• restless legs syndrome
• peripheral neuropathy

The Editorial by Chaudhuri et al¹ opportunely reviews various aspects of restless legs syndrome (RLS), but it is disappointing that RLS associated with peripheral neuropathies is poorly treated. A few types of peripheral neuropathy associated with RLS are mentioned in table 1 (sensory neuropathy, Charcot-Marie-Tooth disease type 2), but are not discussed or referenced.^2,3 The occurrence of RLS in association with peripheral neuropathy may be more frequent than usually thought. Rutkove et al⁴ reported a 5.2% prevalence of RLS in miscellaneous peripheral neuropathies, but we found RLS in 20 out of 70 consecutive patients (28.6%) with various forms of peripheral neuropathy.⁵ Definite types of peripheral neuropathy, such as cryoglobulinaemic neuropathy, CMT2, diabetic neuropathy, and amyloid neuropathy, are especially prone to develop RLS, often as an early manifestation.⁶ A significant association of RLS with positive sensory symptoms of peripheral neuropathy has been found,^3,6 suggesting that a disorder of the sensory inputs may be involved in the pathogenesis. Small fibre involvement could be the crucial factor for neuropathy to develop RLS, as small fibre neuropathy has been often demonstrated in association with the disease, by means of quantitative sensory testing⁷ or skin biopsy with quantification of intraepidermal nerve fibres.²

Restless legs syndrome deserves consideration as a frequent, treatable, and probably underrecognised condition. Its prevalence in the general population may range between 5% and 15%.¹

It is unclear how much of this percentage can be attributed to peripheral neuropathy; however it is suggested that as many as 45% of patients with RLS might have subclinical sensory neuropathies, and it seems that patients can be stratified based on the age of onset, which tends to be later in neuropathy associated RLS.² On the other hand, patients with common forms of neuropathy, such as diabetic and cryoglobulinaemic neuropathy, are known often to have RLS, further contributing to the population of “peripheral” RLS.

Pathogenetic hypotheses on RLS should deal with the paradox of a condition associated with either peripheral or central dysfunction. According to current views, the disease might be caused by dopaminergic dysfunction with loss of supraspinal inhibition and enhanced excitability of propriospinal mechanisms,¹ possibly including generators involved in locomotor patterns. Spinal structures involved in RLS, besides being released by dopaminergic dysfunction, might be activated by abnormal sensory nerve inputs associated with peripheral nerve damage^2,3,6; in particular, changes in small fibres may trigger mechanisms of rewiring in the dorsal horn, as experimentally demonstrated after small fibre injury.⁸

As suggested by Polydefkis et al,² RLS associated with peripheral neuropathy may require a different therapeutic approach, using neuropathic pain medications rather than dopaminergic therapy. In our experience, gabapentin, trazodone, and amitryptiline were anecdotally effective.^3,6