Faculty Bibliography

Familial dysautonomia (FD) features a unique combination of cardiovascular disturbances not seen in patients with any other chronic disorder of the autonomic nervous system. While blood pressure falls and both heart rate and plasma noradrenaline fail to increase during standing in FD, patients demonstrate significant increases in blood pressure and plasma noradrenaline during episodes of emotional arousal. This indicates that vasoconstrictor neurones can be activated during states of emotional arousal, and that noradrenaline is released. Because constriction of arterioles in skeletal muscle vascular beds is one of the primary determinants of total peripheral resistance and hence of blood pressure, we would expect that muscle sympathetic nerve activity (MSNA) -which is vasoconstrictor in function - would be present in patients with FD. However, given the absence of functional baroreflex afferents we predicted that MSNA would not appear as cardiac-locked bursts. We tested this hypothesis using tungsten microelectrodes inserted percutaneously into muscle or cutaneous fascicles of the nerve in 12 patients with FD. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during baroreceptor unloading. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of baroreflex modulation of MSNA contributes to the poor control of blood pressure in FD, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement

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

Reduced parasympathetic modulation of heart rate is an independent predictor of mortality in heart failure. It is not known whether enhancing parasympathetic outflow to the heart impacts survival in these patients. Our aim was to evaluate whether the neck collar technique, a noninvasive method of stimulating the carotid baroreceptors, was a reliable and reproducible means to evaluate baroreflex control of heart rate in patients with heart failure. Twenty-five patients (20 males, mean age 54 +/-10-years) with symptomatic heart failure (NYHA class II-III) were studied on two separate days, one week apart. All were free of cholesterol plaques in the carotid arteries. Blood pressure and RR intervals were measured continuously in the seated position. Graded pressure (-70 to +70 mmHg) was administered to the neck during a held expiration using a custom-designed collar. Maximum change in RR intervals was determined during the onset of neck pressure. Stimulus response curves were plotted for changes in RR intervals against estimated-carotid sinus pressure. The technique was well tolerated and there were no adverse events. The maximal differential, used to estimate baroreflex gain, was tightly correlated between visits 1 and 2 (R2= 0.8063, p < 0.0001). The corresponding "set point" of the reflex was also significantly correlated between visits (R2=0.3324 p=0.049). To our knowledge, this is the first time the neck collar technique has been validated in a medically fragile population. The technique is safe and reproducible and maybe useful to help understand whether strategies that enhance parasympathetic activity change outcomes in heart failure

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: 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.

BACKGROUND: Familial dysautonomia (FD, OMIM# 223900) is an autosomal recessive disease with features of impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. METHODS AND RESULTS: In a retrospective chart review of 665 FD patients, 8 patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person-years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person-years. Mean maximum creatine kinase (CK) level was 32,714 +/- 64,749 U/l. Three patients had a hip magnetic resonance imaging showing gluteal hyperintensities. CONCLUSIONS: Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure (BP) on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise BP by acting at the neurovascular junction to increase vascular tone. This article summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials.