Peripheral diabetic neuropathy or restless legs syndrome in persons with type 2 diabetes mellitus
Restless legs syndrome (RLS) is a chronic long-term sleep and movement disorder that affects more than 40 million Americans; an additional 20 million Americans suffer from other sporadic sleep problems related to RLS (National Institute of Neurological Disorders and Stroke [NINDS], 2014). RLS is characterized as a nighttime (sleep) movement disorder and is described by patients as an uncomfortable urge to “move the legs” to stop the sensations. RLS is a chronic lifelong condition that has no cure. Symptoms will gradually worsen with age and the condition affects women more frequently than men. One third of pregnant women will experience symptoms of RLS, with a peak in symptoms in the third trimester, and they are highly likely to experience symptoms later in life (Picchietti et al., 2015). Some patients with RLS can have remissions when symptoms will subside or potentially disappear for weeks and even months (NINDS, 2014). The symptoms of RLS result in sleep deprivation, ultimately interfering with social activities, employment, and driving skills. It is estimated that medical costs alone surpass the $46 billion mark annually. This does not include the indirect costs associated with lost productivity from poor work attendance, work fatigue, and low work output, resulting in even higher healthcare cost expenditures.
Diabetes mellitus affects 29 million people in the United States with total cost of health care (both direct and indirect) upward of $245 billion (Centers for Disease Control and Prevention [CDC], 2014). T2DM has been positively associated with RLS (odds ratio 1.40; 95%; confidence interval 1.12–1.78; Plantinga, Rao, & Schillinger, 2012). RLS has been identified in up to 21% of the diabetic patient population (Cuellar & Ratcliffe, 2008). The symptoms of RLS may mimic those of peripheral diabetic neuropathy (PDN). Symptoms can be described as numbness, tingling, or discomfort in the lower extremities, all of which are similar to symptoms of PDN, making it difficult to differentiate the two disorders. It has been reported that up to 47% of diabetic patients have PDN, and the cost of care may range from $1600 to $7000 annually per patient (Dworkin, Malone, Panarites, Armstrong, & Pham, 2010). The prevalence of RLS in persons with PDN was reported in a Korean sample to be 8% (Cho et al., 2013). Glycemic control is influenced by sleep duration and sleep disorders, such as RLS (Ford et al., 2014). Because the symptoms of PDN may mimic the symptoms of RLS, delaying appropriate treatment, the sleep disruption caused by RLS may in turn have an indirect effect on the outcomes of the patient with T2DM.
Despite the current treatment options available to the person with diabetes, poor health outcomes, such as PDN, will occur (Lopes et al., 2005). It is important for all healthcare providers to understand the differences between RLS and PDN in order to diagnose and treat appropriately. Nurse practitioners (NPs) are in a position to identify symptoms and manage patients with sleep disorders and diabetes. Therefore, the purpose of this article is to provide NPs with (a) an overview of RLS, (b) the association of RLS with T2DM, (c) the defining characteristics that differentiate PDN from RLS, and (d) implications to improve health outcomes of persons with T2DM.
Overview of RLS
Sir Thomas Willis, an English physician, was the first to report symptoms of RLS in 1672. He documented the syndrome as “leapings and contractions” involving the legs and arms that cause sleep disturbances equal to the most intense torture (Hammerschmidt, 2006). In the 1940s, a Swedish neurologist, Karl Ekbom, defined the disorder as a motor and sensory dysfunction of the limbs occurring mainly at rest (Karroum, Konofal, & Arnulf, 2009). The NINDS (2014) defines RLS as a “neurological disorder characterized by the unpleasant sensation in the legs and an uncontrollable and sometimes overwhelming urge to move them for relief.” RLS is emerging as one of the most common sleep disorders leading to difficulty initiating sleep and frequent awakenings. The symptoms result in daytime sleepiness because of the pain and movement of the legs and sometimes, in intense cases, the arms (NINDS, 2014).
While the exact cause of RLS is unknown, origin theories evolved around brain iron deficiency (measured by ferritin levels below 75) and dopamine dysfunction (Daubian-Nose, Frank, & Esteves, 2014). Other evidence suggests spinal cord, peripheral nerves, and supraspinal networks as contributing to the pathophysiology of RLS (Rye & Trotti, 2012). Six variants of RLS have been identified in genome-wide association studies, and suggest a strong genetic association with the syndrome (Dauvilliers & Winkelmann, 2013). Data suggest that the genetics of RLS may be related to the defective use or lack of iron in the brain that incites RLS (National Heart, Lung and Blood Institute [NHLBI], 2015). Low-serum iron levels have been associated with negative sleep outcomes. Secondary RLS is associated with other conditions (e.g.,diabetes, hypothyroidism, Parkinson's, diabetes, kidney failure, rheumatoid arthritis, pregnancy, and iron deficiency) that can affect the amount of iron in the brain and how it is utilized (Earley et al., 2014). Alcohol and tobacco use may trigger RLS symptoms, as well as certain medications such as antihistamines, calcium channel blockers, antipsychotics, antidepressants, and antiemetics. Exacerbation of RLS associated with these medications is the cause for immediate discontinuation (Cuellar, 2004).
The sensory symptoms of RLS are described by some patients as a deep pulling, throbbing, creeping, crawling, prickling, and/or tingling in the legs. The sensations range from simply uncomfortable, to irritating, to intensely painful. These sensory symptoms are circadian and occur usually at rest or at bedtime, in the evening hours. Periodic limb movements in sleep (PLMS) occur in 80% of persons with RLS; however, it is possible to have PLMS without RLS. PLMS are described as repetitive movements in the lower limbs that occur every 20–40 s during sleep. Persons with RLS may not know that they have PLMS, and the symptoms are often reported by their bed partner (Aurora et al., 2012; Salas, Rasquinha, & Gamaldo, 2010). RLS is identified as idiopathic (or primary) and symptomatic (or secondary; Earley et al., 2014). Idiopathic RLS is the genetic form of RLS, and is seen in generations of families and is often seen in children. Symptomatic RLS is seen with comorbid conditions such as T2DM and occurs later in life, beginning at around age 40 (Rye & Trotti, 2012). The effect of cumulative comorbidities will result in a higher likelihood of developing RLS (Szentkiralyi, Volzke, Hoffmann, Trenkwalder, & Berger, 2014). Despite the etiology, whether idiopathic or symptomatic, the symptoms are lifelong and worsen over time.
The International Restless Leg Syndrome Study Group developed four key signs of RLS and determined these as diagnostic for RLS: (a) a strong urge or sensation to move the legs, (b) symptoms beginning or worsening when resting—either sitting or lying down, (c) relief of symptoms with walking, and (d) worsening of symptoms in the evenings or at night (Allen et al., 2014). While these four essential characteristics are traditionally used for identifying RLS, they should be used with caution, as these diagnostic criteria are unable to exclude mimics. Using only these four essential criteria, the sensitivity and specificity to diagnose RLS have been reported from 69.4% to 84% (Benes & Kohnen, 2009; Hening, Allen, Washburn, Lesage, & Earley, 2009). Therefore, three additional criteria are also considered to confirm the diagnosis of RLS (in addition to the four essential criteria) including (a) PLMS, (b) family history of RLS, and (c) a positive response to dopaminergic treatment. In 2012, a fifth essential criterion was added to address the issue of mimics and false-positive responses for RLS, which requires that the occurrences of the four essential characteristics are not because of a comorbid condition (International RLS Study Group, 2015). Table 1 lists the mimics of RLS that have been reported in the literature.
It is crucial that recognition of RLS symptoms be foremost in devising the correct treatment strategies to alleviate patient suffering. The diagnosis is not easy to make because of the patients' inaccuracy and variability in describing the symptoms. In addition, the physical exam is typically unremarkable; symptoms may mimic other diseases, and there are no biomarkers for RLS (Ondo, 2014). A thorough sleep history is necessary when talking with the patient about RLS. Complaints such as problems with insomnia, anxiety or depression causing insomnia, frequent night awakenings, change in sleep patterns, sleep apnea, and snoring can be helpful in formulating the diagnosis. Having the spouse or significant other present during the history gathering portion of the office visit can be helpful as well. Their input can be beneficial in filling in the gaps that the patient may not be able to provide.
In contemplating the treatment options for the patient with RLS, the primary goal is to eliminate the uncomfortable irritating symptoms for the patient. Caffeine consumption, obesity, poor sleep hygiene, smoking, and lack of exercise can contribute to the exacerbation of symptoms of RLS. Depending on the salient factors of the patient history, treatments for RLS will vary from recommendations of dietary changes and stress management, to massage, cold and heat therapy, whirlpool baths, relaxation techniques, and lifestyle modifications.
The use of pharmacological interventions is often necessary as the disease progresses. The “gold” standards for treatment are the dopamine agonists Requip (ropinirole) and Mirapex (pramipexole). Other medications include dopamine agonists (SINEMET [levodopa with carbidopa] or Parlodel [bromocriptine]), benzodiazepines (Restoril [temazepam] and Klonopin [clonazepam]), low-potency opioids (codeine), alpha2-agonists (Catapres [clonidine]), iron supplements, and anticonvulsants (gabapentin and Tegretol [carbamazepine]). The medications are taken at least 1–2 h before bedtime, normally when the symptoms begin, and in the event when conservative management strategies are ineffective (Ferini-Strambi & Marelli, 2014). For the best treatment outcomes, consultation with a clinical pharmacist may be needed to manage difficult cases of RLS.
Association of RLS in T2DM
Three observational studies have examined the association of RLS in T2DM. In the earliest study reported, 27% of persons (n = 100) with T2DM were diagnosed with RLS (Lopes et al., 2005). The patients with T2DM and RLS had poorer sleep quality, took longer time to fall asleep, were asleep for less time, and used more sedatives (Lopes, 2005). In the second study, 45% of persons (n = 121) with T2DM had symptoms of RLS using the four criteria for diagnosis of RLS symptoms (Cuellar & Ratcliffe, 2008). Quality of life was affected as a result of depression and anxiety caused by RLS in T2DM patients (Cuellar & Ratcliffe, 2008). In the third study, Merlino et al. (2010) found that RLS was independently associated with and diagnosed in 17.7% of persons (n = 124) with T2DM. Even more importantly, glycosylated hemoglobin (A1c) levels contributed to sleep disruption and frequent awakenings (Merlino et al., 2010). Poorly controlled T2DM increases sleep disruption, which may in turn increase the co-occurrence of RLS.
Differentiating PDN and RLS
PDN is one condition that can mimic symptoms of RLS and has been identified as one of the most common peripheral neuropathic conditions (Dworkin et al., 2010). The pain in PDN is a direct effect from a lesion or condition affecting the somatosensory system. Diabetic neuropathic pain has a substantial adverse effect on quality of life similar to RLS and interferes with the emotional, physical, and functional aspects of employment, relationships, mood, sleep, and activities of daily living. The use of the four diagnostic criteria for RLS has been shown not to be reliable in persons with PDN (Cho et al., 2013), so caution should be taken when screening for RLS, particularly in patients with T2DM who are at a greater risk for PDN. Table 2 provides guidelines to differentiate between PDN and RLS.
According to the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK, 2015), PDN is diagnosed through an evaluation of symptoms and a physical examination. Neurological exam may include testing of muscle strength, reflexes, sensitivity, vibration, temperature, or light touch. Foot exams should be included in the evaluation, specifically examining circulation and sensation in the feet. Further evaluation may include nerve conduction studies, electromyography, ultrasound, and heart rate variability.
RLS implications for nurse practitioners
NPs are in a position to screen patients with sleep disorders, which may influence health outcomes of diabetes. This not only includes RLS but also other sleep disorders that have a direct influence on morbidity and mortality of diabetes such as insomnia or obstructive sleep apnea. Treatment options vary from conservative (lifestyle changes, smoking cessation, caffeine restriction, and sleep hygiene) to use of daily medications, to use of a combination of many RLS medications used for treating resistant RLS.
RLS is a chronic sleep and movement disorder that has been associated with T2DM. Ruling out the diagnosis of RLS should be a priority when symptoms of PDN begin. When the symptoms of RLS start, glycemic control should be a priority, as symptoms of RLS may be exacerbated by hyperglycemia. If a diagnosis of RLS is confirmed, treatment for both RLS and T2DM must be carefully orchestrated to maximize the outcomes. Health promotion and patient education will help the patient understand RLS features, causes, treatment, diagnosis, and prognosis. It is essential that NPs are knowledgeable about the diagnostic and defining features of RLS, as well as the characteristics of RLS mimics, particularly PDN.
Allen, R., Picchietti, D., Garcia-Borreguero, D., Ondo, W., Walters, A., Winkelman, J., … Lee, H. (2014). Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—History, rationale, description, and significance. Sleep Medicine
(8), 860-873. doi: 10.1016/j.sleep.2014.03.025.
Aurora, R. N., Kristo, D. A., Bista, S. R., Rowley, J. A., Zak, R. S., Casey, K. R., … Rosenberg, R. S. (2012). The treatment of restless legs syndrome and periodic limb movement disorder in adults—An update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses. An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep
), 1039-1062. doi: 10.5665/sleep.1988.
Benes, H., & Kohnen, R. (2009). Validation of an algorithm for the diagnosis of restless legs syndrome: The Restless Legs Syndrome-Diagnostic Index (RLS-DI). Sleep Medicine
, 515-523. doi: 10.1016/j.sleep.2008.06.006.
Centers for Disease Control (CDC). (2014). National Diabetes Statistics Report
. National Center for Chronic Disease Prevention and Health Promotion, U.S. Department of Health and Human Services. Atlanta, GA. Retrieved from http://www.cdc.gov/diabetes/pdfs/data/2014-report-estimates-of-diabetes-and-its-burden-in-the-united-states.pdf
Cho, Y., Na, G., Lim, J., Kim, S., Kim, H., Earley, C., & Allen, R. (2013). Prevalence and clinical characteristics of restless legs syndrome in diabetic peripheral neuropathy: Comparison with chronic osteoarthritis. Sleep Medicine
, 1387-1392. doi: 10.1016/j.sleep.2013.09.013.
Cuellar, N. (2004). Diagnosis and treatment of persons with restless legs syndrome. Clinical Excellence for Nurse Practitioners
Cuellar, N., & Ratcliffe, S. (2008). Restless legs syndrome in type 2 diabetes: Implications to diabetes educators. Diabetes Educator
(2), 218-234. doi: 10.1177/0145721708314180.
Daubian-Nose, P., Frank, M., & Esteves, A. (2014). Sleep disorders
: A review of the interface between restless legs syndrome and iron metabolism. Sleep Science
(4), 234-237. doi: 10.1016/j.slsci.2014.10.002.
Dauvilliers, Y., & Winkelmann, J. (2013). Restless legs syndrome: Update on pathogenesis. Current Opinion in Pulmonary Medicine
, 594-600. doi: 10.1097/MCP.0b013e328365ab07.
Dworkin, R., Malone, D., Panarites, C., Armstrong, E., & Pham, S. (2010). Impact of postherpetic neuralgia and painful diabetic peripheral neuropathy on health care costs. Journal of Pain
(4), 360-368. doi: 10.1016/j.jpain.2009.08.005.
Earley, C. J., Connor, J., Garcia-Borreguero, D., Jenner, P., Winkelman, J., Zee, P. C., & Allen, R. (2014). Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Medicine
(11), 1288-301. doi: 10.1016/j.sleep.2014.05.009.
Ferini-Strambi, L., & Marelli, S. (2014). Pharmacotherapy for restless legs syndrome. Expert Opinion on Pharmacotherapy
, 1127- 1138.
Ford, E., Wheaton, A., Chapman, D., Li, C., Perry, G., & Croft, J. (2014). Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. Journal of Diabetes
, 338-350. doi: 10.1111/1753-0407.12101.
Hammerschmidt, D. (2006). A restless investigator. Journal of Laboratory & Clinical Medicine
Hening, W. A., Allen, R. P., Washburn, M., Lesage, S. R., & Earley, C. J. (2009). The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions (“mimics”). Sleep Medicine
(9), 976-981. doi: 10.1016/j.sleep.2008.09.015.
International RLS Study Group (2015). Diagnostic criteria
. Retrieved from http://irlssg.org/diagnostic-criteria/
Karroum, E., Konofal, E., & Arnulf, I. (2009). Karl-Axel Ekbom (1907-1977). Journal of Neurology
, 683-684. doi: 10.1007/s00415-009-0140-y.
Lopes, L. A., Lins Cde, M., Adeodato, V. G., Quental, D. P., de Bruin, P. F., Montenegro, R. M., Jr., & de Bruin, V. M. (2005). Restless legs syndrome and quality of sleep in type 2 diabetes. Diabetes Care
National Heart, Lung and Blood Institute of the National Institutes of Health (2015). Health topics: What is restless legs syndrome
? National Institutes of Health. Retrieved from http://www.nhlbi.nih.gov/health/health-topics/rls/
National Institute of Diabetes and Digestive and Kidney Disease (2015). National Diabetes Information Clearinghouse
. National Institutes of Health. Retrieved from http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/index.aspx
National Institute of Neurological Disorders and Stroke (2014). Restless legs syndrome information
. (2014). Retrieved from http://www.ninds.nih.gov/health_and_medical/disorders/restless_doc.htm
Ondo, W. (2014). Common comorbidities and differential diagnosis of restless legs syndrome. Journal of Clinical Psychiatry
(3):e06. doi: 10.4088/JCP.12074nr2c.
Picchietti, D. L., Hensley, J. G., Bainbridge, J. L., Lee, K. A., Manconi, M., McGregor, J. A., … Walters, A. S.; International Restless Legs Syndrome Study Group (IRLSSG). (2015). Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation. Sleep Medicine Reviews
, 64-77. doi: 10.1016/j.smrv.2014.10.009.
Plantinga, L., Rao, M., & Schillinger, D. (2012). Prevalence of self-reported sleep problems among people with diabetes in the United States, 2005-2008. Preventing Chronic Disease
Rye, D., & Trotti, L. (2012). Restless legs syndrome and periodic limb movement disorders. In Barkoukis T. J., Matheson J. K., Ferber R., & Doghramji K.(Eds.), Therapy in sleep medicine
. Philadelphia, PA: Elsevier.
Salas, R., Rasquinha, R., & Gamaldo, C. (2010). All the wrong moves: A clinical review of restless legs syndrome, periodic limb movement of sleep and wake, and periodic limb movement disorder. Clinics in Chest Medicine
Szentkiralyi, A., Volzke, H., Hoffmann, W., Trenkwalder, C., & Berger, K. (2014). Multimorbidity and the risk for restless legs syndrome in 2 prospective cohort studies. Neurology
, 2026-2033. doi: 10.1212/WNL.0000000000000470.