Faculty Bibliography

The glossopharyngeal and vagus cranial nerves provide the brainstem with sensory inputs from different receptors in the heart, lung, and vasculature. This afferent information is critical for the short-term regulation of arterial blood pressure and the buffering of emotional and physical stressors. Glossopharyngeal afferents supply the medulla with continuous mechanoreceptive signals from baroreceptors at the carotid sinus. Vagal afferents ascending from the heart supply mechanoreceptive signals from baroreceptors in different reflexogenic areas including the aortic arch, atria, ventricles, and pulmonary arteries. Ultimately, afferent information from each of these distinct pressure/volume baroreceptors is all relayed to the nucleus tractus solitarius, integrated within the medulla, and used to rapidly adjust sympathetic and parasympathetic activity back to the periphery. Lesions that selectively destroy the afferent fibers of the vagus and/or glossopharyngeal nerves can interrupt the transmission of baroreceptor signaling, leading to extreme blood pressure fluctuations. Vagal efferent neurons project back to the heart to provide parasympathetic cholinergic inputs. When activated, they trigger profound bradycardia, reduce myocardial oxygen demands, and inhibit acute inflammation. Impairment of the efferent vagal fibers seems to play a role in stress-induced neurogenic heart disease (i.e., takotsubo cardiomyopathy). This focused review describes: (1) the importance of the vagus and glossopharyngeal afferent neurons in regulating arterial blood pressure and heart rate, (2) how best to assess afferent and efferent cardiac vagal function in the laboratory, and (3) two clinical phenotypes that arise when the vagal and/or glossopharyngeal nerves do not survive development or are functionally impaired.

: Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.

PURPOSE/OBJECTIVE:Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients. METHODS:Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus. RESULTS:in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls. CONCLUSIONS:Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.

Familial dysautonomia (Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) is a rare autosomal recessive disease characterized by impaired development of primary sensory and autonomic neurons resulting in a severe neurological phenotype, which includes arterial baroreflex and chemoreflex failure with high frequency of sleep-disordered breathing and sudden death during sleep. Although a rare disease, familial dysautonomia represents a unique template to study the interactions between sleep-disordered breathing and abnormal chemo- and baroreflex function. In patients with familial dysautonomia, ventilatory responses to hypercapnia are reduced, and to hypoxia are almost absent. In response to hypoxia, these patients develop paradoxical hypoventilation, hypotension, bradycardia, and potentially, death. Impaired ventilatory control due to chemoreflex failure acquires special relevance during sleep when conscious control of respiration withdraws. Overall, almost all adult (85%) and pediatric (95%) patients have some degree of sleep-disordered breathing. Obstructive apnea events are more frequent in adults, whereas central apnea events are more severe and frequent in children. The annual incidence rate of sudden death during sleep in patients with familial dysautonomia is 3.4 per 1000 person-year, compared to 0.5-1 per 1000 person-year of sudden unexpected death in epilepsy. This review summarizes recent developments in the understanding of sleep-disordered breathing in patients with familial dysautonomia, the risk factors for sudden death during sleep, and the specific interventions that could prevent it.

OBJECTIVES/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS:Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C- reactive protein, yearly frequency of hyper-adrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS:Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body Mass Index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower Inspiratory Capacity (IC) (42.7% predicted vs 62.8% predicted; p=0.04). CONCLUSIONS:Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

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 and multinational NIH-sponsored Natural History Study of the Synucleinopathies.
Method(s): Patients with a clinical diagnosis of probable or possible MSA were prospectively enrolled at 11 participating centers. Demographic data, clinical variables, and autonomic testing results were included.
Result(s): 293 patients with MSA (125 women) have been enrolled. MSA-C was predominant (154 patients, 52.6%). Mean age at symptom onset was 57.6+/-8.4 (mean+/-SD) and at enrollment was 62.0+/-7.8 years old. UMSARS-1 was 21.1+/-7.6 and UMSARS-2 was 21.2+/-9.1. MoCA score was 26.3+/-4.4 indicating normal cognition. In the supine position, blood pressure (systolic BP/diastolic BP) was 143.0+/-25.2/84.0+/-14.5 mmHg, and heart rate was 75.0+/-11.5 bpm. After 3-min head-up tilt, BP fell to 113.1+/-25.5/69.6+/-15.9 mmHg and HR increased to 82.9+/-12.7 bpm. Supine plasma norepinephrine levels were 365.4+/-408.5 pg/ml and increased only to 449.8+/-277.2 pg/ml upon head-up tilt indicating impaired baroreflex-mediated sympathetic activation. The University of Pennsylvania Smell Identification Test (UPSIT) score was 28.5+/-8.1 indicating preserved olfaction. Probable rapid eye movement (REM) sleep behavior disorder was reported by 85%.
Conclusion(s): This is the largest cross-sectional sample of patients with MSA recruited consecutively reported so far. Our results confirm that: i) symptom onset in MSA is remarkable consistent at 57 years; ii) overt cognitive impairment is not a typical feature; iii) sympathetic and cardiovagal deficits are present; iv) olfaction is preserved, and; v) probable REM behavior disorder is very frequent. The prospective follow-up of these patients will provide additional information on the natural history of the disease

Background: Disease progression of multiple system atrophy (MSA) as measured by the Unified Multiple System Atrophy Rating Scale (UMSARS) varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2, respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): 293 patients (62.0+/-7.8 years old) with MSA were enrolled. Disease duration was 4.5+/-3.6 years. 98 patients completed 1-year evaluations and 48 completed the 2-year evaluation. The 12-month progression rates were 5.5+/-5.3 for the UMSARS-I, 6.6+/-5.2 for the UMSARS-II, and 11.9+/-9.8 for the total score. The 24-month progression rates were 10.8+/-7.1 for the UMSARS-I, 12.5+/-7.9 for the UMSARS-II, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p=0.0461) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials