Peripheral Neuropathy Tied to Mortality in Adults Without Diabetes

Jake Remaly

December 07, 2020

Peripheral neuropathy is common in US adults and is associated with an increased risk of death, even in the absence of diabetes, researchers report today in the Annals of Internal Medicine.

The findings do not necessarily mean that doctors should implement broader screening for peripheral neuropathy at this time, however, the investigators say.

"Doctors don't typically screen for peripheral neuropathy in persons without diabetes," said senior author Elizabeth Selvin, PhD, MPH, professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, in an email.

"Our study shows that peripheral neuropathy — as assessed by decreased sensation in the feet — is common, even in people without diabetes," Selvin explained. "It is not yet clear whether we should be screening people without diabetes since we don't have clear treatments, but our study does suggest that this condition is an underrecognized condition that is associated with poor outcomes."

Patients with diabetes typically undergo annual foot examinations that include screening for peripheral neuropathy, but that's not the case for most adults in the absence of diabetes.

"I don't know if we can make the jump that we should be screening people without diabetes," said first author Caitlin W. Hicks, MD, assistant professor of surgery, Division of Vascular Surgery and Endovascular Therapy, Johns Hopkins University School of Medicine. "Right now, we do not exactly know what it means in the people without diabetes, and we definitely do not know how to treat it. So, screening for it will tell us that this person has this and is at higher risk of mortality than someone who doesn't, but we do not know what to do with that information yet."

Nevertheless, the study raises the question of whether physicians should pay more attention to peripheral neuropathy in people without diabetes, said Hicks, who is the director of research at the university's diabetic foot and wound service.

Heightened Risk

To examine associations between peripheral neuropathy and all-cause and cardiovascular mortality in US adults, Hicks and colleagues analyzed data from 7116 adults aged 40 years or older who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004.

The study included participants who underwent monofilament testing for peripheral neuropathy. During testing, technicians used a standard 5.07 Semmes-Weinstein nylon monofilament to apply slight pressure to the bottom of each foot at three sites. If participants could not correctly identify where pressure was applied, the test was repeated. After participants gave two incorrect or undeterminable responses for a site, the site was defined as insensate. The researchers defined peripheral neuropathy as at least one insensate site on either foot.

The researchers determined deaths and causes of death using death certificate records from the National Death Index through 2015.

In all, 13.5% of the participants had peripheral neuropathy, including 27% of adults with diabetes and 11.6% of adults without diabetes. Those with peripheral neuropathy were older, were more likely to be male, and had lower levels of education, compared with participants without peripheral neuropathy. They also had higher BMI, were more often former or current smokers, and had a higher prevalence of hypertension, hypercholesterolemia, and cardiovascular disease.

During a median follow-up of 13 years, 2128 participants died, including 488 who died of cardiovascular causes.

The incidence rate of all-cause mortality per 1000 person-years was 57.6 in adults with diabetes and peripheral neuropathy, 34.3 in adults with peripheral neuropathy but no diabetes, 27.1 in adults with diabetes but no peripheral neuropathy, and 13.0 in adults without diabetes or peripheral neuropathy.

Among participants with diabetes, the leading cause of death was cardiovascular disease (31% of deaths), whereas among participants without diabetes, the leading cause of death was malignant neoplasms (27% of deaths).

After adjustment for age, sex, race, or ethnicity, and risk factors such as cardiovascular disease, peripheral neuropathy was significantly associated with all-cause mortality (hazard ratio [HR], 1.49) and cardiovascular mortality (HR, 1.66) in participants with diabetes. In participants without diabetes, peripheral neuropathy was significantly associated with all-cause mortality (HR, 1.31), but its association with cardiovascular mortality was not statistically significant.

The association between peripheral neuropathy and all-cause mortality persisted in a sensitivity analysis that focused on adults with normoglycemia.

Related Conditions

The study confirms findings from prior studies that examined the prevalence of loss of peripheral sensation in populations of older adults with and without diabetes, said Elsa S. Strotmeyer, PhD, MPH, associate professor of epidemiology at the University of Pittsburgh, Pittsburgh, Pennsylvania. "The clinical significance of the loss of peripheral sensation in older adults without diabetes is not fully appreciated," she said.

A limitation of the study is that peripheral neuropathy was not a clinical diagnosis. "Monofilament testing at the foot is a quick clinical screen for decreased lower-extremity sensation that likely is a result of sensory peripheral nerve decline," Strotmeyer said.

Another limitation is that death certificates are less accurate than medical records for determining cause of death.

"Past studies have indicated that peripheral nerve decline is related to common conditions in aging such as the metabolic syndrome and cardiovascular disease, cancer treatment, and physical function loss," Strotmeyer said. "Therefore it is not surprising that is related to mortality as these conditions in aging are associated with increased mortality. Loss of peripheral sensation at the foot may also be related to fall injuries, and mortality from fall injuries has increased dramatically in older adults over the past several decades."

Prior research has suggested that monofilament testing may play a role in screening for fall risk in older adults without diabetes, Strotmeyer added.

"For older adults both with and without diabetes, past studies have recommended monofilament testing be incorporated in geriatric screening for fall risk. Therefore, this article expands implications of clinical importance to understanding the pathology and consequences of loss of sensation at the foot in older patients," she said.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. Hicks, Selvin, and a coauthor, Kunihiro Matsushita, MD, PhD, disclosed NIH grants. In addition, Selvin disclosed personal fees from Novo Nordisk and grants from the Foundation for the National Institutes of Health outside the submitted work, and Matsushita disclosed grants and personal fees from Fukuda Denshi outside the submitted work. Strotmeyer receives funding from the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and is chair of the health sciences section of the Gerontological Society of America.

Ann Intern Med. Published online December 7, 2020. Abstract

Jake Remaly is a staff journalist at Medscape Medical News and MDedge. He has covered healthcare and medicine for more than 5 years. He can be reached at

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