Anna Maria Saltalamacchia

Sensory deficit in Parkinson's disease: evidence of a cutaneous denervation

Sensory disturbances are part of the clinical picture of Parkinsons disease. Abnormalities in sensory processing, through a basal ganglia involvement, are thought to be responsible for the sensory dysfunction since sensory nerve conduction velocity (NCV) is usually normal. However, NCV does not examine small fibres or terminal endings of large sensory fibres, whereas skin biopsy is more suitable for these purposes. To evaluate peripheral sensory nerves in Parkinsons disease, we studied cutaneous free and encapsulated sensory nerve endings in 18 patients and 30 healthy controls using 3-mm punch biopsies from glabrous and hairy skin. Ten patients had additional skin biopsies from the contralateral side. Further evaluation included NCV and Quantitative Sensory Testing. Parkinsons disease patients showed a significant increase in tactile and thermal thresholds (P < 0.01), a significant reduction in mechanical pain perception (P < 0.01) and significant loss of epidermal nerve fibres (ENFs) and Meissner corpuscles (MCs) (P < 0.01). In patients with bilateral biopsies, loss of pain perception and ENFs was higher on the more affected side (P < 0.01). We found evidence suggesting attempts at counteracting degenerative processes as increased branching, sprouting of nerves and enlargement of the vascular bed. Morphological and functional findings did not correlate with age or disease duration. Disease severity correlated with loss of MCs and reduction in cold perception and pain perception. We demonstrated a peripheral deafferentation in Parkinsons disease that could play a major role in the pathogenesis of the sensory dysfunction.

Small fibers involvement in Friedreich's ataxia.

Although the involvement of large myelinated sensory fibers in Friedreichs ataxia (FA) is well documented, an impairment of unmyelinated fibers has not been described. We demonstrate an involvement of cutaneous unmyelinated sensory and autonomic nerve fibers in FA patients. We performed a morphological and functional study of cutaneous nerve fibers in 14 FA patients and in a population of control subjects. We used immunohistochemical techniques and confocal microscopy applied to punch skin biopsies from thigh, distal leg, and fingertip, and compared the density of epidermal nerve fibers (ENFs) with the results of mechanical pain sensation and thermal and tactile thresholds performed on hand dorsum, thigh, distal leg, and foot dorsum. We observed in our patients a statistically significant loss of ENFs, a reduced innervation of sweat glands, arrector pilorum muscles and arterioles, and an impairment of thermal and tactile thresholds and mechanical pain detection.

Evidence of small fiber neuropathy in a patient with Ehlers-Danlos syndrome, hypermobility-type.

http://dx.doi.org/10.1016/j.clinph.2015.12.004 1388-2457/ 2015 International Federation of Clinical Neurophysiology. Joint hypermobility syndrome (JHS) and Ehlers–Danlos syndrome hypermobility type (EDS-HT) are two clinically overlapping heritable connective tissue diseases. Their clinical identity has been recently suggested and many researchers are now considering EDS-HT and JHS as one and the same (i.e. JHS/EDS-HT) (Castori et al., 2013). As the molecular basis of JHS/EDS-HT is largely unknown, the diagnosis remains based exclusively on clinical criteria. Generalized joint hypermobility, joint complications and skin hyperextensibility are the major features of JHS/EDS-HT and chronic pain, fatigue, headache and dysautonomia represent the major causes of patient disability (Castori et al., 2013; De Wandele et al., 2014). We studied morphology and function of cutaneous sensory and autonomic innervation in a 41 years old male subject with JHS/EDS-HT who arrived to our observation for an unbearable neuropathic pain (burning feet) and chronic fatigue. His clinical history retraced the 3 different phases, hypermobility, pain and stiffness, as classically described in typical JHS/EDS-HT disease course (Castori et al., 2013). In fact, since childhood he had been suffering of recurrent sprains due to an abnormal ligamentous laxity, followed by development of progressive musculoskeletal pain in adulthood. At the age of 38 years he started to complain of burning pain, unpleasant cold feeling and mechanical allodynia involving distal lower limbs. These symptoms worsened progressively leading to severe sleep disturbance and marked limitation in walking and in daily activities. He also reported post-prandial abdominal discomfort, constipation, gastro-esophageal reflux, tension-type headache and fatigue. For the complex clinical picture he underwent several clinical and instrumental investigations including cerebral and spinal MRI, all unremarkable. At neurological examination we found reduced deep tendon reflexes, diminished muscle bulk, tone and strength and impaired vibratory perception. Gait was slow, unsteady and impossible on heels and toes because of pain. Perception of pin-prick and light touchwas impairedwith a symmetrical ‘‘stocking and glove” distribution. Beighton score was 5 out of 9 (hypermobility: scoreP 5). Blood analysis showed normal hepatic, renal, endocrinological, immunologic and metabolic function. Electrodiagnostic evaluation (Supplementary Table S1) (not including needle electromyography, that was refused by the patient) showed only a slight reduction of sural nerve conduction velocity which was however above the normal cutoff after correction for skin temperature (Oh, 2003). Ewing’s standard cardiovascular reflex tests (Supplementary Table S2) were unremarkable. The peak to peak amplitude of the sympathetic skin responses (SSR) evoked at feet by electrical

Small fiber pathology parallels disease progression in Parkinson disease: a longitudinal study

A small fiber pathology, unrelated to l-Dopa treatment [5], has been demonstrated in Parkinson’s disease (PD) [1, 2, 4]. However, a correlation with disease duration and severity has not been reported. To understand if intraepidermal nerve fiber (IENF) density may be an objective biological parameter which reflects disease progression, we assessed morpho-functional changes over time of cutaneous nerves in 28 patients affected by idiopathic PD. Patients (Supplemental Tab. 1) were enrolled in a neurorehabilitative unit, where they undergo yearly physical training courses of 30 days. Subjects with neuropathy or conditions potentially affecting peripheral nerves were excluded. All patients underwent at recruitment and after variable time periods (1 month in 6, 12 months in 8, 24–36 months in 7, 48–108 months in 7 patients), a complete clinical and sensory/autonomic functional and morphological assessment (Supplemental Tab. 2) including pain and autonomic symptoms through the SFN-SIQ and the SCOPA-AUT questionnaires, neurographic study, quantitative sensory testing, sympathetic skin response (SSR), dynamic sweat test (DST), and skin biopsies from thigh and leg bilaterally. IENF densities, assessed using indirect immunofluorescence [5] were compared with data from a population of age and sex-matched (ratio = 1:3) healthy controls (Supplemental Tab. 3). Functional sensory and autonomic findings were compared with data extracted from our age and sex-stratified normative dataset including 300 healthy volunteers. Institutional Ethics Committee approval and participant informed consent were acquired. Among patients, 92% reported autonomic complaints and 30% sensory symptoms. At baseline, patients showed normal neurographic study, increased sensory thresholds, lower SSR amplitude, impaired postganglionic sudomotor function (assessed by DST), and lower IENF densities compared to controls (Supplemental Tab. 3), revealing a sensoryautonomic small fiber involvement. Except for a lowering of cold pain thresholds at the foot and hand, mean values of functional and morphological findings did not change over time (Supplemental Tab. 4) due to the heterogeneity of the individual changes. In particular, changes in IENF density (IENFΔ) were negative (loss, Fig. 1b compared to a) in 10 and positive (gain, Fig. 1d compared to c) in 18 patients. Percent IENFΔ (

Cutaneous innervation in ross syndrome: a functional and morphological study in 8 patients

Ross syndrome is described as a very rare disorder characterized by segmental anhydrosis, hyporeflexia and tonic pupils. We observed 8 subjects (6 males and 2 females; age range 31–57 years) affected by Ross syndrome in the last 4 years. They had suffered heat intolerance for at least 7 years with severe impairment of thermoregulation before diagnosis of Ross syndrome was defined. All patients underwent neurological examination, electrophysiological study, quantitative sensory testing, Minor test, silastic imprint test, sympathetic skin response, cardiovascular reflexes and 3 mm punch biopsies from fingertip, thigh, leg and from residual hyperhydrotic areas. Skin samples were cut in 80‐micron sections and incubated with a panel of primary antibodies and then with secondary antibodies conjugated with fluorophores Cy2, Cy3, Cy5 to visualize neural and vascular structures. Different primary antibodies were used to distinguish myelinated and sensory and autonomic unmyelinated fibers. Digital images were obtained using a non‐laser confocal microscope (CARV, Atto Biosciences, Rockville MD, USA) and analyzed by dedicated image analysis software (Neurolucida, Microbrightfield, Willistone VT, USA). As we previously described in 3 patients (Perretti et al., Clin Neurophysiol, 2003), besides a lack of cholinergic sudomotor fibers we found a milder involvement of unmyelinated and myelinated sensory fibers. These morphological findings were in keeping with a moderate subclinical impairment of tactile and thermal thresholds and mechanical pain detection. Sensory nerve conduction study was normal indicating a very distal involvement of sensory nerve endings. This study confirms our previous observation that Ross syndrome is a degenerative process involving progressively, besides cholinergic autonomic fibers, sensory unmyelinated and myelinated nerve fibers.