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

Does Restless Legs Syndrome Have a Different Pathomechanism in Premotor and Motor Parkinson’s Disease?

“…This hypothesis has been corroborated by recent findings on skin biopsies JMD 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.…”

“…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.…”

Clinical diagnosis and management of small fiber neuropathy: an update on best practice

“…SFN has been reported in patients with Gaucher disease as possible explanation for neuropathic origin of chronic pain [65]. Finally, SFN has been also described in association with disorders characterized by widespread pain such as fibromyalgia [5] and Ehlers-Danlos syndrome [66], and in neurodegenerative diseases like Parkinson's disease [14][15][16][17][18][19][20][21] and ALS [10][11][12][13].…”

“…The introduction of skin biopsy, which allows a reliable quantification of intraepidermal nerve fiber density (IENFD), has been a milestone for the diagnosis of SFN [8,9]. In the following decades, a flourishing of studies widened the spectrum of diseases associated with small nerve fiber degeneration, from painless amyotrophic lateral sclerosis [10][11][12][13] and Parkinson's disease [14][15][16][17][18][19][20][21] to painful erythromelalgia [22]. These findings further emphasized that the diagnosis of SFN cannot disregard the clinical context and the accurate characterization of patients' phenotype.…”

Premotor Parkinson's disease: Overview of clinical symptoms and current diagnostic methods

“…A recent study suggested that small fiber pathology may precede the development of motor symptoms of PD (ref. 172 ). Small fiber functions may be investigated bedside by responsiveness to heat, cold, and pain evoked by pinprick.…”