Faculty Bibliography

Background: Patients with familial dysautonomia have a selective defect in the afferent neurons of the baroreflex. Failure to sense blood pressure result in the unregulated release of plasma catecholamines and volatile blood pressure. One of the most disabling features of familial dysautonomia are the recurrent attacks of nausea, retching and vomiting triggered by emotional or physiological stressors and associated with hypertension, tachycardia and psychomotor agitation. A pronounced surge in circulating norepinephrine during these crises readily explains the hypertension, but the cause of the nausea and vomiting remains unknown. Methods: Seven patients with familial dysautonomia (mean age 17 +/- 3 years, 4 females) confirmed by genetic testing were studied. We monitored blood pressure and heart rate and measured plasma catecholamines when they were feeling well and during typical vomiting crises triggered by emotionally charged situations. Results: When the patients were feeling well, average supine blood pressure was 124 +/- 7/64 +/- 5 mmHg with a heart rate of 81 +/- 3 beats/min. All patients experienced typical crises when they complained of severe nausea and were retching loudly. Vomiting was prevented by the fundoplication surgery. During crises, all patients were hypertensive (180 +/- 9/116 +/- 4 mmHg) and tachycardic (124 +/- 4 beats/min) but denied feeling palpitations. While supine, plasma norepinephrine levels increased from 130 +/- 42 to 772 +/- 151 pg/ml (p<0.002), plasma epinephrine levels increased from 20 +/- 5 to 63 pg/ml, and plasma dopamine levels increased markedly from 22 +/- 2 to 96 +/- 20 pg/ml. Conclusions: Our finding of high levels of circulating dopamine during crises in patients with familial dysautonomia suggest that the severe nausea and vomiting is due to activation of dopamine receptors in the chemoreceptor trigger zone

Familial dysautonomia is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced or absent pain and temperature sensibilities, postural hypotension, absent baroreflex function and labile blood pressure that increases markedly during emotional excitement (Norcliffe-Kaufmann et al. 2010). Given the absent baroreflex function we tested the hypothesis that cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 10 patients with FD. Spontaneous bursts of MSNA were absent, but we found evidence of tonically firing sympathetic neurones that increased during emotional arousal. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia

The glutamate neurotransmitter system has the potential to transform our knowledge of the pathophysiology of schizophrenia and help us identify potential treatment targets. In this section of the supplement, the dopamine system is first reviewed as it relates to schizophrenia and its treatment with the currently available antipsychotics, followed by a discussion of glutamate receptors and how they, too, can impact on positive, negative, and cognitive symptoms. Symptoms of schizophrenia can be theoretically explained by a hyper-dopaminergic state existing in the mesolimbic pathway and a hypodopaminergic state in the mesocortical pathways; the former results in positive symptoms and the latter leads to negative, cognitive, and affective symptoms. Current FDA-approved pharmacologic options for the treatment of schizophrenia involve dopamine blockade at the dopamine D2 receptor. Although commercially available antipsychotic agents have at least some degree of antagonism at the dopamine D2 receptor, there are some investigational agents that produce an antipsychotic effect in the absence of direct dopamine D2 receptor antagonism. The glutamate-dopamine model of schizophrenia offers new therapeutic targets, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists.

BACKGROUND: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause. METHODS: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons. RESULTS: During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF. CONCLUSION: The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients

We report the case of a woman with Munchausen syndrome who surreptitiously injected epinephrine causing recurrent ventricular tachyarrhythmias accompanied by dramatically high plasma levels of epinephrine and normal norepinephrine levels

Renal failure is a common problem in patients with familial dysautonomia (FD). By age 25, 20% of patients with FD have end stage renal disease. To determine the role of arterial hypertension in the development and progression of kidney disease, we compared glomerular filtration rate (Cockcroft-Gault equation) over time in 50 patients with FD according to their level of arterial hypertension throughout childhood (until age 15). In addition, to assess the possible impact of increased blood pressure variability on renal function we examined the relationship between the standard deviation of ambulatory blood pressure over 24-h, an indicator of blood pressure volatility, and glomerular filtration rate. Patients with average systolic blood pressure[180 mmHg during childhood (stage III and IV hypertension American Heart Association) had a faster decline in glomerular filtration rate over time than patients with lower blood pressures (Kaplan-Meyer survival curve). There was an inverse relationship between the standard deviation of ambulatory blood pressure over 24-h and glomerular filtration rate, i.e., patients with higher standard deviation had lower glomerular filtration rates (y = - 3.3044x + 167.54, R² = 0.1949, p<0.01). Our results indicate that arterial hypertension during childhood and the magnitude of blood pressure volatility are risk factors for the development of renal failure in patients with familial dysautonomia. Prospective studies are warranted to determine whether controlling hypertension and blood pressure variability can delay the onset or slow the progression of renal failure in these patients

OBJECTIVE: To determine whether the heart rate changes during tilt table testing could be used in the differential diagnosis between vasovagal syncope and chronic autonomic failure. METHODS: We compared the relationship between electrocardiographic R-R intervals and beat-to-beat blood pressure in 43 patients with typical vasovagal responses and 30 patients with chronic autonomic failure (6 pure autonomic failure, 23 multiple system atrophy, and 1 Parkinson's disease). RESULTS: In every patient with vasovagal syncope, at the time when the blood pressure was falling, it was possible to identify at least 12 successive heart beats (mean 33 +/- 2 heart beat, range 12-57) when blood pressure and heart rate fell in parallel, i.e., there was a negative relationship between blood pressure and R-R intervals (P < 0.001). In contrast, the relationship between blood pressure and R-R intervals in patients with chronic autonomic failure was never negative, i.e., heart rate always increased, albeit less than expected for the given fall in blood pressure, or remained unchanged. INTERPRETATION: The heart rate changes during the fall in blood pressure can distinguish patients with vasovagal responses from those with chronic autonomic failure

OBJECTIVE: The susceptibility to suffer neurally mediated syncope and loss of consciousness varies markedly. In addition to vasodilatation and bradycardia, hyperventilation precedes loss of consciousness. The resultant hypocapnia causes cerebral vasoconstriction and peripheral vasodilatation. We postulate that more pronounced cerebral and peripheral vascular responses to reductions in arterial CO(2) levels underlie greater susceptibility to neurally mediated syncope. METHODS: We compared vascular responses to CO(2) among 31 patients with histories of recurrent neurally mediated syncope and low orthostatic tolerance and 14 age- and sex-matched control subjects with no history of syncope and normal orthostatic tolerance. Vascular responses to CO(2) were calculated after all subjects had fully recovered and their blood pressures and heart rates were stable. We measured blood flow velocity in the middle cerebral artery (transcranial Doppler) and in the left brachial artery (brachial Doppler), and end-tidal CO(2) during voluntary hyperventilation and hypoventilation (end-tidal CO(2) from 21-45mm Hg), and determined the slopes of the relations. RESULTS: Hypocapnia produced a significantly greater reduction in cerebral blood flow velocity and in forearm vascular resistance in patients with neurally mediated syncope than in control subjects. Opposite changes occurred in response to hypercapnia. In all subjects, the changes in cerebral blood flow velocity and forearm vasodilatation were inversely related with orthostatic tolerance. INTERPRETATION: Susceptibility to neurally mediated syncope can be explained, at least in part, by enhanced cerebral vasoconstriction and peripheral vasodilatation in response to hypocapnia. This may have therapeutic implications. Ann Neurol 2007

We investigated carotid baroreflex control of vascular resistance in two groups of high-altitude natives: healthy subjects (HA) and a group with chronic mountain sickness (CMS), a maladaptation condition characterized by high haematocrit values and symptoms attributable to chronic hypoxia. Eleven HA controls and 11 CMS patients underwent baroreflex testing, using the neck collar method in which the pressure distending the carotid baroreceptors was changed by applying pressures of -40 to +60 mmHg to the chamber. Responses of forearm vascular resistance were assessed from changes in the quotient of blood pressure divided by brachial artery blood velocity. Stimulus-response curves were defined at high altitude (4338 m) and within 1 day of descent to sea level. We applied a sigmoid function or third-order polynomial to the curves and determined the maximal slope (equivalent to peak gain) and the corresponding carotid pressure (equivalent to 'set point'). The results showed that the peak gains of the reflex were similar in both groups and at both locations. The 'set point' of the reflex, however, was significantly higher in the CMS patients compared to HA controls, indicating that the reflex operates over higher pressures in the patients (94.4 +/- 3.0 versus 79.6 +/- 4.1 mmHg; P < 0.01). This, however, was seen only when subjects were studied at altitude; after descent to sea level the curve reset to a lower pressure with no significant difference between HA and CMS subjects. These results indicate that carotid baroreceptor control of vascular resistance may be abnormal in CMS patients but that descent to sea level rapidly normalizes it. We speculate that this may be explained by CMS patients having greater vasoconstrictor activity at altitude owing to greater hypoxic stimulation of chemoreceptors.