Restless Legs Syndrome in Neurological Disorders

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Chapter 26 Restless Legs Syndrome in Neurological Disorders

Despite the importance of genetic factors in restless legs syndrome (RLS) (see Chapter 8), environmental factors and acquired conditions are likely to play major roles in determining which individuals develop RLS. They are likely to also affect when RLS symptoms begin. Patients without a positive family history are now classified as having either primary RLS, if no other predisposing condition is found, or secondary RLS, if they concurrently have a condition known to be associated with and likely to cause RLS. At least twenty medically related conditions have been reported in the literature in association with RLS. Most of these are likely to be chance occurrences owing to the past underestimated prevalence of RLS. However, several specific neurological conditions appear to have a “greater-than-chance” occurrence and are discussed in this chapter.

Neuropathy

Numerous forms of neuropathy, including hereditary, diabetic, alcoholic, amyloid, motor neuron disease, poliomyelitis, and radiculopathy, have been associated with RLS.¹^–¹⁴ Investigating the association between RLS and neuropathy, however, has been challenging. The definition of neuropathy varies in studies. Some include neuropathy diagnosed by standard electrophysiological methods, which only detect abnormalities in large-fiber myelinated nerves, whereas others incorporate measures of unmyelinated nerve fibers through skin biopsy or other physiological studies, which in some instances do not have well-established normative data. Depending on the sensitivity of the tests used and the definition of neuropathy used, more patients with neuropathy may be identified and it would not be surprising that two common conditions would overlap by chance alone. Referral bias may also affect results, because neuropathy patients with positive symptoms (RLS or pain) are more likely to seek medical attention than those with pure sensory loss. Moreover, neuropathy and RLS clearly share many features. Symptoms of both conditions are generally worse in the evening and nighttime, both affect primarily the legs and feet, and they share risk factors such as uremia, diabetes, amyloid, and cryoglobulinemia. The two disorders also respond to many of the same therapeutic interventions.

Several series have reported the prevalence of RLS in populations of patients presenting with neuropathy. One retrospective study evaluated 800 diabetic patients for neuropathic features and reported that only 8.8% complained of RLS.³ This was not significantly greater than the 7% RLS prevalence among the control subjects. Interestingly, the percentage of people with type 2 diabetes affected with RLS was significantly higher than those with type 1 diabetes; an association with type 2 diabetes that has been confirmed, particularly in patients with polyneuropathy.¹⁵ This difference, however, may have resulted from the older age of the type 2 population. A prospective study evaluating consecutive patients with electrophysiologically diagnosed neuropathy reported that 8 of 154 (5%) meet International Restless Legs Syndrome Study Group (IRLSSG) clinical criteria for RLS.⁶ Symptoms improved with L-dopa in five patients. Interestingly, the RLS symptoms in two patients with Lyme disease–associated neuropathy improved after antibiotic treatment. Although the authors thought that this represented an association of neuropathy and RLS, the 5% prevalence is actually lower than the percentage reported in surveys of RLS symptoms in the general population. More recent studies, however, have suggested that the frequency in general polyneuropathy may be higher.¹⁶

Specific forms of neuropathy may incur different risks for the development of RLS. Gemignani and colleagues ¹⁶ reported that 10 of 27 (37%) of patients with Charcot-Marie-Tooth type II (CMT II), an axonal neuropathy, had RLS, whereas RLS was not seen in any of the 17 patients with CMT I, a demyelinating neuropathy.¹⁶ The presence of RLS in CMT II correlated with other positive sensory symptoms such as pain. The same group reported a high prevalence of RLS among patients with essential mixed cryoglobulinemia, which also typically causes a painful neuropathy.⁷ Another group reported a high prevalence of RLS in a kindred with familial amyloid neuropathy.² In several instances, RLS symptoms preceded the diagnosis of the neuropathy.

Studies that have tried to detect neuropathy in populations of patients presenting with RLS have found a quite robust association. In a case series of eight patients with “idiopathic” RLS, Iannoccone and coworkers ⁴ found that all subjects had at least one peripheral nerve abnormality among a battery of peripheral nerve tests including electrophysiology, quantitative sensory testing, and sural nerve biopsy. In a series of 98 RLS patients, 37 demonstrated evidence of neuropathy by standard electromyelography (EMG)/nerve conduction velocity (NCV) techniques.⁵ Most of these had mild to moderate sensory axonal neuropathies; however, the exact etiologies varied. Many of these patients had no evidence of neuropathy on clinical examination. The presence of neuropathy was much higher in patients who did not have a family history of RLS compared with those who did have a family history—22 of 31 (71%) versus 15 of 67 (24%), p <.001. Another four of those nine nonfamilial RLS with normal EMG examinations had very low ferritin levels, possibly accounting for their RLS. These findings are consistent with, but do not prove, that neuropathy can cause a secondary form of RLS.

The phenotype of neuropathic RLS may be slightly different from idiopathic RLS.^5,⁸ Several studies have found that patients with neuropathic RLS present at an older age and tend to have more severe RLS. In addition, the RLS appears to progress more rapidly. A large number of patients with neuropathic RLS reached maximum symptom intensity within 1 year from the initial symptom onset, which is unusual in idiopathic cases. Idiopathic RLS tended to begin with sensations between the ankle and knee, whereas neuropathic RLS tended to initially occur distally or randomly throughout the leg.⁵ Neuropathic RLS may also have accompanying neuropathic pain, which is often burning and more superficial. The painful component and the urge to move, however, are seldom differentiated by the patient. Finally, neuropathic RLS patients are less like to develop augmentation with chronic dopaminergic treatment.¹⁷ Neuropathic RLS patients, however, might be more easily managed with dopaminergic medications over long periods of time.

Small-fiber neuropathy, determined by punch skin biopsy, has also been reported in patients presenting with RLS.⁸ There is reason to believe that this population of nerve fibers may be important in RLS. These fibers are preferentially and predominantly affected in diseases such as diabetes, uremia, amyloidosis, and cryoglobulinemia—precisely the same conditions that have been implicated as risk factors in RLS. Furthermore, damage to small-caliber sensory nerve fibers is associated with neuropathic pain, and studies have suggested that the pain associated with neuropathy may be important in RLS. Among 22 consecutive patients with established RLS, 3 had a predominantly large-fiber neuropathy, 3 had a predominantly small-fiber neuropathy, and 2 had mixed neuropathies. Several additional patients did not fulfill diagnostic criteria for small-fiber neuropathy but had prominent structural abnormalities in epidermal nerve fibers such as nerve fiber swellings, which often precede the development of small-fiber neuropathy.¹⁸ RLS patients with neuropathy did not have a positive family history for RLS, although their RLS symptoms were associated with pain, tended to be more severe, and began at an older age. Other studies have found that, in general polyneuropathy and diabetic neuropathy, a small-fiber neuropathy is more likely to be associated with RLS.^11,¹³

In addition to length-dependent forms of peripheral neuropathy, other forms of peripheral nerve injury such as radiculopathy ¹⁹ and spinal stenosis²⁰ have also been associated with RLS. The underlying feature of these conditions may be the presence of pain. Pain has been a unifying theme among studies investigating neuropathy in RLS patients, and the specific causes of neuropathy associated with RLS are typically painful. Interestingly, dopamine, the primary target of RLS treatments, has also been implicated in pain processing. High levels of dopaminergic activity in the striatum have been shown to reduce neuronal encephalin content and lead to a compensatory rise in μ-opioid receptor expression.^21,²² A role for dopamine as an inhibitor of pain perception is further supported by its efficacy in relieving the pain associated with breast cancer, bone metastases,^23,²⁴ herpes zoster,²⁵ painful Parkinson’s disease,²⁶ and diabetic neuropathy.²⁷

Despite these phenotypical differences, it is currently not possible to discern the role that peripheral nerve abnormalities play in RLS, and neurologists differ in their assessment of neuropathy in RLS patients. Some centers may obtain EMG/NCV in all RLS patients, although their usefulness is admittedly debatable in cases with an early age at onset and a strong family history. One could also expand this evaluation to include an assessment of small unmyelinated nerve fibers through punch skin biopsies. If a neuropathy is discovered, a proper investigation of underlying and potentially treatable conditions is warranted. Many patients presenting with painful neuropathy are now appreciated to have occult diabetes or impaired glucose tolerance. In many of these patients, improvement of the hyperglycemia parallels improvements in neuropathy symptoms. It is possible that the same holds true for those subjects with neuropathic RLS, although this remains unanswered. It has also been suggested that all patients presenting with neuropathic sensory symptoms should be screened for RLS, which may occur quite commonly with such presentations.²⁸

The clinical similarities between neuropathic and idiopathic RLS suggest a common pathogenesis. Both animal models ²⁹^–³¹ and clinical movement disorders^32,³³ suggest that permanent perturbation of central nervous system neurotransmitter function can follow a peripheral nervous system injury. Recent studies in patients with primary RLS demonstrate that they share similarities to neuropathic pain patients such as an exaggerated perception to pin-prick sensation³⁴ or exaggerated spinal reflexes.³⁵ Modulation of gain in spinal nociceptive transmission is controlled in two principal ways—from ascending afferent input and/or modulation by supraspinal descending pathways. Thus, the association between peripheral neuropathy, particularly painful peripheral neuropathy, and RLS may reflect central sensitization changes induced by peripheral nerve injury. Better understanding of the exact relationship between RLS and neuropathy awaits more detailed epidemiological data, and a better understanding of RLS pathogenesis as a whole, but recent studies emphasize that the relationship is likely to be frequent and important.