Faculty Bibliography

Background: Patients with familial dysautonomia (FD) have asthmalike exacerbations with coughing, wheezing, and hypoxia. While many are treated empirically with bronchodilators, it is still unknown whether airway obstruction in these patients is pharmacologically reversible by modifying autonomic tone.
Method(s): We conducted a two-center, randomized, placebo-controlled, double blind, crossover study to assess the safety and efficacy of albuterol (a direct acting sympathomimetic) vs. ipratropium bromide (a parasympatholytic muscarinic blocker). Albuterol (0.083 %, 2.5 mg/3 ml), ipratroprium bromide (0.02 %, 500 mcg/2.5 ml) and placebo (0.9 % sodium chloride 3 ml) were administered by nebulization in random order over 15 min in the seated position. Airway responses were assessed with spirometry and impulse oscillometry pre- and 30 min post-dose. Continuous blood pressure, RR-intervals and cardiac impedance were measured non-invasively (TaskForce Monitor, CNSystems, Graz, Austria). Raw data tracings were analyzed blindly.
Result(s): Fifteen patients were enrolled. All had a documented history of aspiration into the airway and acute episodes of coughing and wheezing. Beta-adrenergic activation with albuterol significantly increased forced vital capacity (p = 0.041) and forced expiratory volume within 1 s (p = 0.002). In line with this, impulse oscillometry at 5 Hz was significantly lower post-albuterol (p = 0.006), suggesting a reduction in total airway resistance. Blockade of muscarinic acetylcholine receptors with ipratroprium had less bronchodilatory effects. Both treatments were well tolerated and had no effects on blood pressure, heart rate or derived cardiac output.
Conclusion(s): In patients with FD, beta-adrenergic stimulation more effectively reversed airway obstruction than muscarinic blockade. Both treatments were well tolerated and had no measureable systemic effects

The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 +/- 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP >/=10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.

Objective: To evaluate the cutaneous silent period (CSP) in patients with hereditary sensory and autonomic neuropathies (HSAN) type III (HSAN-III) with decreased pain perception and type IV (HSAN-IV) with complete insensitivity to pain. Background: Decreased pain perception is a cardinal feature of HSAN. The CSP, the electrophysiological equivalent of a withdrawal reflex from a painful stimulus, may help to evaluate A-delta fibers in patients with different types of HSAN. Methods: Twenty patients with HSAN-III, 3 patients with HSAN-IV and 24 age-matched healthy control subjects were evaluated. The CSP was recorded from voluntarily contracted thenar muscles while electrical pulses were given to the second finger at 75 and 90 mA intensities. The percentage of appearance, latency, and duration of CSP responses were quantified. Kruskal-Wallis test was used for between group comparisons. Results: Patients with HSAN-III and control subjects showed 100[percnt] of appearance of CSP for both intensities of stimulation. However, when compared to controls, patients with HSAN-III showed significantly longer latencies (75 mA: 79+/-11 versus 69+/-12, p=0.02; 90 mA: 74+/-8 versus 67+/-11, p=0.0001) and increased durations (75 mA: 54+/-21 versus 32+/-13, p=0.0001; 90 mA: 54+/-12 versus 43+/-17, p=0.04) for the two intensities of stimulation. Patients with HSAN-IV showed no CSP responses at both intensities of stimulation. Conclusions: Relatively preserved, albeit delayed and prolonged, CSP responses in HSAN-III are congruent with the clinical observation that these patients are able to perceive some forms of pain (e.g., sharp pain). We speculate that even a reduced population of A-delta fibers is sufficient to produce CSP in HSAN-III. In contrast, the absence of CSP in HSAN-IV, congruent with complete insensitivity to pain, suggests that these patients have no functional A-delta nociceptive fibers. CSP can be used as an efficient physiologic aid to discriminate between complete insensitivity to pain and dulled pain perception

Objective: To compare ESC in patients with autonomic synucleinopathies and healthy controls and to evaluate its relationship to sympathetic adrenergic function. Background: Disorders of the autonomic nervous system may affect sweat production and result in abnormally low electrochemical skin conductance (ESC). ESC can be evaluated by applying a low direct voltage to the skin of the palms and soles, which generate a current based on sweat chloride concentrations. Methods: We assessed ninety-nine subjects: 59 patients with synucleinopathies (15 patients with multiple system atrophy [MSA], 20 patients with pure autonomic failure [PAF], 17 patients with Parkinson's disease [PD] and 7 patients with REM sleep behavior disorder [RBD]) and 40 healthy controls. ESC was measured in micro-Siemens (muS) and categorized into normal (>60 muS); moderately decreased (60-40 muS); and severely decreased (<40 muS). Percent of asymmetry between the right and left ESC was also calculated. All subjects underwent medical assessments, neurological examination, and standardized autonomic testing with plasma measurements of norepinephrine in the supine and tilted positions. Results: ESC in both the palms and soles was significantly lower in MSA, PAF and RBD patients compared to controls (p=0.04). Asymmetry between right and left ESC measurements of palms and soles were significantly higher in MSA, PAF and PD than in controls. ESC in palms was positively correlated with the increase in norepinephrine from supine to head-up tilt (r= 0.363; p=0.005). ESC below 73.5 muS in the soles identified accurately 85[percnt] of patients with synucleinopathies. Asymmetry in ESC in the soles above 1.5 [percnt] identified 92[percnt] of patients with syncleinopathies, while asymmetry above 2.5[percnt] in the palms identified 87[percnt] of patients with syncleinopathies. Conclusions: ESC measured in palms and soles was both decreased and asymmetric in patients with synucleinopathies compared to controls. Decreased ESC is associated with impaired sympathetic adrenergic function

Objectives: Although dementia is still considered as non-supporting diagnostic feature by current consensus diagnostic criteria, several studies reported that MSA patients experience cognitive deficits (1-3). Our aim is to identify the anatomical pattern of cognitive impairment (CI) inMSA patients. Methods: A multi-center-cohort of seventy-two MSA patients was collected from 5 international centers. CI was assessed by the MMSE score (< 26) [4]. We identified twenty-two MSA with CI (MSAeCI) [mean age 66.4(6.5), education 8.4(4.1)], and fifty MSA without CI (MSAeCNT) [mean age 62.6(6.6), education 12.4(4.5)]. VBM was run using FSLeVBM tool. GLM analysis comparison between MSAeCI and MSAeCNT subgroups was run controlling for intracranial volume, age, education, UPDRS-III and centers. Results: VBM analysis revealed significant wide gray-matter densities decrease in the MSAeCI group mainly in frontal, temporal, occipital, parietal areas and left cerebellum (Table 1). Moreover, an increase cortex density area was found on the left middle temporal area (Figure 1), which might be due to a compensative cognitive mechanism in a group of patients characterized by a not severe cognitive status [mean MMSE 22.8(2.7)]. All these areas survived after Alphasym correction (p<0.01; cluster threshold >22). Conclusions: Our study suggests that CI is associated with wide cortical and sub-cortical changes in MSA group. These findings support similar VBM evidence of graymatter loss in MSA cognitively impaired patients (1). (Table Presented)

Takotsubo cardiomyopathy (TC) often occurs after emotional or physical stress. Norepinephrine levels are unusually high in the acute phase, suggesting a hyperadrenergic mechanism. Comparatively little is known about parasympathetic function in patients with TC. We sought to characterize autonomic function at rest and in response to physical and emotional stimuli in 10 women with a confirmed history of TC and 10 age-matched healthy women. Sympathetic and parasympathetic activity was assessed at rest and during baroreflex stimulation (Valsalva maneuver and tilt testing), cognitive stimulation (Stroop test), and emotional stimulation (event recall, patients). Ambulatory blood pressure monitoring and measurement of brachial artery flow-mediated vasodilation were also performed. TC women (tested an average of 37 months after the event) had excessive pressor responses to cognitive stress (Stroop test: p <0.001 vs baseline and p = 0.03 vs controls) and emotional arousal (recall of TC event: p = 0.03 vs baseline). Pressor responses to hemodynamic stimuli were also amplified (Valsalva overshoot: p <0.05) and prolonged (duration: p <0.01) in the TC women compared with controls. Plasma catecholamine levels did not differ between TC women and controls. Indexes of parasympathetic (vagal) modulation of heart rate induced by respiration and cardiovagal baroreflex gain were significantly decreased in the TC women versus controls. In conclusion, even long after the initial episode, women with previous episode of TC have excessive sympathetic responsiveness and reduced parasympathetic modulation of heart rate. Impaired baroreflex control may therefore play a role in TC.