Medical Comorbidity of Sleep Disorders

Dimitris Dikeos; Georgios Georgantopoulos


Curr Opin Psychiatry. 2011;24(4):346-354. 

In This Article

Sleep-related Limb Movements

The most important sleep-related limb movements are RLS and PLMS.

General Remarks on Restless Legs Syndrome

RLS is a disorder characterized by an urge to move the extremities, frequently associated with paraesthesia or dysaesthesia; temporary relief of the urge with movement; and onset or worsening of the symptoms at rest, inactivity or at night.[35] RLS has a prevalence of about 3–15% in the general population[36–39,40•] and it has a negative impact on physical functioning, bodily pain, general health and vitality.[41]

Iron Deficiency/Kidney Disease and Restless Legs Syndrome

A well established association is that of RLS with iron deficiency; it has been observed in cases of malignancies, various iron-deficiency anaemias, regular blood donors, pregnancy and many other conditions characterized by low iron stores.[35,38,40•] In many cases, RLS appears even with subclinical iron deficiency (as revealed by reduced ferritin levels) while levels of haemoglobin might be normal.[38,42]

An association of RLS with kidney disease/uraemia has been found, which is usually inverted after kidney transplantation; iron deficiency might be a contributing factor to this association, but it does not seem to be the only one.[38,42]

Restless Legs Syndrome in Neurological Disorders

The comorbidity of RLS with Parkinson's disease was examined in a large cohort of men participating in the Health Professional follow-up study on 23 119 men after excluding those suffering from diabetes and arthritis. The prevalence of Parkinson's disease was found to be about double among sufferers with RLS compared with nonsufferers.[43••] Inversely, RLS was found to have 3% prevalence among 200 Parkinson's disease patients, vs. 0.5% among normal controls.[44] In a controlled study, the prevalence of RLS among 76 patients with amyotrophic lateral sclerosis (ALS) was found to be 25% compared with 8% among 100 controls.[45]

Restless Legs Syndrome in Cardiovascular Disease and Related Factors

In a population-based cross-sectional study examining the prevalence of cardiovascular risk factors in participants with and without RLS (N = 1537), blood tests of RLS participants showed significantly higher fasting blood glucose level, higher prevalence of hypercholesterolaemia, reduced renal function and increased prevalence of low haematocrit. Participants with RLS had a higher BMI, larger hip circumference and were less fit. It was found that female sex and the high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol ratio were significantly associated with RLS.[46]

An association of RLS with obesity has been found in a recent study on a sample of about 90 000 individuals assessed by mailed interviews. It was found that 6.4% of women and 4.1% of men had RLS and the prevalence increased progressively with increasing BMI and waist circumference. This association was independent of age, smoking status, anxiety score, use of antidepressants and presence of a number of chronic diseases. A similar association was found between obesity in early adulthood (age 18–21) and RLS prevalence in mid-life or later (age 40 years and higher), suggesting that obesity is a risk factor for the development of RLS.[39]

RLS is strongly related to coronary artery disease (OR 2.2) and any cardiovascular disease (including coronary artery disease, heart failure or stroke);[47–50] findings on hypertension are still controversial,[47–50] although there seems to exist a possible relationship between mean blood pressure and RLS or PLMS symptoms.[50] It has been argued that the sympathetic hyperactivity associated with RLS/PLMS leads to heart disease and stroke via hypertension and/or via atherosclerotic plaque formation and rupture; alternatively, comorbidities associated with RLS/PLMS, such as renal failure, diabetes, iron deficiency and insomnia, may predispose to heart disease and stroke.[50]

In a controlled study on 124 diabetes mellitus patients vs. 87 controls with other endocrine disorders, the prevalence of RLS was higher among the diabetes mellitus group by a factor of about 3 (17.7 vs. 5.5).[51] In another study on 121 type 2 diabetes patients, for whom it was not mentioned whether they suffered from polyneuropathy or not, it was found that 45% of them were suffering from secondary RLS.[52] This association was found also in prediabetic patients with normal fasting glucose and abnormal glucose tolerance test;[46,53] other studies have suggested that RLS in diabetes mellitus is a result of diabetic polyneuropathy[54–56] and that it may respond better to neuropathic pain medications rather than dopaminergic drugs.[54] Polyneuropathy, however, does not seem to fully explain the presence of RLS in diabetes mellitus patients.[51,53] Presence of RLS among diabetic patients has a significant impact on patients' quality of sleep.[55]

Restless Legs Syndrome in other Disorders

RLS has also been found to be associated with a variety of rheumatological and immunological conditions, showing a prevalence of 20–30% (two to six times that of the general population) among patients with rheumatoid arthritis, various other arthropathies, fibromyalgia, Sjogren's syndrome and scleroderma.[57,58] Neuropathy due to rheumatoid arthritis is being suggested as an explanation for the increased prevalence of RLS in this condition based on neurophysiological findings,[59] but also subclinical iron deficiency due to chronic use of nonsteroidal anti-inflammatory agents, as well as dopamine transmission abnormalities due to chronic pain, has been proposed.[57,58]

Finally, a strong association between respiratory symptoms, asthma, COPD and RLS was described in a study on a well defined population (N = 1937) from two countries.[40•] The relationship between RLS and COPD has also been described before,[60,61] but the pathogenesis is unknown.

General Remarks on Periodic Leg Movement Syndrome

PLMS is a condition characterized by periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep and in wakefulness (particularly during rest). The movements usually occur in the legs and consist of extension of the big toe in combination with partial flexion of the ankle, knee and sometimes hip. They may also occur in the upper limbs and can be unilateral or bilateral.[62]

The criteria for the syndrome are polysomnographic and first require identification of a PLM.[63] The mean number of PLMs per hour of total sleep time is the PLM index (PLMI). A PLMI of more than 5 is considered pathological, although it has also been suggested that the cut-off should be put at 10.[64] PLMS is considered mild for a PLMI up to 25, moderate for 25–50 and severe for an index 50 or higher or if there are more than 25 PLMs per hour associated with arousal.[63] The prevalence of PLMS in the general population is estimated to be 4–11%.[64]

Periodic Leg Movement Syndrome in Other Sleep Disorders

PLMS is a frequent finding in various sleep disorders such as obstructive sleep apnoea syndrome (OSAS), narcolepsy and RBD; the prevalence of PLMS in OSAS is 24%, decreasing with continuous positive airway pressure (C-PAP) treatment, whereas up to 70% of RBD patients have a PLMI of 10 or higher.[64,65]

Periodic Leg Movement Syndrome in Medical Conditions

PLMs are also a frequent finding in RLS and both conditions share common somatic comorbidities. Similar to RLS, PLMS is found to be more frequent among individuals with uraemia (20–45%) and/or ESRD, Parkinson's disease (in which the PLMI has been reported up to 68), iron deficiency, severe congestive heart failure (52 vs. 11% in controls), juvenile fibromyalgia (38%), scleroderma (48%) and hypertension (mean prevalence 18%, associated with severity); PLMS' frequency is furthermore elevated in syringomyelia (61%), spinal cord injury (mean PLMI 35) and Gille de la Tourette syndrome (mean PLMI 19, PLMS found in five out of seven patients examined).[42,64] Finally PLMs (and, to some extent, RLS symptoms) increase with various psychoactive drugs, especially antidepressants [mainly selective serotonin reuptake inhibitors (SSRIs) and venlafaxine] and lithium.[64]


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