Comorbid Conditions

Over the years, a large number of disorders or other conditions have been suggested to be associated with restless legs syndrome (RLS) (see Chapter 16, Box 16-2). The evidence for some is stronger than that for others, but these associations indicate that many different medical specialists need to be concerned about RLS (Table 21-1). Many of these conditions share an association with depleted iron stores—iron deficiency and anemia, kidney failure, pregnancy, rheumatoid arthritis—but others cannot yet be explained on the basis of a single pathophysiologic diathesis. An intriguing question, now that specific genetic variants associated with RLS have been reported (see Chapter 8), is whether these same variants will be associated with increased risk of RLS in these comorbid conditions.

TABLE 21-1 Specialties Important for Comorbid Restless Legs Syndrome

Polyneuropathies and Other Lower Motor Neuron Diseases

A subgroup of patients with RLS is found to have sensorimotor neuropathies, occasionally lumbosacral radiculopathies or motor neuron disease (amyotrophic lateral sclerosis); however, the relation between RLS and these entities remains uncertain. Before addressing this controversy, I would like to make some general comments. The sensory complaints of primary RLS patients resemble mostly the central type of sensory discomfort or central pain syndrome and are characterized by deep, disagreeable, unpleasant, often nonlocalizable, nonradiating discomfort unaccompanied by objective sensory impairment in contrast to sensory manifestations of peripheral neuropathy or radiculopathy, consisting of positive symptoms of tingling, numbness, burning (hyperalgesia), and stabbing, present in the stocking and glove distribution or radiating along root distribution, accompanied by sensory impairment distally or along the root distribution. However, if polyneuropathy or lumbosacral radiculopathy occurs in patients predisposed to developing RLS symptoms sometime in the future, then the sensory symptoms may be similar in both primary and secondary cases. Lumbosacral radiculopathies or polyneuropathies simply trigger the symptoms in such patients. It is notable that RLS-like symptoms have never been described, to my knowledge, in patients with cervical radiculopathy. For differentiating comorbid from primary RLS, particular attention should therefore be paid to the nature of the sensory complaints and the duration of the disease. Sensory symptoms of polyneuropathy are present either intermittently or throughout the day and not necessarily worse in the evening and are generally not relieved by movements. In about 20% to 25% of primary RLS patients, actual pain rather than intense disagreeable feeling is a prominent symptom. Comorbid RLS patients generally seek a physician’s advice within 5 years of onset of symptoms, but patients with idiopathic or primary cases, if questioned carefully, will often divulge that their symptoms have been present for many years (10, 20, 30 years, or longer). Another important point of distinction is the family history which may be present in patients with primary RLS rather than in comorbid cases.

Ondo and Jankovic¹ reported that 15 of 41 patients with RLS had electrodiagnostic evidence of polyneuropathy or radiculopathy, although only 7 of these 15 patients showed clinical signs of neuropathy. In an early systematic study, Rutkove and colleagues² studied a consecutive series of patients with polyneuropathy and documented only a 5% frequency of RLS, which is similar to what is found in the general population. Studies have found a greater frequency of RLS in diabetic neuropathy and polyneuropathy (see Chapter 27). RLS may also be particularly prevalent in certain types of neuropathies, such as cryoglobulinemic or familial amyloid polyneuropathy. Newer studies have more decisively implicated the polyneuropathies and diabetic neuropathy as associated with RLS. Gemignani anc coworkers³ in a series of 44 consecutive patients with Charcot-Marie-Tooth (CMT) disease found RLS in 10 of 27 CMT type 2 patients (37%) with prominent sensory symptoms and in none of the patients with CMT type 1, suggesting a role for sensory (afferent) input in the pathogenesis of RLS. Certain studies found morphological evidence of subtle nerve damage. Sural nerve biopsy⁴ findings in 7 of 8 patients with primary RLS were consistent with an axonal neuropathy, and skin punch biopsy⁵ in the legs documented evidence of subclinical small fiber neuropathy in 8 of 22 patients (36%) with primary RLS. There may be other explanations for these subtle morphological changes, such as age-related changes in the sural and skin nerves and trauma caused by vigorous rubbing of the legs, resulting from an urge to move and rub to get relief from the discomforting urge to do so. It is not clear why some patients with polyneuropathy or lumbosacral radiculopathy develop symptoms of RLS, whereas many patients with polyneuropathies or other lower motor neuron disorders do not develop RLS. Sometimes motor neuron disease has been mistaken for RLS, but the diffuse fasciculations, muscle weakness, wasting, and presence of upper motor neuron manifestations should simplify the differentiation.

Anemia and Restless Legs Syndrome

There have been isolated reports of iron, cobalamin (vitamin B₁₂), and folate deficiency causing secondary RLS. The strongest evidence is for iron deficiency. Ekbom,⁶ in his original description, mentioned iron deficiency with low serum iron in 25% of his cases. Nordlander⁷ in 1953 reported resolution of RLS symptoms in over 90% of subjects after intravenous iron infusion. The iron deficiency theory for RLS was revived after a long hiatus by O’Keefe and colleagues⁸ in 1994, who reported low iron, measured by serum ferritin levels in RLS patients. Subsequent elegant studies by the Johns Hopkins group of investigators^9–15 firmly established the role of iron in its pathogenesis and therapy (see Chapters 9, 10, and 34). Iron is needed as a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine; therefore, iron deficiency may interfere with the normal production of dopamine. Furthermore, the D₂ receptor is an iron-containing protein and hence, iron deficiency may impair the normal function of D₂ receptors. Magnetic resonance imaging (MRI)¹⁴ study of the brain and limited pathological¹⁵ findings in RLS patients clearly established brain iron acquisition and storage problem deficiencies in the substantia nigra of these patients. The appearance of RLS symptoms after multiple blood donations^16,17 associated with iron deficiency anemia, low serum hemoglobin and ferritin levels, and improvement after iron supplementation also clearly supports the role of iron deficiency in the pathogenesis of RLS. Reports of failure^18,19 to find a significant difference in serum iron indices or hemoglobin between patients with RLS and control subjects with renal failure and pregnancy as well as a single report²⁰ of a randomized, double-blind placebo-controlled trial of iron supplementation failing to show any significant difference in RLS symptoms with treatment point to the incompleteness of the iron deficiency theory. RLS appears to be a heterogeneous syndrome with several subtypes associated with different neurobiological mechanisms.

End-Stage Renal Disease and Hemodialysis

There is an increased prevalence of RLS (20% to 50% or even higher) with end-stage renal disease (ESRD) on dialysis^18,21–24