Vincenzo Donadio

Skin nerve α-synuclein deposits: a biomarker for idiopathic Parkinson disease.

Objective:To investigate (1) whether phosphorylated &agr;-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD. Methods:Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have &agr;-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated &agr;-synuclein considered the pathologic form of &agr;-synuclein. Results:Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated &agr;-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation. Conclusions:The search for phosphorylated &agr;-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of &agr;-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage. Classification of evidence:This study provides Class III evidence that the presence of phosphorylated &agr;-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.Objective: To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD. Methods: Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein. Results: Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation. Conclusions: The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage. Classification of evidence: This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.

Skin sympathetic adrenergic innervation: an immunofluorescence confocal study.

The aim of this study was to characterize sympathetic adrenergic innervation of the skin in healthy subjects using dopamine β hydroxylase (DβH) as a specific marker for noradrenergic fibers.

Small nerve fiber involvement in patients referred for fibromyalgia

Introduction: Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain often accompanied by other symptoms suggestive of neuropathic pain. We evaluated patients for small fiber neuropathy (SFN) who were referred for fibromyalgia (FM). Methods: We studied 20 consecutive subjects with primary FM. Patients underwent neurological examination, nerve conduction studies, and skin biopsies from distal leg and thigh. Results: Electrodiagnostic studies were normal in all patients. SFN was diagnosed in 6 patients by reduced epidermal nerve fiber density. These patients also showed abnormalities of both adrenergic and cholinergic fibers. Conclusions: A subset of FM subjects have SFN, which may contribute to their sensory and autonomic symptoms. Skin biopsy should be considered in the diagnostic work‐up of FM. Muscle Nerve 49: 757–759, 2014

Autonomic disturbances in narcolepsy

Narcolepsy is a clinical condition characterized mainly by excessive sleepiness and cataplexy. Hypnagogic hallucinations and sleep paralysis complete the narcoleptic tetrad; disrupted night sleep, automatic behaviors and weight gain are also usual complaints. Different studies focus on autonomic changes or dysfunctions among narcoleptic patients, such as pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache and extremities dysthermia. Even if many studies lack sufficient standardization or their results have not been replicated, a non-secondary involvement of the autonomic nervous system in narcolepsy is strongly suggested, mainly by metabolic and cardiovascular findings. Furthermore, the recent discovery of a high risk for overweight and for metabolic syndrome in narcoleptic patients represents an important warning for clinicians in order to monitor and follow them up for their autonomic functions. We review here studies on autonomic functions and clinical disturbances in narcoleptic patients, trying to shed light on the possible contribute of alterations of the hypocretin system in autonomic pathophysiology.

Autonomic innervation in multiple system atrophy and pure autonomic failure

Background Pure autonomic failure (PAF) and multiple system atrophy (MSA) are both characterised by chronic dysautonomia although presenting different disability and prognosis. Skin autonomic function evaluation by indirect tests has revealed conflicting results in these disorders. Here, the authors report the first direct analysis of skin sympathetic fibres including structure and function in PAF and MSA to ascertain different underlying autonomic lesion sites which may help differentiate between the two conditions. Methods The authors studied eight patients with probable MSA (mean age 60±5 years) and nine patients fulfilling diagnostic criteria for PAF (64±8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability. Results MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with a long disease duration, morphological abnormalities and/or a slightly decreased autonomic score could be found in the leg reflecting a mild postganglionic involvement. Conclusion Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.

Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease

To characterize the expression in skin nerves of native (n‐syn) and misfolded phosphorylated (p‐syn) α‐synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n‐syn and p‐syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits.

Inhibition of human muscle sympathetic activity by sensory stimulation

Surprising sensory stimuli causing arousal are known to evoke short‐lasting activation of human sympathetic activity in skin but not in muscle nerves; anecdotal observations suggest that there may even be an inhibition of muscle sympathetic nerve activity (MSNA). To test this hypothesis we recorded multiunit MSNA in the peroneal nerve in 19 subjects aged 19–71 years, while sensory stimuli, consisting of either an electrical skin stimulus to a finger or a visual flash, were delivered repeatedly with intervals of approximately 20 s. The stimuli were given either 200 or 400 ms after the R wave of the electrocardiogram. Dummy stimuli, consisting of trigger pulses without sensory stimulation served as controls. Electrical skin resistance reductions were monitored from the palm of a hand as electrodermal signs of arousal‐induced cutaneous sympathetic activity. On a group basis both types of sensory stimuli attenuated the amplitude of one or two bursts of MSNA, while no such effects occurred after dummy stimuli. Individually, the inhibition was evoked by at least one stimulus modality or delay in 16 subjects whereas in three subjects no significant inhibition occurred. Skin resistance responses were evoked in all subjects. Some subjects responded to one, others to both stimulus modalities, and electrical stimuli were more effective than visual stimuli in causing MSNA inhibition as well as skin resistance reduction. On the other hand, electrodermal signs of arousal were equally common in subjects with and without inhibitory responses. We suggest that the MSNA inhibition evoked by sensory stimuli is an arousal effect which varies markedly between individuals.

Interindividual differences in sympathetic and effector responses to arousal in humans

Surprising sensory stimuli have been found to attenuate one or two sympathetic discharges in human muscle nerves of some, but not all subjects, an effect suggested to be due to arousal. The aims of the present study were: (1) to provide evidence for or against an arousal mechanism by searching for evidence of habituation, and (2) to investigate if the presence or absence of inhibitory response is reproducible. To this end we recorded peroneal muscle sympathetic nerve activity (MSNA), electrocardiogram (ECG), finger blood pressure and changes of skin electrical resistance in 17 awake healthy subjects, while sensory stimuli consisting of five electrical pulses were delivered to a finger. The electrical pulses were triggered on five consecutive R waves of the ECG after a delay of 200 ms. Dummy stimuli, consisting of five trigger pulses without electrical pulses were used as controls, and the interval between two successive stimuli (real or dummy) was 30 s. On a group basis, the stimuli attenuated two initial and one late MSNA bursts. On an individual basis, significant attenuation of one or two initial bursts occurred in eight subjects, whereas in nine subjects there was no significant inhibition. In nine subjects the experiments were repeated once and in three subjects they were repeated twice. The effects on MSNA were reproducible in 11 of the12 subjects. In the group of subjects without significant MSNA inhibition the stimuli induced a small, transient increase in mean blood pressure, which was not present in the group with significant MSNA inhibition. Heart rate did not change in either group. In conclusion, the inhibitory effect on MSNA of five repeated electrical pulses to a finger is largely similar to that previously shown for one pulse, i.e. there is rapid habituation of the response, compatible with an arousal‐induced effect. The inhibitory responsiveness shows marked interindividual differences, which are reproducible over several months and associated with different effects on blood pressure.

Small fiber neuropathy in female patients with fabry disease.

Recent studies suggest that heterozygous female Fabry disease (FD) patients develop peripheral neuropathy. We used skin biopsy to define somatic and autonomic peripheral nerve characteristics in 21 females with FD who were mainly asymptomatic and had normal renal function. Somatic epidermal and dermal autonomic nerve fiber reductions were found, prevalently in the leg, and no differences were found between symptomatic and asymptomatic individuals. Our findings suggest that females with FD, although asymptomatic, may have somatic and autonomic small fiber neuropathy. Muscle Nerve, 2010

Somatic and autonomic small fiber neuropathy induced by bortezomib therapy: an immunofluorescence study

Bortezomib is a new chemotherapeutic agent approved for the treatment of relapsed/refractory and newly diagnosed multiple myeloma. One of the major side effects of bortezomib is a peripheral length-dependent sensory axonal neuropathy and, less frequently, a small fiber neuropathy. Autonomic symptoms like postural dizziness, syncope, diarrhoea, ileus, impotence and urinary disturbances have been reported, nevertheless, autonomic neuropathy has never been characterized. We describe by means of immunofluorescence, the involvement of autonomic skin nerve fibers in three patients with small fiber neuropathy induced by bortezomib treatment.