Faculty Bibliography

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

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

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

Introduction: Depressive symptoms are common in patients with multiple systematrophy (MSA). We aimed to determine the prevalence of depression in MSA and its impact on quality of life and disease progression. Methods: MSA patients enrolled in a natural history study to determine the natural progression of disease. Patients completed psychiatric (Zung Depression scale, Spielberg's anxiety scale and Body vigilance scale) and autonomic (OHQ, COMPASS, UMSARS-I and II, SCOPA-Autonomic and SF36 Quality of life scale) rating scales, and underwent autonomic and cardiovascular assessments at baseline, and then followed at regular intervals for repeat assessments. Results: Forty-five MSA patients (mean age 61.8 years, 4.3 years disease duration) were included. Thirty patients (67%) scored as having depression on the Zung depression scale (15 mild, 13 moderate, and 2 severe). Seventy-three percent had orthostatic hypotension (OH). Depressed patients had higher trait/state anxiety and body vigilance scores than non-depressed patients. Depressed patients had significantly higher OHQ scores on each of the 6 OHSA items and each of the OHDAS items (OH interference with activities of standing and walking). Trait-anxiety and depression correlated with OHSA and OHDAS items. Depressed patients reported greater OHQscores for the same amount of blood pressure change than non-depressed. Linear regression showed significant effect of depression on progression of UMSARS-II scores. Depression correlated with orthostatic and urinary function symptoms on the COMPASS scale. Conclusions: Depression is common in MSA. It impacts the progression and severity of autonomic symptoms. Recognizing and treating depression may improve quality of life and ameliorate symptoms

Background: Clinical distinction between Lewy body disorders (Parkinson disease [PD] and dementia with Lewy bodies [DLB]) and multiple system atrophy (MSA) is sometimes challenging. Aim: We investigated whether activation of afferent and central baroreceptor pathways could differentiate between Lewy body disorders and MSA. Methods: We determined the effect of supine and upright tilt on circulating levels of vasopressin and catecholamines in patients with PD/DLB and MSA. Results: Thirty-five patients with probable MSA (22 MSA-C, 13 MSA-P) and 24 patients with Lewy body disorders (20 with PD, 4 with DLB) were included. All patients had documented neurogenic orthostatic hypotension. In patients with PD and DLB upright tilt induced marked hypotension and a significant increase in plasma vasopressin (from 0.82 +/- 0.77 to 4.85 +/- 13.9 pmol/l in PD (p = 0.0027); from 1.18 +/- 0.81 to 5.1 +/- 3.76 pmol/l in DLB (p = 0.11). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin did not increase significantly (from 0.51+/- 0.08 to 0.70 +/- 0.71 pmol/l, p=0.092). Plasma norepinephrine did not increase significantly on head-tilt in any of the subjects. A plasma vasopressin concentration during upright tilt of <0.6 pmol/l in a patient with neurogenic orthostatic hypotension had a sensitivity of 89% and a specificity of 71% to differentiate between MSA and Lewy bodies disorders. Conclusions: Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are preserved in patients with Lewy body disorders but are impaired in patients with MSA. Thus, measurement of baroreceptor mediated vasopressin release is helpfulmarker to differentiate between these diagnoses

Background: Multiple system atrophy (MSA) is a fatal and poorly understood rare neurodegenerative disorder. Here we describe the baseline characteristics of patients with MSA enrolled in a prospective multicenter natural history study of the NIH-sponsored U.S. Autonomic Disorders Consortium. Methods: Patients with a clinical diagnosis of MSA were prospectively enrolled at 5 participating centers. Demographic data, clinical variables, and autonomic testing results were included. Results: One hundred and nine patients with MSA (45 women) have been enrolled. MSA-C was predominant (60 patients, 55%). Mean age at symptom onset was 56.5 +/- 8.8 and at enrollment was 61.2+/-8.04 years old. Mini Mental score was 28.9 +/-1.4 indicating normal cognition. Both the E:I ratio (1.09+/-0.08) and the Valsalva ratio (1.24+/-0.28) were low, indicating cardiovagal impairment. In the supine position, blood pressure (SBP/

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