Restless Legs Syndrome Linked to Higher Mortality

Pauline Anderson

June 12, 2013

After adjustment for age, men with restless legs syndrome (RLS) have a 39% increased risk for death, and the risk is still elevated after adjustment for lifestyle habits and sleep disturbances, among other factors, a new study shows.

The results underline the clinical importance of RLS, which is under-recognized but common, affecting 5% to 10% in the general population, with 1% to 2% of these cases considered severe, said study author Xiang Gao, MD, PhD, assistant professor and research scientist, Harvard Medical School and Harvard School of Public Health, and associate epidemiologist, Brigham and Women's Hospital, Boston, Massachusetts.

"The study highlights the importance of understanding RLS, "instead of paying too little heed to it as is often the case, Dr. Gao told Medscape Medical News, adding that it also lays some groundwork for future research.

The study is published online June 12 in Neurology.

Frequent Symptoms

The analysis included 18,425 men participating in the Health Professionals Follow up Study (HPFS), an ongoing prospective project involving American men aged 40 to 75 years that began in 1986.

At study baseline in 2002, 3.7% of the cohort met criteria for RLS, defined as having symptoms 5 or more times a month. RLS is characterized by an uncomfortable feeling in the legs during the night that is alleviated only by movement. The frequency of this feeling is a "crude surrogate for disease severity," said Dr. Gao.

With follow-up to 2010, researchers documented 2765 deaths. Controlling for age, the study found an increased risk for death among those with RLS (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.19 - 1.62; P ˂ .0001).

Dr. Xiang Gao

After also factoring in ethnicity, body mass index (BMI), lifestyle risk factors (such as smoking, diet, and physical activity), presence of common chronic conditions, and sleep performance, the mortality HR for men with RLS was reduced to 1.30 (95% CI, 1.11 - 1.52; P = .001).

"We thought RLS could be due to some disease associated with it, but after we controlled for those kinds of diseases, the association between RLS and mortality was attenuated, but still significant," said Dr. Gao. "It suggests RLS, per se, is associated with an increased risk of mortality," or possibly, RLS could be associated with conditions beyond those controlled for in the study, he said.

A further adjustment for dietary intake of iron, magnesium, folate, and vitamin B12; regular use of a benzodiazepine; and having multiple sclerosis brought the HR down to 1.25 (95% CI, 1.07 - 1.47).

The association appeared to be largely driven by respiratory disease (HR, 1.73); endocrine diseases, nutrition/metabolic diseases, and immunity disorders (HR, 4.97); and diseases of the blood and blood-forming organs (HR, 5.87). According to the authors, this is consistent with research suggesting that RLS may co-occur with chronic obstructive pulmonary disease and iron-deficiency anemia.

There was also a nonsignificant trend between RLS and increased risk for cardiovascular disease (CVD) mortality or cancer mortality.

Healthy Men

After excluding men with cancer, Parkinson's disease (PD), high blood pressure, CVD, diabetes, arthritis, obesity, snoring every night, cancer, emphysema or chronic bronchitis, chronic obstructive pulmonary disease, pneumonia, asthma, pernicious anemia, ulcerative colitis or Crohn's disease, and renal failure — leaving a relatively healthy cohort — the HR for total mortality was 1.92 (95% CI, 1.03 - 3.56; P = .04).

In a sensitivity analysis excluding persons with PD, a condition associated with RLS, the HR for total mortality compared with men without RLS was 1.31 (95% CI, 1.12 - 1.54).

It makes sense that PD can't explain the increased mortality risk, said Dr. Gao. "The prevalence of PD in the general population is pretty low relative to RLS, so PD alone can't explain this strong association."

Although the researchers controlled for poor sleep quality, the study may not have captured all factors. "We asked about insomnia, and we asked about snoring, but there could still be residual confounding," said Dr. Gao.

The authors surmised that the increased mortality risk in men with RLS could be through increased effects on blood pressure and cardiovascular risk. Or RLS may reflect an underlying neurodegenerative disorder, perhaps a preclinical symptom of PD, they said.

The study didn't control for RLS medications, but Dr. Gao pointed out that RLS status was assessed in 2002, at a time when probably only a small proportion of people knew anything about RLS and few would have been taking medications for it.

Although the prevalence of RLS in this male cohort was almost 4%, the numbers are higher among women. In another study that included only women, the Nurses' Health Study (NHS), the prevalence was about 6%. An earlier analysis of NHS participants found that women with RLS had an elevated risk for coronary heart disease. ( Circulation. 2012;126:1689-1694).

Unclear Picture

Reached for comment, Richard A. Hauser, MD, professor, neurology, molecular pharmacology and physiology, and director, University of South Florida Parkinson's Disease and Movement Disorders Center of Excellence, Tampa, said that the authors present "interesting data" indicating that mortality is increased in people with RLS.

This finding could be related to underlying medical conditions that cause RLS or to consequences of RLS, such as shorter duration of sleep, but because the increased mortality persisted even after controlling for these factors, the full picture as to why RLS is associated with increased mortality is unclear, said Dr. Hauser.

"It may be impossible to completely control for underlying conditions that cause RLS as some might be unrecognized, undiagnosed, or undiagnosable," he told Medscape Medical News."RLS itself might be associated with metabolic abnormalities that affect health and longevity. Poor sleep quality and medications could also play a role."

Further investigation, he added, is warranted. A key question that should be addressed is whether appropriate treatment can reduce mortality associated with this common condition, he said.

The study was supported by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. Dr. Gao has disclosed no relevant financial relationships.

Neurology. Published online June 12, 2013. Abstract

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