ALS women live longer than men despite faster functional decline

Understanding effects of sex may help predict disease course, guide treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A single leaf clings to a tree as other leaves lie around its trunk in this illustration of disease mortality.

While women with amyotrophic lateral sclerosis (ALS) see a faster functional decline, men have shorter survival times, mostly due to more rapid weight loss and lung function worsening, a study shows.

The findings highlight the importance of considering sex-specific differences when studying the mechanisms leading to ALS and when designing individual  treatment plans. The study, “Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis,” was published in Annals of Neurology.

ALS tends to develop earlier and is more frequent in men than women. Clinical features may differ too. For example, men are more likely to have flail arm, marked by progressive weakness and atrophy in the arms, as an initial symptom of ALS. But women are more often diagnosed with bulbar-onset ALS, which first affects the muscles in the head and neck.

Since age and where initial symptoms happen are both strongly associated with survival and the rate of disease progression, researchers at the University of Turin, Italy drew on data from the Piemonte and Valle d’Aosta Register for ALS (PARALS), which included those diagnosed with ALS between 2007 and 2019, to better understand how the interaction of sex with these two clinical factors could improve predicting the disease’s course and survival, and guide treatment.

Of 1,890 patients, more than half (55.2%) were men. On average, men developed ALS at 66.4 years old, while women had their first symptoms about a year later, with bulbar-onset ALS being more common (41.2% vs. 25.9%). The median diagnostic delay was nine months for both sexes.

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ALS survival in men, women

A survival analysis showed men tended to live shorter lives than women, but the difference only became significant when evaluating limb-onset ALS, which is sometimes called spinal ALS, and bulbar-onset ALS separately. This difference persisted even after considering factors like genetic makeup, cognitive function, and age at onset.

At the time of their diagnosis, men had a lower percentage of forced vital capacity (FVC), meaning worse respiratory function than women. Men also lost more weight each month (about 0.15 kg), regardless of having limb-onset or bulbar-onset ALS.

The fact that this occurred despite women having more bulbar symptoms, which often cause trouble breathing and eating, was “an apparently counterintuitive result,” wrote the researchers.

A “cause-and-effect” analysis showed the faster declines in respiratory function and weight were the strongest factors contributing to worse survival in men, accounting for about 66% of the sex differences.

“These findings elucidate that the shorter survival in male ALS patients stems from their faster decline in respiratory function and weight loss, although other factors are involved,” the researchers wrote.

When men and women were matched for a number of clinical and demographic variables, men continued to have a 19% higher risk of death than women. But this worse survival didn’t correspond to faster disability progression since women actually progressed faster on the ALS Functional Rating Scale-Revised (ALSFRS-R) scale, a measure of disease severity, by about 0.1 points a month.

This included a significantly faster progression in ALSFRS-R domains of fine motor function, gross motor function, and bulbar function. While there was no difference in the respiratory domain, it took women longer to start noninvasive ventilation to help with breathing.

These findings were confirmed in two additional groups of patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, which includes data from participants in previous ALS clinical trials, and the Answer ALS database.

“The present study casts new light on the multifaceted nature of sex-related differences in ALS prognosis [outlook] and has a direct impact on clinical practice, guiding the management of ALS patients toward sex-personalized care, and improving the design and interpretation of clinical trials,” the researchers said.