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Biomedical subjects

Davide Pareyson

Publications and source records attributed to Davide Pareyson.

13 recordsLinked to original sources
PubMed2007

Balance control in Sensory Neuron Disease.

OBJECTIVE: Balance control under static and dynamic conditions was assessed in patients with Sensory Neuron Disease (SND) in order to shed further light on the pathophysiology of ataxia. METHODS: Fourteen patients with diabetic polyneuropathy and 11 with SND underwent clinical and neurophysiological evaluation, stabilometric recording of body sway during quiet stance with and without vision, stereometric analysis of body segment displacement while riding a platform translating in anterior-posterior direction with and without vision (dynamic condition), and EMG recording of leg muscle responses to abrupt stance perturbation produced by rotation of a supporting platform. The findings were compared to those of age matched normal subjects. RESULTS: Clinical and neurophysiological evaluation revealed a more severe motor impairment in patients with diabetes than SND, while sensory impairment was superimposable. Some patients with SND had vestibular dysfunction of diverse severity. Body sway during stance was larger in patients with SND than diabetes with and without vision. In the stance perturbation condition, the latency of the long-loop EMG response to platform rotation was disproportionately increased with respect to the spinal response in the SND but not in diabetic patients. Under dynamic condition, patients with SND oscillated more than diabetic patients and several of them easily lost balance with eyes closed. CONCLUSIONS: Patients with SND show severe unsteadiness under both static and dynamic conditions, particularly with eyes closed. The patchy sensory loss of SND, disrupting sensation from territories other than the lower limbs and possibly including the vestibular nerve, could be responsible for this instability. Ataxia is correlated to the abnormal latency of the muscle responses to stance perturbation. Since increased response latencies cannot be attributed to a vestibular deficit, the deterioration of equilibrium control would be ascribed mainly to the degeneration of the central branch of the afferent fibres. SIGNIFICANCE: Measures of body balance under quiet stance and dynamic conditions can provide relevant diagnostic information as to the pathophysiology and severity of ataxia and viability of the central branch of the sensory fibres, and help in separating patients with peripheral neuropathy from patients with loss of sensory neurones.

Aged↗
PubMed2006

A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27].

There is no treatment for Charcot-Marie-Tooth disease 1A (CMT1A), but ascorbic acid (AA) is efficacious in the transgenic mouse model. Thus, a clinical trial of AA in CMT1A is warranted. The CMT-TRIAAL is a phase III randomized, double-blind, placebo-controlled study involving 222 CMT1A adults from eight Italian centers. Eligible for the study are symptomatic adults with genetically confirmed CMT1A. Treatment consists of 2-year oral AA (1500mg/day) or placebo. The primary trial endpoint is an improvement in CMT Neuropathy Score. Secondary efficacy endpoints are changes in distal arm and leg maximum voluntary isometric contraction; 10m timed walking; 9-hole-peg test; overall neuropathy limitations scale; pain and fatigue visual analog scales; health-related quality of life (SF-36); and electrophysiology. Clinical-electrophysiological assessments are performed at baseline and every 6 months thereafter. In consenting patients from three centers, skin biopsy is performed to evaluate PMP22 expression. The study will last 34 months, starting from March 2006.

Adolescent↗
PubMed2006

Normal expression of myelin protein zero with frame-shift mutation correlates with mild phenotype.

Mutations in the gene encoding for myelin protein zero (MPZ) cause inherited demyelinating peripheral neuropathies of different severity. The molecular and cellular mechanisms by which the MPZ mutations cause neuropathy are incompletely understood. We investigated MPZ, myelin basic protein, and peripheral myelin protein 22 (PMP22) protein expression levels in a nerve biopsy of a Charcot-Marie-Tooth type 1B patient heterozygous for the Val 102 frame-shift mutation. We demonstrate by quantitative immunohistochemical as well as by Western blot analyses that MPZ expression levels were not reduced in myelin membranes, a finding that is in accordance with the mild phenotype of this patient. Our data show that heterozygous 'loss-of-function' of MPZ may not necessarily lead to reduced protein levels. In conclusion, we demonstrate that careful analysis of protein expression levels in peripheral nerve tissues provides important information with respect to the understanding of the molecular basis of these neuropathies.

Adult↗
PubMed2006

Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies.

We describe the expression of the capsaicin receptor (TRPV1) in human peripheral nervous system (PNS) and its changes in sural nerve and skin nerve fibers of patients with painful neuropathy. Dorsal root ganglion (DRG), root, and spinal cord autopsy specimens from subjects without PNS diseases were immunoassayed with anti-TRPV1 antibodies. Bright-field and confocal microscope studies using anti-TRPV1, protein gene product 9.5 (PGP 9.5), and unique-beta-tubulin (TuJ1) antibodies were performed in skin biopsies from 15 healthy subjects and 10 painful neuropathies. The density of intraepidermal nerve fiber (IENF) labeled by each antibody was quantified. Sural nerve biopsies from three patients with painful, one patient with nonpainful diabetic neuropathy, and two patients with multifocal motor neuropathy used as controls were immunoassayed with anti-TRPV1 antibodies and investigated by immunoelectron microscopy. TRPV1 strongly labeled laminae I and II of dorsal horns, most small-size and some medium-size DRG neurons, and small-diameter axons of dorsal roots. In sural nerve, TRPV1 was expressed within the cytoplasm of most unmyelinated and some small myelinated axons, in the muscular lamina of epineural vessels, and in the endothelium of endoneurial vessels. The density of IENF labeled by TRPV1, PGP 9.5, and TuJ1 did not differ. TRPV1 colocalized with TuJ1 in all IENF and dermal nerve bundles. Painful neuropathies showed a diffuse loss of TRPV1-positive axons both in the sural nerve and in the skin. Our findings demonstrated that TRPV1 is normally expressed throughout the nociceptive pathway of PNS and that TRPV1-positive peripheral nerve fibers degenerate in painful neuropathies.

Adult↗
PubMed2005

Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis.

In order to clarify the role of angiogenic factors in polyneuropathy of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome, we measured the serum concentrations of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in 11 patients and correlated these with VEGF and EPO peripheral nerve expression and the degree of endoneurial vessel involvement. We found that POEMS syndrome was associated with high levels of serum VEGF and, conversely, low levels of serum EPO. Similarly, in POEMS nerves VEGF was highly expressed in blood vessels and some non-myelin-forming Schwann cells. In contrast, the expression of VEGF receptor 2 was down-regulated compared with that in normal nerves. Both EPO and EPO receptor were localized to the nerve vasculature and were expressed to similar extents in normal and POEMS nerves. The inverse correlation between VEGF and EPO serum levels was maintained during the clinical course; however, both levels returned to normal when there was a response to therapy. High serum VEGF, low serum EPO and high peripheral nerve VEGF were all associated with more severe endoneurial vessel involvement and nerve damage. Light microscopy showed an increased thickness of the basal lamina and a narrowing of the lumina of endoneurial vessels in POEMS samples, while proliferation of endothelial cells and opening of tight junctions were observed by electron microscopy. The present data support the role of angiogenic factors as diagnostic and prognostic markers of POEMS syndrome. They also suggest that VEGF and EPO are involved in the pathogenesis of polyneuropathy. In conclusion, establishing the role of angiogenic factors in polyneuropathy may lead to a better understanding of the effects of VEGF and EPO on microangiopathy and Schwann cell function.

Adult↗
PubMed2005

Lack of on-going adaptations in the soleus muscle activity during walking in patients affected by large-fiber neuropathy.

The aim of this study was to investigate the contribution of feedback from large-diameter sensory fibers to the adaptation of soleus muscle activity after small ankle trajectory modifications during human walking. Small-amplitude and slow-velocity ankle dorsiflexion enhancements and reductions were applied during the stance phase of the gait cycle to mimic the normal variability of the ankle trajectory during walking. Patients with demyelination of large sensory fibers (Charcot-Marie-Tooth type 1A and antibodies to myelin-associated glycoprotein neuropathy) and age-matched controls participated in this study. The patients had absent light-touch sense in the toes and feet and absent quadriceps and Achilles tendon reflexes, indicating functional loss of large sensory fibers. Moreover, their soleus stretch reflex response consisted of a single electromyographic (EMG) burst with delayed onset and longer duration (P < 0.01) than the short- and medium-latency reflex responses observed in healthy subjects. In healthy subjects, the soleus EMG gradually increased or decreased when the ankle dorsiflexion was, respectively, enhanced or reduced. In the patients, the soleus EMG increased during the dorsiflexion enhancements; however, the velocity sensitivity of this response was decreased compared with the healthy volunteers. When the dorsiflexion was reduced, the soleus EMG was unchanged. These results indicate that the enhancement of the soleus EMG is mainly sensitive to feedback from primary and secondary muscle spindle afferents and that the reduction may be mediated by feedback from the group Ib pathways. This study provides evidence for the role of sensory feedback in the continuous adaptation of the soleus activity during the stance phase of human walking.

Adaptation, Physiological↗
PubMed2005

IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy.

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with predominant involvement of large sensory fibers and deposits of IgM and complement on sural nerve myelinated fibers. We assessed the presence of IgM deposits on skin myelinated nerve fibers and the involvement of unmyelinated axons in anti-MAG neuropathy. Skin biopsies were performed in 14 patients with anti-MAG neuropathy, in 8 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and in 2 patients with IgM paraproteinemic neuropathy. Biopsies were taken at the proximal thigh in 20 patients, at the distal leg in 21 patients, at the proximal arm in 13 patients, and at the hand or fingertip in 10 patients. We found IgM deposits on dermal myelinated fibers in all anti-MAG neuropathy patients, with a greater prevalence at the distal site of the extremities. Deposits were located throughout the length of the fibers and at the paranodal loops. CIDP and IgM paraproteinemic neuropathies did not show any deposit of IgM. Anti-MAG neuropathy and CIPD patients showed a decrease in epidermal nerve fiber density reflecting an associated axonal loss. In anti-MAG neuropathy, both large- and small-diameter nerve fibers are affected, and specific deposits of IgM are found on skin myelinated nerve fibers.

Biopsy↗
PubMed2005

Sensory neuron diseases.

Sensory neuron diseases (SND) are a distinct subgroup of peripheral-nervous-system diseases, first acknowledged in 1948. Acquired SND have a subacute or chronic course and are associated with systemic immune-mediated diseases, vitamin intoxication or deficiency, neurotoxic drugs, and life-threatening diseases such as cancer. SND are commonly idiopathic but can be genetic diseases; the latter tend to involve subtypes of sensory neurons and are associated with certain clinical pictures. The loss of sensory neurons in dorsal root ganglia causes the degeneration of short and long peripheral axons and central sensory projections in the posterior columns. This pathological process leads to a pattern of sensory nerve degeneration that is not length dependent and explains distinct clinical and neurophysiological abnormalities. Here we propose a comprehensive approach to the diagnosis of acquired and hereditary SND and discuss clinical, genetic, neurophysiological, neuroradiological, and neuropathological assessments.

Ganglia, Spinal↗
PubMed2004

Tubule and neurofilament immunoreactivity in human hairy skin: markers for intraepidermal nerve fibers.

The cytoplasmic protein gene product 9.5 (PGP 9.5) is considered a reliable marker for intraepidermal nerve fibers (IENFs). However, PGP 9.5 expression has never been compared with antibodies against the main components of the cytoskeleton. We compared the density of PGP 9.5-positive IENF at the leg with that obtained using a panel of antibodies specific for certain cytoskeletal components, namely, anti-unique beta-tubulin (TuJ1), anti-nonphosphorylated microtubule-associated protein-1B (MAP1B), anti-70 and 200 KDa neurofilament (NF), and antiphosphorylated neurofilament (SMI 312), in 15 healthy subjects and in 10 patients with painful neuropathy. We also performed colocalization studies and investigated the relationship between IENFs and Schwann cells. In both controls and neuropathies, the density of IENF labeled by PGP 9.5, TuJ1, and MAP1B did not differ, whereas that of NF and SMI 312 was significantly lower. Double-staining studies confirmed that antibodies against cytoskeletal markers can be used to reliably stain skin nerve fibers, suggesting that they might provide insight into specific axonal impairment in peripheral neuropathies.

Biomarkers↗
PubMed2003

Diagnosis of hereditary neuropathies in adult patients.

This paper reviews the clinical diagnostic approach to hereditary neuropathies in adults by analysing: elements that point to a neuropathy of inherited origin, different modalities of presentation, laboratory and instrumental diagnostic tests, including molecular tests, symptoms and signs of involvement of other organs. Different phenotypes may be identified according to: disease course; involvement of motor, sensory, autonomic fibres; site of lesion (neuropathy versus neuronopathy); calibre of involved fibres (small-fibre versus large-fibre neuropathy); presence of distinctive symptoms (neuropathic pain); involvement of other organs or apparatus. Charcot-Marie-Tooth disease, Familial Amyloid Polyneuropathy, Hereditary Sensory and Autonomic Neuropathy, Fabry disease, Tangier disease, Porphyric Neuropathies, Refsum disease, Hereditary Neuropathy with liability to Pressure Palsies, Hereditary Neuralgic Amyotrophy, and other rare disorders involving the peripheral nervous system are reviewed.

Acute Disease↗
PubMed2003

Neurophysiological diagnosis of acquired sensory ganglionopathies.

We examined 29 patients with chronic progressive ganglionopathy of different etiology. Neurophysiological abnormalities were dominated by a widespread decrease in sensory nerve action potential amplitudes, which involved both upper and lower limb nerves, even in patients with asymmetrical or patchy clinical presentation. This impairment of sensory nerve conduction, reflecting a nonlenght-dependent pattern of peripheral axon degeneration, should be considered the hallmark of ganglionopathies. The evidence of central sensory pathway impairment, which allows to localize the pathology to the dorsal root ganglion neurons, could be better confirmed by cervical magnetic resonance imaging, which showed a diffuse hyperintensity in the posterior columns in all patients, than by somatosensory evoked potentials, which were undetectable in most of the patients. Few patients showed an impairment of individual motor nerves, which appeared more severe in paraneoplastic associated ganglionopathies. Neurophysiological abnormalities did not appear significantly changed at the 4-year follow-up. We emphasize that distinct abnormalities allow to differentiate ganglionopathies from axonal sensory neuropathies on routine neurophysiological examination.

Action Potentials↗