Only two studies have prospectively investigated the subsequent occurrence of PD in subjects with prevalent RLS. Although all the known comorbidities associated with RLS and RLS mimics had not been excluded, a higher incidence of PD mainly in male subjects with pre-existing RLS compared to the control group without RLS was found during a median follow-up period of 4 and 7.8 years, respectively, suggesting that this sensorymotor disorder may be a risk factor or more likely an early feature of PD [
4,
5]. Indirect support for this view has been provided by a more recent longitudinal study showing a positive, although moderate, association between persistent/recurrent RLS and symptoms/signs currently regarded as prodromal of PD in men, such as rapid eye movement sleep behavior disorder (RBD) and constipation [
6]. However, this finding does not explain whether RLS and PD are linked by a common pathomechanism and whether the pathomechanism involved in RLS occurring in the setting of PD differs from that of primary RLS. In this context, decreased intraepidermal small fiber density [
7] and impairments in thermal somatosensory function in the lower limbs [
8] in subjects with idiopathic RBD led to the hypothesis of the possible involvement of cutaneous sensory small fibers, as a condition intrinsic to the neurodegenerative process in Lewy body disease, in the pathomechanism of RLS emerging in the premotor phase of PD. This hypothesis has been corroborated by recent findings on skin biopsies showing a decrease in intraepidermal somatosensory unmyelinated C fiber density in the lower limbs with a non-length dependent pattern in four patients with late-onset RLS that developed in the premotor phase of PD in the absence of large fiber damage [
9]. Although an incidental cooccurrence of RLS and small fiber pathology cannot be completely excluded in these PD patients, this finding may represent the first report of the association of RLS with PD-related distal somatosensory axonopathy, providing support to the concept that RLS may be an intrinsic early prodromal feature of PD rather than a risk factor, as has been previously proposed [
4,
5]. The exclusion of known secondary causes of both RLS and small fiber pathology in the same patients supports this view [
9]. The non-length-dependent pattern found on skin biopsy is indicative of involvement of small neurons located in the somatosensory dorsal root spinal ganglia, consistent with sensory neuronopathy, which could represent the counterpart of that found in the peripheral sympathetic ganglia in 50% of incidental Lewy body disease cases believed to represent the premotor phase of PD [
10]. However, whether small fiber pathology with a non-length dependent pattern characterizes only RLS predating the onset of motor PD remains to be established and deserves further investigation, since it cannot be excluded that the same pathomechanism may also be involved in the development of RLS in the motor phase of PD. Overall, these data support the view that the impairments in somatosensory epidermal C fibers may occur early in the neurodegenerative process and, thereby, enlarge the spectrum of small fiber dysfunction in the prodromal phase of PD that, to date, is believed to affect nearly exclusively the autonomic sympathetic terminal axons, mainly in the cardiovascular system [
11]. If this finding is confirmed in a larger population of patients, intraepidermal somatosensory small fiber pathology should be regarded to underlie most cases of RLS emerging in the premotor phase of PD, supporting its “peripheral” origin. Considering the low estimated occurrence of RLS onset in the premotor phase of PD, it is expected that not all somatosensory small fiber pathology intrinsic to PD detected in this phase will be associated with RLS.