R score), meaning that edaravone treatment slowed progression of disease. The FDA approved a new drug application (NDA) for an oral formulation of edaravone for treatment of ALS on May 12, 2022. This new formulation will allow the drug to be taken easily at home rather than requiring an IV.

Delayed diagnosis of ALS not only defers access to approved treatments, but it also prevents timely enrollment in clinical trials, which often require a clinical definition of definitive or probable diagnosis of ALS for eligibility. There are 100-plus products in development2 for management of ALS, including numerous investigational therapies3 in phase 3 trials. Delayed diagnosis prevents individuals with ALS from gaining access to investigational therapies that may improve their disease and simultaneously hinders the research and development process for new, potentially effective treatments.

Animal studies of ALS have shown that interventions assessed preclinically are more effective when implemented earlier in the course of disease. Typically, however, individuals are not diagnosed with ALS until they have already lost a considerable number of motor neurons and are demonstrating clinical symptoms. Although it may not yet be feasible to diagnose individuals before they experience symptoms, it may be possible to close the gap between the start of symptoms and a formal diagnosis. This will allow individuals with ALS to begin treatment as early as possible.

Improving Diagnostic Sensitivity

The revised Awaji and El Escorial criteria are the most commonly used diagnostic criteria for ALS, and consensus diagnostic classifications based on these 2 criteria are also available. Although use of these scales is commonplace, their diagnostic sensitivity is relatively low, often leading to a diagnosis of probable ALS. There is an effort in the research community, therefore, to determine better methods to identify ALS in patients.

A recent study from Juan F. Vázquez-Costa, associate professor of neurology at the University of Valencia in Spain, and colleagues, analyzed factors that may contribute to the diagnostic delay in ALS.4 The study demonstrated that the type of hospital center, departmental vs referral ALS centers, can significantly affect the time to diagnosis. Patients evaluated in an ALS referral unit, which is a center that typically receives referrals from the private and public hospitals in the region, were diagnosed in a median of 8.5 months compared with the 12 months of patients studied in departmental hospitals. The study included 25% of ALS patients who did not meet Awaji criteria for ALS at the time of the diagnosis but for whom the ALS diagnosis was confirmed after 2 years of follow up. This finding emphasizes the importance of connecting with experienced clinicians, who may better recognize the early signs and symptoms of disease, when an ALS diagnosis is suspected.

Searching for Pre-Symptomatic Disease Markers

It is increasingly clear that conditions such as Alzheimer disease, frontotemporal dementia, Huntington disease, Parkinson disease, and spinal muscular atrophy are preceded by a pre-symptomatic period, during which affected individuals experience no clinical symptoms, but the underlying disease process begins. Insights from the study of these diseases highlights opportunities for understanding ALS. For example, the identification of amyloid, tau, and other biomarkers of AD has allowed earlier definition based on histopathology.

Similarly, deciphering the biology of pre-symptomatic ALS could help define the earliest stages of disease. Although the 10% to 15% of individuals with familial ALS have potentially identifiable genetic markers, the vast majority have an unknown cause of disease. Investigators are working to identify non-genetic risk factors and biomarkers for use in predicting emergence of clinical ALS. They are also searching for behavioral, cognitive, or motor impairments that may precede clinical presentations of ALS.

Investigators at Columbia University are on the forefront of efforts to detect ALS before symptoms arise. Matthew Harms, associate professor of neurology and a member of Columbia’s Institute for Genomic Medicine; Elizabeth Harrington, genetic counselor at the Eleanor and Lou Gehrig ALS Center; and Neil Shneider, associate professor of neurology at Columbia’s Vagelos College of Physicians and Surgeons, run the ALS Families Project,5 which follows asymptomatic relatives of patients living with familial ALS. These relatives share known disease-associated gene mutations with the affected patients and have an elevated risk of developing ALS. This study represents a major effort to identify early changes associated with ALS in the months or years preceding the appearance of obvious symptoms.

Another effort, directed by Michael Benatar, MD, professor of neurology and the chief of the neuromuscular division at the Miller School of Medicine at the University of Miami, has led to the creation of a “roadmap” to early intervention for ALS.6 The study relied on the understanding that like ALS, conditions, such as AD, frontotemporal dementia, Huntington disease, Parkinson disease, and spinal muscular atrophy present with neurodegenerative and neuroinflammatory changes in the brain. By mapping neuroimaging markers, pre-symptomatic identifiers, and gene mutations found in these other neurodegenerative diseases before the appearance of clinical symptoms, investigators were able to predict pre-symptomatic changes that may take place in ALS.

Pre-Symptomatic Intervention Strategies

One of the goals of detecting ALS earlier is to prevent the emergence of disease symptoms with early interventions. Toward this end, Benatar’s group, in collaboration with Biogen, is testing treatment of presymptomatic participants with ALS in the multicenter, phase 3 ATLAS clinical trial.7 Mutations in the SOD1 gene cause about 2% of all cases of ALS. ATLAS will evaluate the effects of the investigational drug tofersen, which targets SOD1, in participants who carry the SOD1 mutation but do not yet have clinical manifestations of disease. The trial will evaluate whether tofersen can delay onset or slow progression of ALS in this high-risk population.

Work Towards Early Diagnosis of ALS

The Muscular Dystrophy Association (MDA) is committed to funding research and education that improves the lives of individuals with neuromuscular diseases. In 2023, the MDA research team plans to release a request for applications to support projects promoting innovations in the early diagnosis of ALS. Additionally, the MDA’s professional medical education program is developing content to support clinicians in early ALS detection. Raising awareness and educating health care providers about the signs and symptoms of ALS, as well as the new scales and studies centered on diagnosis, may help reduce the diagnostic journey of individuals with ALS. Finally, the MDA’s multi-disease patient registry, neuroMuscular ObserVational Research,8 has collected clinic-entered data from more than 2000 patients with ALS, which is being used to track the gap between symptom onset and formal diagnosis. This multi-pronged approach supports the innovative work being done by clinicians and investigators in the area of early diagnosis and intervention. Although efforts are still focusing on the search for effective targets for ALS therapies, meaningful improvements in care can be achieved by earlier diagnosis.


1. Cho H, Shukla S. Role of edaravone as a treatment option for patients with amyotrophic lateral sclerosis. Pharmaceuticals. 2021;14(1):20. doi:10.3390/ph14010029

2. Amyotrophic lateral sclerosis. Delve Insight. January 2022. Accessed September 28, 2022. https://www.delveinsight.com/report-store/amyotrophic-lateral-sclerosis-als-pipeline-insight?utm_source=globenewswire&utm_medium=pressrelease&utm_campaign=vpr

3. Chen JJ. Overview of current and emerging therapies for amyotrophic lateral sclerosis. Am J Manag Care. 2020;26(9 Suppl):S191-S197. doi:10.37765/ajmc.2020.88483

4. Martínez-Molina M, Argente-Escrig H, Polo MF, et al. Early referral to an ALS center reduces several months the diagnostic delay: a multicenter-based study. Front Neurol. 2020;11:604922. doi:10.3389/fneur.2020.604922

5. New program hopes to make early detection and treatment of ALS a reality. Columbia University Irving Medical Center. November 19, 2018. Accessed September 28, 2022. https://www.cuimc.columbia.edu/news/new-program-hopes-make-early-detection-and-treatment-als-reality

6. Benatar M, Wuu J, McHutchinson C, et al. Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases. Brain. 2022;145(1):27-44. doi.org/10.1093/brain/awab404

7. A study of BIIB067 when initiated in clinically presymptomatic adults with a confirmed superoxide dismutase 1 mutation (ATLAS). ClinicalTrials.gov. Updated September 28, 2022. Accessed October 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04856982

8. MOVR data hub (neuroMuscular ObserVational Research). Muscular Dystrophy Association. Accessed October 2, 2022. https://www.mda.org/science/movr-data-hub-neuromuscular-observational-research

Related Videos
Related Content
© 2024 MJH Life Sciences

All rights reserved.