Non-length-dependent Somatosensory Small Fiber Pathology Presenting with Restless Legs Syndrome in Pre-motor Parkinson's Disease. Evidence from Skin Biopsy in Four Patients

Background: The determinants of restless legs syndrome (RLS) occurring in co-morbid association with Parkinson's disease (PD) are currently unknown.

Methods: We performed a skin biopsy in proximal and distal sites of lower limbs in four PD patients, in which RLS had emerged in the pre-motor phase.

Results: A reduced somato-sensory intraepidermal nerve fiber (IENF) density mainly in the proximal sites, indicative of non-length-dependent small fiber pathology (SFP), was found in all patients, in absence of electroneurographic signs of large fiber neuropathy.

Discussion: The lack of known secondary causes of SFP is consistent with a process intrinsic to PD and, likewise, the absence of known disease conditions associated to RLS, would support the view of a link between the latter disorder and the distal axonopathy. The non-length-dependent pattern of SFP suggest an involvement of the somato-sensory dorsal root ganglia small neurons, consistent with a somato-sensory neuronopathy, which characterizes the RLS in these patients.

Conclusion: If these findings will be confirmed in a larger cohort of patients, the RLS co-morbid with PD should be regarded as an heterogeneous condition, since the one emerging in the pre-motor phase might represent a prodromal feature of the neurodegenerative disease as an epiphenomenon of somato-sensory SFP. In contrast, for the RLS developing in clinically manifest PD, a possible association with the impairment of the DAergic diencephalo-spinal pathway and the induction by chronic DAergic treatment has been hypothesized.