Faculty Bibliography

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.

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.

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)

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

BACKGROUND: Objective measures of disease progression that can be used as endpoints in clinical trials of MSA are necessary. We studied retinal thickness in patients with MSA and assessed changes over time to determine its usefulness as an imaging biomarker of disease progression. METHODS: This was a cross-sectional study including 24 patients with MSA, 20 with PD, and 35 controls, followed by a longitudinal study of 13 MSA patients. Patients were evaluated with high-definition optical coherence tomography and the Unified Multiple System Atrophy Rating Scale. Evaluations were performed at baseline and at consecutive follow-up visits for up to 26 months. RESULTS: MSA subjects had normal visual acuity and color discrimination. Compared to controls, retinal nerve fiber layer (P = 0.008 and P = 0.001) and ganglion cell complex (P = 0.013 and P = 0.001) thicknesses were reduced in MSA and PD. No significant differences between MSA and PD were found. Over time, in patients with MSA, there was a significant reduction of the retinal nerve fiber layer and ganglion cell complex thicknesses, with estimated annual average losses of 3.7 and 1.8 mum, respectively. CONCLUSIONS: Visually asymptomatic MSA patients exhibit progressive reductions in the thickness of the retinal nerve fiber layer and, to a lesser extent, in the macular ganglion cell complex, which can be quantified by high-definition optical coherence tomography. Specific patterns of retinal nerve fiber damage could be a useful imaging biomarker of disease progression in future clinical trials. (c) 2015 International Parkinson and Movement Disorder Society.

Familial dysautonomia (FD) is a rare genetic disease with extremely labile blood pressure due to baroreflex deafferentation. Patients have marked surges in sympathetic activity, frequently surrounding meals. We conducted an observational study to document the autonomic responses to eating in patients with FD, and to determine whether sympathetic activation was caused by chewing, swallowing or stomach distension. Blood pressure and RR intervals were measured continuously while chewing gum (n = 15), eating (n = 20) and distending the stomach with a percutaneous endoscopic gastrostomy (PEG) tube feeding (n = 9). Responses were compared to those of normal controls (n = 10) and of patients with autonomic failure (n = 10) who have chronically impaired sympathetic outflow. In patients with FD, eating was associated with a marked, but transient pressor response (p<0.0001) and additional signs of sympathetic activation including tachycardia, diaphoresis and flushing of the skin. Chewing gum evoked a similar increase in blood pressure that was higher in patients with FD than in controls (p = 0.0001), but was absent in patients with autonomic failure. In patients with FD distending the stomach with a PEG tube feeding failed to elicit a pressor response. The results provide indirect evidence that chewing triggers sympathetic activation. The increase in blood pressure that is exaggerated in patients with FD due to blunted afferent baroreceptor signalling. The chewing pressor response may be useful as a counter-manoeuvre to raise blood pressure and prevent symptomatic orthostatic hypotension in patients with FD

Background: Familial dysautonomia (FD) is a rare genetic disorder affecting the development of sensory and autonomic neurons. Patients with FD have impaired ventilatory responses to hypoxia and hypercapnia. The disease is associated with an increased risk of sudden death, particularly during sleep. Aim: To define sleep structure and respiratory function during sleep in FD. Methods: Cross-sectional study of 63 patients with FD that underwent fullnight polysomnography (age 17 +/- 12 years, range 2-50, 30 women). Information on sleep structure, apnea hypopnea index (AHI), oxygen saturation and periodic limb movement index (PLMI) was assessed. Data on EtCO2 was available in 9 subjects. Results: Total sleep time was 361 +/- 110 minutes. Sleep efficiency 78 +/- 14%; REM latency 114 +/- 85 min. Time spent in REM sleep was 20 +/- 11%. The mean heart rate (HR) was 82 +/- 16 bpm. Maximum HR was 128 +/- 31 bpm and the minimum was 58+/- 13 bpm. Average AHI was 11.4 +/- 12 events/h. Thirty-one patients had an AHI < 4; 11 patients had an AHI 5-15; 16 patients had an AHI 15-30; and 4 patients had an AHI > 30. Mean oxygen saturation was 96.6+/- 2.8%. Mean minimum (nadir) oxygen saturation was 58.5 +/- 43%. Average % of time spent with an oxygen saturation < 90% was 9.3 +/- 18%. Mean EtCO2 was 44.1 +/- 5.1 mmHg; maximum EtCO2 was 50.9 +/- 9.4 mmHg. PLM index was 0.14+/- 0.7 events/h. Conclusions: This is the largest series of sleep studies in FD and confirms that sleep disordered breathing (sleep apnea and sleep-related hypoventilation) is highly prevalent. Sleep structure was preserved and none of the patients exhibited periodic limb movements

Background: Sudden death during sleep is the leading causes of death in patients with familial dysautonomia (FD). Patients with FD have impaired ventilatory responses to hypoxia and hypercapnia and sleep disordered breathing, but it is unclear whether these are associated with sudden death. Aim: To identify features that are associated with sudden death during sleep in FD. Methods: We retrospectively selected patients who died suddenly during sleep and compared their sleep studies, arterial blood gases and ECG, performed within 1-year prior to death with those of FD subjects that were alive. Results: Of 108 patients that died suddenly during sleep, 32 had a sleep study, arterial blood gases and ECG performed within 1-year prior to death. Similar information was available in 23 patients with FD that were alive. There were no significant differences in the apnea hypopnea index (p= 0.10), average heart rate (p=0.30) or other ECG parameters. The average lowest oxygen saturation during sleep was not different either (p =0.17), although in 7 deceased patients oxygen saturation fell below 60% while in none of the alive group fell as low. The arterial HCO3 levels were significantly higher in the deceased group (p= 0.005) although there were no differences in average pCO2 levels (p=0.10). Conclusions: FD patients that died suddenly during sleep had a propensity toward more pronounced nocturnal oxygen desaturations and had significantly higher levels of plasma HCO3 suggesting compensatory metabolic alkalosis

Patients with familial dysautonomia (FD) have afferent baroreflex failure and often experience extremely low blood pressure when upright, but rarely complain of symptoms of hypoperfusion. This suggests that patients either fail to recognize cerebral ischemia or have a better than normal cerebrovascular auto-regulatory capacity. Our aim was to examine the relationship between blood pressure, cerebral blood flow, and orthostatic symptoms in FD patients. We measured continuous blood pressure, RR intervals, end-tidal carbon dioxide and middle cerebral artery blood flow velocity (transcranial Doppler) supine, sitting, and standing in eleven patients with FD (age 27+/-2 years, 5males) and seven age-matched controls. Subjects were asked to report the presence or absence of symptoms at one-minute intervals. In patients with FD, systolic blood pressure fell significantly from 137+/-8 mmHg to 105 +/- 9 mmHg after 3 minutes of standing (p < 0.006, range 55 to 149 mmHg). Despite the fall in blood pressure none of the patients reported symptoms of orthostatic hypotension. Changes in cerebral blood flow were minimal (mean DELTA-6+/-3%), and not statistically different to controls (DELTA-3+/- 2%, p=0.39), which maintained their blood pressure well on standing. The results show that patients with FDhave an excellent auto-regulatory capacity and maintain cerebral blood flow within the normal range despite severe hypotension. This study highlights the usefulness of cerebral blood flow recordings to understand the relationship between symptoms and blood pressure in patients with abnormal baroreflex function