Faculty Bibliography

Background: In synucleinopathies, deposits of alpha-synuclein occur in sympathetic neurons innervating sweat glands, leading to impaired sudomotor function. Hence, measurement of sweat production may be relevant as a diagnostic biomarker. We hypothesized that patients with synucleinopathies have decreased electrodermal activity, and that this is associated with sympathetic adrenergic impairment.
Objective(s): To evaluate electrodermal activity in subjects with synucleinopathies.
Method(s): Cross-sectional study including 106 patients with synucleinopathies (55 with idiopathic Parkinson disease-PD-, 18 with probable multiple system atrophy-MSA-, 25 with pure autonomic failure-PAF-, and 8 with idiopathic REM behavior disorder-RBD-) and 57 healthy controls enrolled in New York University (New York, NY) and Hospital de Cruces (Bilbao, Spain). Electrodermal activity was assessed with a device (Sudoscan). Standard cardiovascular autonomic testing (in all subjects) and I¹²³metaiodobenzylguanidine myocardial scintigraphy (in 30 patients with PD) were performed to quantify sympathetic adrenergic dysfunction.
Result(s): Electrodermal activity both in the palms and in the soles was lower in patients than in controls (p<0.01). When considered separately, MSA, PAF and RBD had lower electrodermal activity in the palms than in controls (p<0.001), whereas electrodermal activity in the soles was lower in MSA, PAF and PD (p<0.05). Linear regressions showed that reduced electrodermal activity was associated with markers of sympathetic adrenergic impairment (p<0.05), but not with disease duration.
Conclusion(s): Decreased electrodermal activity in palms and soles is a frequent finding in synucleinopathies. Decreased electrodermal activity was associated with decreased sympathetic adrenergic function, suggesting a parallel degeneration of both adrenergic and cholinergic sympathetic fibers

Background: Pure autonomic failure is a neurodegenerative synucleinopathy largely restricted to the peripheral nervous system. Later in the clinical course of the disease some patients may develop parkinsonism, cerebellar ataxia or cognitive impairment. The purpose of this study is to define the clinical features and biomarkers that predict which patients will retain a pure autonomic failure phenotype, and which will develop clinical deficits indicating spread of the synucleinopathy to the central nervous system.
Method(s): One hundred patients with pure autonomic failure were recruited at 5 medical centers in the US. Participants were followed at 12-months intervals, for 4 years to determine whether they had developed motor/cognitive abnormalities and met the diagnostic criteria of Parkinson disease (PD)/dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). Smell discrimination, occurrence of REM sleep behavior disorder (RBD) and sympathetic and parasympathetic cardiovascular autonomic functions were assessed.
Finding(s): Mean age of onset of autonomic failure was 61 (+/-12) years. Patients had a 10 % per year cumulative risk for developing a CNS synucleinopathy with locomotor dysfunction or dementia. All patients who developed a CNS synucleinopathy had subtle motor impairment and RBD at the time of enrolment. Factors that predicted a future diagnosis of MSA included younger age at onset of autonomic failure, severe bladder/bowel abnormalities, normal olfaction and a >10 bpm cardiac chronotrophic response to tilt. Factors that predicted future diagnosis of PD/DLB were abnormal olfaction, a lesser chronotrophic response to tilt and longer disease duration. Patients that retained a PAF phenotype had very low circulating norepinephrine levels, slow resting heart rate, no RBD or subtle motor deficits and preserved smell discrimination.
Interpretation(s): Pure autonomic failure can be a premotor stage of a central nervous system synucleinopathy or may remain as a restricted peripheral disorder. Patients who developed PD/DLB or MSA have distinct premotor features. Patients who retain a pure autonomic failure phenotype had more severe peripheral sympathetic involvement

Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic neurogenic orthostatic hypotension (nOH). The pressor response is variable with some patients responding to doses of 100 mg while others requiring up to 600 mg three times/day. It is not known which factors predict the magnitude of the pressor response to droxidopa. We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH in an outpatient setting. BP supine and after 3-min standing was measured before and 1-h after oral administration of 100 mg of droxidopa. Droxidopa was progressively increased until (i) complete relief of symptoms, (ii) supine systolic BP >180 mmHg, (iii) occurrence of side effects, or (iv) the maximum dose of 600 mg was reached. Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure, 3 with autoimmune autonomic ganglionopathy, and 2 with multiple system atrophy) were evaluated. Mean BP was 126 +/- 28/72 +/- 11 mmHg supine, and 89 +/- 19/ 53 +/- 15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine while supine was 192 +/- 216 pg/ml. Maximum droxidopa dose during the titration was 212 +/- 102 mg (range 100-400 mg). Droxidopa increased BP to an average of 148 +/- 53/ 90 +/- 13 mmHg supine and 135 +/- 38/66 +/- 16 mmHg after 3-min standing (p<0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after 3-min standing following droxidopa treatment (R2 = 0.42; p = 0.023). Four patients (3 with AAG and 1 with PAF) with very low plasma norepinephrine levels (<90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnostic categories did not predict response to droxidopa. In patients with nOH, lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa. This response is probably related to the degree of denervation supersensitivity. Supine norepinephrine levels may be useful to predict appropriate dosing of droxidopa in a clinical setting

Hereditary sensory and autonomic neuropathy type III features disturbed proprioception and a marked ataxic gait. We recently showed that joint-angle matching error at the knee is positively correlated with the degree of ataxia. Using intraneural microelectrodes, we also documented that these patients lack functional muscle spindle afferents but have preserved large-diameter cutaneous afferents, suggesting that patients with better proprioception may be relying more on proprioceptive cues provided by tactile afferents. We tested the hypothesis that enhancing cutaneous sensory feedback by stretching the skin at the knee joint using unidirectional elasticity tape could improve proprioceptive accuracy in patients with a congenital absence of functional muscle spindles. Passive joint angle matching at the knee was used to assess proprioceptive accuracy in 25 patients with HSAN III and 9 age-matched control subjects, with and without taping. Angles of the reference and indicator knees were recorded with digital inclinometers, and the absolute error, gradient and correlation coefficient between the two sides calculated. Patients with HSAN III performed poorly on the joint angle-matching test (mean matching error +/- SE 8.0 +/- 0.8 degrees , controls 3.0 +/- 0.3 degrees ). Following application of tape bilaterally to the knee in an X-shaped pattern, proprioceptive performance improved significantly in the patients (mean error 5.4 +/- 0.7 degrees ) but not in the controls (3.0 +/- 0.2 degrees ). Across patients, but not controls, significant increases in gradient and correlation coefficient were also apparent following taping. We conclude that taping improves proprioception at the knee in HSAN III, presumably via enhanced sensory feedback from the skin.

Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control.