Risk of Amyotrophic Lateral Sclerosis Is Dramatically Greater in Veterans

Air Force Personnel, Healthcare Workers Especially Vulnerable

Military veterans face a significantly higher risk of amyotrophic lateral sclerosis (ALS), with both prevalence and cumulative incidence especially greater among Air Force personnel compared to other service branches and among tactical operation officers and health care workers compared to general and administrative officers. While ALS, formerly Lou Gehrig’s disease, remains a dire diagnosis with no cure, survival and quality of life have improved in recent years.

SALT LAKE CITY — Five years ago, in March 2020, an important new study was published in Military Medicine about the prevalence and incidence of amyotrophic lateral sclerosis (ALS) among deployed post-9/11 U.S. veterans. Concurrent with the COVID-19 pandemic shutdowns, the report might not have gotten as much notice as it normally would have.

But the conclusions were dire when it came to the outsized risks deployed veterans faced for the devastating diagnosis.

The researchers from the Salt Lake City VA and colleagues pointed out that ALS is a recognized military service-connected condition, adding that previous prevalence studies of ALS among U.S. war fighters were not able to address issues related to neurodegenerative sequelae of traumatic brain injury (TBI) and might have disregarded risk heterogeneity from occupational categories within service branches.¹

ALS, previous known as Lou Gehrig’s disease after the baseball star who suffered from it, is a motor neuron disease that leads to rapid degeneration of nerves in the brain and spinal cord, with eventual loss of voluntary movements, including breathing.

The case-control study looking at the years 2002-2015 evaluated the association of TBI and major military occupation groups with ALS, adjusting for demographics and comorbidities.

The authors reported that the prevalence of ALS was 19.7 per 100,000 over 14 years, advising that “both prevalence and cumulative incidence of definite ALS were significantly higher among Air Force personnel compared to other service branches and among tactical operation officers and health care workers compared to general and administrative officers.”

In comparison, the ALS Association estimates prevalence at between 5–7 cases within a population of 100,000 in the general U.S. population.

While neither TBI nor younger age (<45 years) was linked with ALS, certain conditions, mainly depression, cardiac disease, cerebrovascular disease, high blood pressure and obstructive sleep apnea, were significantly associated, they wrote.

“This study among a cohort of relatively young veterans showed a high ALS prevalence, suggesting an early onset of ALS among deployed military service members,” the study concluded. “The higher prevalence among some military specific occupations highlights the need to determine which occupational exposures specific to these occupations (particularly, Air Force personnel, tactical operations officers, and health care workers) might be associated with early-onset ALS.”

Studies at the VA have continued to focus on various aspects of ALS in veterans, with one of the most recent published late last year in Medical Science Monitor. It pointed out, “Most of the studies on ALS have been conducted in the general population and few in the veteran population, who make up 7% (22 million) of the U.S. population. Therefore, this retrospective study of medical record data from 105 U.S. veterans diagnosed with ALS at the Oklahoma City VA Medical Center between 2010 and 2021 aimed to identify patient demographics, and the cause and place of death.”²

The researchers from that VAMC and the University of Oklahoma advised, “The information collected will help improve acute and end-of-life (palliative and hospice) care provisions. Determining the location of death (i.e., within or outside a medical facility) for veterans with ALS will help us allocate the resources needed for highly specialized care, in different care settings such as hospice and nursing homes.”

Results indicated that, during the 11-year follow-up period, 80 (76.2%) veterans with ALS died. The mean (SD) follow-up time was 4.53 (4.55) years.

Respiratory Failure

The researchers determined that most of the deaths were due to respiratory failure and pneumonia (n=43, mortality rate=9.21 per 100 person-years) and that most patients died at home (n=71, 88.7%). The annual crude mortality rate was calculated at 16.7 and the all-cause death SMR was 25.63 (95% CI, 20.32-31.55).

“This study’s findings are that in veterans with ALS, the main cause of death is respiratory disease (failure),” the authors explained. “The main location of death was the home, with their family members. The all-cause mortality rate among veterans with ALS was 26 times greater than for the general Oklahoma population.”

ALS, which is a presumptive condition for VA care, presents as “painless voluntary muscle wasting with fasciculations and weakness from lower motor neuron involvement (amyotrophy); and upper motor neuron findings of hyperreflexia and spasticity from axonal loss involving the corticospinal tracts in the lateral spinal cord columns (lateral sclerosis),” according to the study.

The Oklahoma City VAMC study noted that the quality of clinical care and life for patients with ALS has recently improved with earlier use of gastrostomy tubes (PEG), noninvasive ventilation (NIV) for respiratory support, cough assist and suction devices to prevent aspiration pneumonia, better communication devices, and provision of mobility devices to help achieve independence in their environment.

Earlier studies agreed that the leading cause of death was respiratory failure (in 77% of cases), followed by cardiac failure (in 3.4%), suicide (in 1.3%) and sudden death (in 0.7%). One difference is that, in previous research, the majority of patients died in the hospital.

One earlier study, published in 2015 in PLoS One had findings that could be especially significant for the VA patient population, It analyzed data on a cohort of ALS cases diagnosed between 2009-2011 as part of the Los Angeles and San Francisco Bay Area Metropolitan ALS Surveillance projects. Some veteran deaths were included in the data.³

Of the 618 cases identified, 283 died during the follow-up time period. The median age at death was 64.3 years, and median survival time post-diagnosis was 2.6 years. The authors concluded, “Age at diagnosis and year of diagnosis were predictors of survival time in adjusted models; those diagnosed at age 80 or older had shorter survival than those diagnosed at age 50 or younger. Most (92%) had ALS noted as a cause of death.”

The studies suggested that pharmacological treatment has improved and increasingly affects survival, although ALS has no cure. Researchers explained that symptomatic management as recommended by a multidisciplinary ALS team is the main treatment option in patients with ALS.

The first treatment approved for ALS was riluzole (Rilutek; Sanofi) in 1995 in an effort to block glutamate release. That was a theory as to why motor neurons die in ALS. Since that time, riluzole has been approved in oral suspension (Tiglutik in 2018) and dissolvable oral film formulations (Exservan in 2019).

With those drugs in the arsenal, symptom progression and death were delayed by only 3 months in some trials.

In May 2017, edaravone (Radicava; Mitsubishi Tanabe Pharma Corp.) was approved by the Food and Drug Administration based on the evidence that oxidative stress might contribute to the pathophysiology of ALS. Edaravone works as an antioxidant, although the mechanism of action is not fully understood.

Edaravone first came in the form of an intravenous (IV) infusion, but, with patient about treatment with the IV formulation due to the burden of infusions (daily for 10–14 days per 28-day cycle), an oral suspension was approved in May 2022. After fasting overnight, the oral suspension is either taken by mouth or through a feeding tool the next morning tube.

The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.

A study last year in the American Journal of Therapeutics noted that the oral formulation, edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The authors explained that ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour.⁴

“Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting,” the authors wrote.

 

1. Sagiraju HKR, Živković S, VanCott AC, Patwa H, Gimeno Ruiz de Porras D, Amuan ME, Pugh MJV. Amyotrophic Lateral Sclerosis Among Veterans Deployed in Support of Post-9/11 U.S. Conflicts. Mil Med. 2020 Mar 2;185(3-4):e501-e509. doi: 10.1093/milmed/usz350. PMID: 31642489; PMCID: PMC8921606.
2. Rabadi MH, Russell KA, Xu C. Analysis of Mortality Causes and Locations in Veterans with ALS: A Decade Review. Med Sci Monit. 2024 Nov 17;30:e945816. doi: 10.12659/MSM.945816. PMID: 39550606; PMCID: PMC11580304.
3. Paulukonis ST, Roberts EM, Valle JP, Collins NN, English PB, Kaye WE. Survival and Cause of Death among a Cohort of Confirmed Amyotrophic Lateral Sclerosis Cases. PLoS One. 2015 Jul 14;10(7):e0131965. doi: 10.1371/journal.pone.0131965. PMID: 26172548; PMCID: PMC4501568.
4. Singh P, Belliveau P, Towle J, Neculau AE, Dima L. Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis. Am J Ther. 2024 May-Jun 01;31(3):e258-e267. doi: 10.1097/MJT.0000000000001742. PMID: 38691665.